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Editorial CHICAGO MEDICAL SOCIETY. Jan. 18th. The regular meeting of the Society was almost wholly occupied with the subject of City Health Regulations. Dr. N. S. Davis, from the Special Committee on that subject, made the following report, which, after free discussion, was adopted. The Committee was instructed to present the same to the Common Council, with the draft of an amendment to the present laws, as indicated in the report. REPORT OF THE COMMITTEE ON THE HEALTH DEPARTMENT OF OUR CITY GOVERNMENT. Presented to the Chicago Medical Society, January 18th, 1867. The subject assigned to your Committee for consideration, is certainly one of the most important that can engage the of the people of this, or any other large city. The and enforcement of proper sanitary regulations is so closely connected with the preservation of health and the prolongation of life and happiness, that no community can ne,gleet them without, sooner or later, suffering the severest penalties. In fulfilling the duties assigned to your Committee, three questions require careful consideration. 1st. What are principles upon which a Municipal Health should be organized, in order to ensure the highest degree of enlightinent and efficient action? 2d. Is the present organization of the Health Department of our city defective; and if so, in what particulars? 3d. What changes are necessary to remedy its defects, and complete its efficiency? In answer to the first question, we would state, that the basis of a proper Health Organization, should consist of a Board of Commissioners, embodying in its members a high degree of ability or business capacity, and a thorough knowledge of sanitary science, as applied to the preservation of the health of communities and the prevention of the spread of contagious diseases. No board can embody these qualities, without composed in part, at least, of thoroughly-educated ; simply because, In our country, no other class of men are educated to an adequate extent, in reference to those subjects on which a Board of Health must continually act. The truth of this proposition is too plain to need either or illustration. A Board of Health Commissioners, composed of properly educated and qualified members, should be invested with power to devise and carry into prompt effect, all such measures as the safety and welfare of the community requires. The term of office of its members should be long enough to a reasonable degree of permanency in whatever sanitary measures or policy may be adopted. In no department of municipal affairs, is a vaccillating, temporizing policy more than in that relating to the preservation of the public health. A show of energy, or a display of zeal, or a prodigal expenditure of money just while some fearful epidemic disease is threatening to commence its work of death, and a negligent indifference at all other times, is but little better than no action at all. Sanitary measures, to be successful in lessening the sickness and mortality of communities, and in protecting them from the ravages of epidemics, must be founded on an accurate knowledge of all those local causes that tend to deteriorate the public health, and then they must be rigidly and perseveringly enforced from year to year. To enable a Board of Health Commissioners to devise such measures, and establish an enlightened and permanent sanitary policy, its members should not only possess the requisite and business capacity, with a term of office long enough to add experience to their previous knowledge, but they should be appointed in such a manner as to free them as far as possible from all partisanship, or feelings of dependence on the success or failure of mere political parties. And yet they should be fully accountable to the municipal government for all their official acts. Such are the principles on which a Board of Health Commissioners should be organized. The next question is, how far the present health department of our city government is organized in accordance with these principles, and in what particulars is it defective? Our present Health Department consists of a Board of three Commissioners, who are also at the same time Commissioners of the Police and Fire Departments; a Health-Officer; and a City Physician. The three members of the Board are elected by the people, one from each division of the city, and hold their offices for six years. The Health-Officer is appointed by the Board. The City Physician is elected by the Common Council, and holds office for two years. The present city charter confers on the Common Council power "to do all acts and make all regulations which may be necessary or expedient, for the preservation of health, and the suppression of disease." And, in accordance with this power, we find in the present laws and ordinances of the city full and ample powers conferred and duties enjoined upon the Board of of Health and Health-Officer, for the efficient and thorough regulation of everything relating to the public health and safety. After a full examination of the present laws and , we can see no need of further legislation, so far as relates to the conferring of power upon the Board of Health or its agents. Wherein, then, is the present organization defective? Chiefly in three important particulars. The first and most radical is, the absence of all provision for securing the selection of members of the Board of Health so thoroughly educated in matters as to fit them for an enlightened and efficient of their duties. To make up a Board of Health, charged with the duty of making and enforcing all such regulations as are necessary to mitigate or prevent the prevalence of diseases in a great city, of men who, neither by education, occupation, nor business habits, have acquired any special knowledge of the nature and causes of disease, or of the laws by which they are developed and diffused, is just as absurd as it would be to elect a practising physician to the office of City Attorney. If there is lack of efficiency in the practical working of our health organization, it is not because the members of the present Board of Police, acting as a Board of Health, are in integrity or business capacity, or from deficient legal authority to-act, but simply because they have not that special sanitary or medical education which enables them to clearly the nature, extent, and importance of the work entrusted to them. The second defect consists in an imperfect and injudicious distribution of duties between the Health-Officer, City , and Clerk of the Board of Health. The Health-Officer shall be simply an intelligent and efficient executive officer, to superintend the prompt enforcement of all the laws and orders of the Board of Health. The City Physician should keep at* all times a free vaccine dispensary for the poor, and have the immediate charge or superintendence of such sick persons as came under the care and authority of the Health and Police Departments of the City Government. And there should be a competent Clerk, who should perform the duties of Secretary to the Board of Health and the Health-Officer, and also the duties of Register of Vital Statistics. The third defect in the present organization is the absence of efficient regulations for the accurate registry of births, and deaths, with the causes of the latter. The of this needs no comment here. After a somewhat careful and candid examination of the whole subject, we feel certain that whatever inefficiency or defectiveness there is in the practical working of the present health organization of our city, can be traced directly or indirectly to the three sources just enumerated. This leads us to the third and last question' involved in this report, namely: What changes are necessary to remedy the defects to which we have alluded? We answer, so far as State legislation is concerned, we need but a single brief amendment to the laws now in force. If the present law relating to the action of the Board of Police, in the capacity of a Board of Health, was so amended as to provide for the of three thoroughly competent Physicians, (one from each Division of the City,) to act with said Police in all matters pertaining to health or sanitary regulations, to possess coequal powers and duties, and to constitute a part of said Board whenever acting in the capacity of a Board of Health, it would be all the legislation really required. This done, the other defects pointed out could be easily remedied under the authority already possessed by the Common Council and Board of Health. While the proposed amendment should leave the present mode of electing the three Police undisturbed, it should provide some other and less method of appointing the three medical members of the Board acting as a Board of Health. Those members of our profession who have acquired that education, experience, and 'reputation, which would enable them to impart that kind of and efficiency to a Board of Health, imperatively needed in all large cities, will never be found seeking from political parties, nor lobbying for appointments by a Governor and Senate, or a Mayor and Council. They must be sought ought and invited to accept the position, or their will not be obtained. We would suggest whether this would not be done more judiciously and with less reference to anything of a political or partisan character, by the Judges of the Superior Court of this city, than by any other authority. It will be seen that the defects we have pointed out and the remedies proposed are few and simple; yet they are really of vital importance to the practical working and beneficial of the Health Department of our city. Should the views thus far expressed in this report meet the approbation of this Society, an amendment could be in due form, relating to the appointment of three medical men as members of the Board of Health, and an ordinance in relation to the proper registry of vital statistics, and we have no doubt but both would meet the prompt sanction of the Mayor and Council. Before this report, it may be expected that some notice will be taken of the several amendments and health bills which have already been prepared and placed before the Legislature, the Council, and the public. There are three separate projects of this kind. The first consists in amendments to the present laws prepared and recommended by the Common Council. The only item in these, that relates to the important defects we have explained, is the section proposing to give the Common Council power, in cases of imminent danger from the of epidemic diseases, to appoint an additional number of members of the Board of Health, to act as such simply while such danger lasts. But it is not provided that even these appointees shall be medical men. And hence it does not in any degree remedy the radical defect in the constitution of of the present Board. The second project is in the form of a bill recently introduced into the State Senate by Senator Ward. By the provisions of this bill, everything pertaining to the Health Department, and sanitary regulations, is removed from the control of the people of the city and its municipal , and placed in the hands of a Board of Commissioners, consisting of the President of the Board of Police, and two Commissioners appointed by the Governor and Senate, one of whom must be a physician. The two persons thus appointed by the Governor and Senate are to hold office four years, and, with the President of the Board of Police, constitute a Board of Health, with full power to make all needful rules, , and appointments of agents, etc., sufficient to devise and execute a complete and independent sanitary system. There are two leading and fatal objections to this bill. The first is, that it deprives the people of this city of all power to regulate and control some of their most important local interests, and assumes that a Governor and Senate, at Springfield, are -better qualified to judge of the capacities and qualifications for office, of citizens of Chicago, than are the local authorities of the city, or the people themselves. The second, and more objection is, that it creates a large number of new and officers and employes, requiring a regular annual tax upon the city, of from $75,000 to $150,000, without regard to any extraordinary expenditures on account of the prevalence of severe epidemics. And yet it does not provide for the accomplishment of a single valuable object, that would not be as well and certainly accomplished, by simply adding hree thoroughly competent physicians to our present Board of Health. Serious objections could also be made to several items in the details of this bill. For instance, the section relating to the registration of births, marriages, and deaths, is utterly worthless. The third project is that presented by the Citizens' , and entitled the "Metropolitan Health Bill." This is amenable to precisely the same objections as we have made to the bill introduced by Senator Ward; while, practically, it would be far less efficient. Like Ward's bill, it takes from the people and local authorities the selection of a Board of Health, and confers it on the Governor and Senate, at Springfield. Like Ward's bill, it creates a long list of new and additional city officers and employees, requiring a correspondingly large additional expenditure of money annually. But, unlike Ward's bill, it does not fix the salary of the members of the Board of Health, or provide for the appointment of a full corps of Police. It allows the Common Council to fix their , thereby making the officers perform the difficult task of serving two masters; the Governor for their appointment, and the Council for their pay. Again, by depending in part upon the ordinary police for executing the orders of the Health Board, it places the police in the equally embarassing position of to the orders of two separate and independent Boards a plan that never has and never will work satisfactorily in practice. In conclusion, we cannot refrain from again expressing the opinion, that a single amendment to our present laws, for the addition of three competent and thoroughly members of the medical profession to the present Board of Health, with the aid of one additional Clerk, as Register of Vital Statistics, would result in rendering our Health as efficient and beneficial to the interests of the city, as it could be by any number of new and expensive schemes. It would require but one police organization, capable of being or diminished, as public exigencies might require, and practically amenable to but one Board. It would require a larger ratio of medical to the non- intelligence in the Board of Health, than is proposed in either Ward's bill, or that of the Citizens' Committee. of requiring an annual aggregate increased tax upon the city of $75,000 or $100,000 for salaries of new' officers and agents, it would require for the three additional members of the Board of Health and the Register of Vital Statistics an of not over $5,000. It would also,leave our City far less complicated in its details, and, in all its strictly local interests, under the control of its own citizens, where it properly belongs. All of which is respectfully submitted. N. S. DAVIS, ) R. C. HAMILL, V Committee. J. P. ROSS, J Medical Department of University of Michigan. We have seen in some of our exchanges, a statement of the number of Medical Students in the University of Michigan, by the assertion that the large number congregated there could not have been drawn thither by the small pecuniary charges, as the aggregate of attendance is greater, owing to the length of the Lecture-term, than in any other school in the North-west. The entire falsity of such a statement is shown by the following facts: The fee for admission to the Medical Department of the Michigan University is, for students in the State $10, from out of the State $20, paid but once. The Lecture-term being six months, allowing $25 per month for board, would make a total necessary expenditure for the full term of $160 for the student of the State, and $170 for students from other States. The Chicago Medical College, in this city, has a Lecture-term of full five months. If we put board here at the same rate as supposed for Ann Arbor, namely, $25 per month, the cost of attending the regular annual course here, would be as follows: Five months board, at $25 per month, $ 125 00 Lecture fees, 50 00 Matriculation fee, 5 00 Dissecting fee, 5 00 Hospital fee, 6 00 Total,_______________________________ $191 00 Clinical Items. A subscriber wishes to know how to cure "an obstinate, tormenting, intolerable itching, of years ," either in the genital organs of the female or around the anus of the male. The following cases may answer his purpose: Case I. Mrs. B., a married lady, aged about 25 years, had been for several years subject to periodical attacks of puritus pudendi, or intolerable itching of the labia and vulva. She generally suffered most from it after the menstrual periods, and it was generally accompanied by a thin leucorrhoeal discharge. She was placed on the following treatment: 1^. Ext. Hyoscyamus, SOgrs. Sulph Ferri, 30grs. Pulv. Aloes, 15grs. Blue Mass, lOgrs. Ext. Nux Vom., lOgrs. Mix and di vide, into thirty pills. One to betaken before breakfast and dinner each day. For local use she was directed a solution of borate of soda (borax), 5iij and sulphate of , 20grs., in water, one pint, the vulva to be wet with it , and a small quantity injected into the vagina each night and morning. Under this treatment the patient recovered, without any return of the disease. Case II. Mrs. W., aged 40 years, had been very severely troubled with the same disease several months, without any to the menstrual periods. The same solution of borax and morphine, applied locally, and the use of eight drops of Fowlers's arsenical solution, taken before each meal, in a spoonful of sweetened water, and continued for about four weeks, resulted in a cure. Both patients were required to live on plain food and to avoid all stimulating drinks. Case III. Mr. G., aged 30 years, sanguine temperament and full habit, had pruritis of the anus for three years. the itching would be intolerable for several days and then better for a week or ten days at a time. On examination, the skin, over a circle of an inch, around the opening of the , was thickened, slightly fissured, and whiter than usual, lie was directed to take eight drops of Donovan's solution each meal time, and the affected surface was wet with the liquid persulphate of iron, o.f the strength usually found in the drug stores, every third day. After four local applications he was entirely relieved. He continued to take the drops for three weeks, and although more than one year has elapsed the disease has not returned. I recollect treating several cases of old chronic cases of ani sucessfully, by applying locally, each night and , the following ointment: ly. Iodide Sulphur, 3ij Oil Tobacco, + 2gtts. Simple Crete, SSij Attention should always be paid to the general health, and especially to. the condition of the digestive organs. ^iie Chair of Surgery in Rush Medical College. According to statements in the daily papers of this city, the chair of Surgery made vacant by the death of the late Prof. I). Brainard, has been filled by the appointment of Moses Gunn, of Detroit, Professor of Surgery in the University of Michigan. It is also stated that Prof. Gunn has accepted the appointment. City Mortality. The following is the report of the of the mortality of the City of Chicago for the month of December, 1866: CAUSES OF DEATH. Accidents, u Asthma, 2 Bronchitis,____________________ 1 Burned,_________________________ 1 Cancer, 2 Childbed, 2 Cholera Infantum,_______________ 1 Consumption, 42 Convulsions,____________________35 Croup, 7 Cold____________________________ 2 Chicken Pox,____________________ 1 Congestion of Brain,____________ 3 Congestion of Lungs,____________ 2 Decline,________________________ 1 Delirium Tremens,______________ 1 Diarrhoea,______________________ 5 Diphtheria,___________________<<. 15 Disease of Heart, 8 Disease of Liver,______________ 2 Disease of Lungs,______________ 7 Disease of Brain,______________ 6 Dropsy,_________________________ 7 Drowned,________________________ 2 Erysipelas, 3 Fever, Childbed, 2 Fever, Remittent,_______________ 4 rever, scarlet,_______________ 13 Fever, Typhoid, 4 Fever, Typhus,_________________ 1 Fever, not stated, 1 Hydrocephelus,_________________ 7 Inflammation of Kidneys,_______ 1 Inflammation of Bowels,________ 9 Inflammation of Lungs,_________ 6 Inflammation of Liver,_________ 1 Marasmus,______________________ 1 Old Age, k 15 Palsy,_______________________ 2 Pneumonia,_____________________ 7 Phthisis Pulmonalis,___________ 1 Spasms,________,_______________ 1 Spinal Meningitis,_____________ 1 Suffocation,___________________ 2 Small Pox,_____________________ 2 Suicide, ______________________ 1 Stillborn,____________________ 10 Teething,______*_______________ 3 Whooping-Cough.________________17 Gun shot Wound,________________ 1 #White Swelling, 1 Unknown,______________________ 33 Total,_________________309 ages of the DECEASED. Under o years, loo ; over o and under 1U years, 19; over 10 and under 20, 15; over 20 and under 30, 28; over 30 and under 40, 34; over 4o and under 50, 16; over 50 and under 60, 11; over 60 and under 70, 11; over 70 and under 80, 12; over 80 and under 90, 6; unknown, 4. Total, 309. N \TTVTTTFS Chicago,____________128 Other States, 63 Belgium, 1 Bohemia, 2 Canada,__________1__ 2 England,____________ 5 Germany, 47 Ireland,____________38 Norway, 6 On the Sea,_________ 1 Sweden, 5 Scotland,___________ 4 Wales,______________ 1 Unknown,____________ 6 Total, 309 DIVISIONS OF THE CITY. North,..... 75 | South,....105 | West,....129 | Total,... 309 Total number during the month of November,_______________ 382 Decrease from last month, 73 Total number last year for the month of December,________ 333 Dr. Conneau. It bus been remarked that nearly every profession but that of medicine was represented in the French Senate. This anomaly has struck the Emperor, it would Appear, as the Evenement announces that his Majesty's physician, Dr. Conneau, is to be promoted forthwith to a seat at the . |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34766 Obstetrics/Gynecology Oncology Clear Cell Ovarian Carcinoma With C1 Lateral Mass Metastasis and Pathologic Fracture: A Case Report Muacevic Alexander Adler John R Sassine Dib 1 Rogerson Daniella 2 Banu Matei 3 Reid Patrick 4 St. Clair Caryn 1 1 Gynecologic Oncology, Columbia University Department of Obstetrics and Gynecology, New York, USA 2 Obstetrics and Gynecology, Columbia University Vagelos College of Physicians and Surgeons, New York, USA 3 Neurosurgery, Columbia University Department of Neurological Surgery, New York, USA 4 Neurosurgery, Columbia University, New York, USA Caryn St. Clair [email protected] 8 2 2023 2 2023 15 2 e347668 2 2023 Copyright (c) 2023, Sassine et al. 2023 Sassine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Osseous metastasis (OM) in ovarian cancer (OC) are rare, with an incidence ranging from 0.8% to 2.6%, and are associated with poor prognosis. The available literature on their management and associated complications is scarce. We report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial OC (EOC) who presented with neck pain. Imaging revealed multiple cervical spine metastases with left vertebral artery encasement and concurrent C1 lateral mass compression fracture, without neurological deficit, requiring occiput to C2 posterior instrumentation and fusion. Early OM may be associated with shorter overall survival, and survival after OM diagnosis is on the order of months. Management of OM should include a multidisciplinary team and may require surgical stabilization in addition to systemic chemotherapy, local radiotherapy, and osteoclast inhibitors. ovarian clear cell carcinoma vertebral fusion pathological fracture osseous metastasis ovarian carcinoma The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Ovarian cancer (OC) is the most common cause of gynecological cancer death . Direct spread to adjacent pelvic organs, peritoneal spread, and metastasis via the lymphatic route are common, while hematogenous spread to further sites such as the liver, lung, bone and brain occur less commonly and have a poor prognosis [2-4]. Osseous metastases (OM) in OC are among the rarest, with incidences between 0.82% and 4.0%, and may occur by direct invasion, hematogenous, lymphatic, and transperitoneal spread . The vertebral column is the most common site, though case reports document findings throughout the axial skeleton and pelvis . OMs are associated with shorter overall survival . A recent study found the 1-, 5-year survival after OM diagnosis were 33%, 15%, and 8%, respectively . Skeletal-related events (SREs) and neurovascular compromise secondary to OM have rarely been described. Here, we report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial ovarian cancer (EOC) complicated by C1 vertebral metastases with vertebral artery involvement and C1 vertebral fracture, necessitating occiput to C2 posterior instrumentation and fusion and palliative C2 neurectomy. Case presentation A 59-year-old African American P0 (nulliparous) with a history of uterine leiomyoma presented with abdominal pain and bloating. A transabdominal sonogram demonstrated multiple large, complex adnexal masses. Staging computed tomography (CT) chest, abdomen and pelvis was suspicious for metastatic ovarian carcinoma, with bilateral complex adnexal masses, peritoneal carcinomatosis, omental caking, and pericardiac, abdominal, peripancreatic, mesenteric, retroperitoneal, and pelvic lymphadenopathy. No osseous lesions were identified at the time of the initial scan. An initial consult with gynecological oncology revealed an abdominal mass above the umbilicus, pelvic masses, and a palpable left supraclavicular node. Ca-125 was 6,773. Pathological examination of interventional radiology-guided peritoneal mass biopsies had an immunoprofile compatible with a high-grade adenocarcinoma of Mullerian origin, favoring clear cell carcinoma. The tumor showed preserved mismatch repair (MMR) proteins expression (positive for MLH1, PMS2, MSH2, MSH6). Immunostain for human epidermal growth factor receptor 2 (HER-2) was equivocal and difficult to interpret on the scant cell block material with mostly cytoplasmic staining, no convincing membranous staining, score 0-1, and immunostaining for PD-L1 was limited by scant cellularity in the cell block, focal positivity with an estimated combined positive score (CPS) 3-4. Further genetic testing did not show any mutations for possible targeted therapy. The patient was diagnosed with FIGO stage IVB clear cell EOC. She received her first cycle of carboplatin, paclitaxel, and bevacizumab, with a plan for 3-4 cycles of neoadjuvant chemotherapy and interval debulking pending clinical response. After her first cycle of chemotherapy, the patient endorsed persistent neck pain of moderate severity. Magnetic resonance imaging (MRI) cervical spine revealed contrast-enhancing osseous lesions within the anterior arch and left lateral mass of C1, as well as in the C4 and C7 vertebral bodies, left articulating facet of C6 and T4 vertebral body extending into the left pedicle. There was lateral tumor extension with encasement of the vertebral artery at the C1 level. There was no evidence of epidural disease or spinal cord impingement . CT angiogram (CTA) demonstrated multiple osseous lytic lesions and a C1 lateral mass compression fracture extending to the left transverse foramen, with asymmetry of the lateral atlantodental interval measuring 8 mm on the right and 2 mm on the left. There was circumferential tumor encasement of the left vertebral artery in the sulcus arteriosus, with severe narrowing with preserved flow and no evidence of dissection . Metastatic cervical and supraclavicular lymphadenopathy were confirmed. The total body bone scan did not show further OM. Figure 1 Sagittal (left) and axial (right) MRI of the patient A. T2-weighted and B. T1 fat saturation MRI sequences demonstrating C1 lateral mass lesion (red arrow) and displacement of the vertebral artery with no epidural tumor extension or cord compression. C. Parasagittal T1 sequence demonstrating lateral tumor extension with encasement of the vertebral artery (red arrow). D. Coronal (left) and axial (right) CT angiogram demonstrating osteolytic left lateral mass lesion encasing and narrowing the vertebral artery (red arrows). The patient was admitted to neurosurgery with gynecological oncology consultation, where she continued to endorse left-sided cervical pain radiating to the occiput which worsened with movement and improved with opioids, steroids and immobilization with a hard collar. There were no focal neurological deficits, paresthesias, anesthesia, gait difficulties, or bowel or bladder dysfunction. The patient had full strength in the upper and lower extremities and an intact gait. She had no signs of myelopathy and had a negative Hoffman's sign. Given normal cervical alignment, with imaging demonstrating articular facet involvement and lateral mass fracture, this pain was considered to be caused by cervical spine instability . Figure 2 Preoperative (A) and postoperative (B and C) radiographs A. Preoperative anterior-posterior (left) and upright lateral (right) radiographs demonstrating normal cervical spine alignment. B. Postoperative anterior-posterior (left) and lateral (right) cervical spine radiographs demonstrating appropriate instrumentation placement and alignment after posterior hardware fixation of the occiput to C2. C. Postoperative anterior-posterior (left) and lateral (right) standing scoliosis series illustrating normal alignment. Urgent surgery was not indicated without neurological deficits or compressive pathology. A multidisciplinary team discussed the case to determine if surgical decompression was required prior to local radiation, and surgical intervention with occiput to C2 instrumentation and fusion was decided upon. Surgery was performed two days after diagnosis. Intraoperatively, there was extensive tumor involvement of the C1 lateral mass and posterior arch, encasing the vertebral artery and extending towards the occipital condyle. A palliative C2 neurectomy was performed for pain control. A right C1 lateral mass screw, bilateral C2 pedicle screws, and occipital keel plate with three bicortical screws were placed. The fusion bed was prepared by decorticating the occiput and bilateral C1-2 joint spaces with the placement of allograft over the decorticated spaces. Intraoperative monitoring was stable throughout and the patient awoke at neurological baseline. Postoperatively, the patient endorsed significant improvement of her cervical pain. Incisional pain was controlled with methocarbamol, gabapentin and hydromorphone PCA (patient-controlled analgesia). Radiographs demonstrated excellent instrumentation placement and alignment . The patient ambulated without assistance on postoperative day (POD) 1 and was discharged in stable condition on POD3. Radiographs of the spine confirmed stable spinal fusion rods three weeks postoperatively . There was complete resolution of the cervical pain. The patient received her second cycle of carboplatin and paclitaxel four weeks postoperatively; at that time, progression of cervical lymphadenopathy was noted on exam. She since received two additional cycles three and six weeks later, with a downtrending CA-125 of 2,301. Bevacizumab has been held to allow for surgical healing. Denosumab injection of 120 mg every 4 weeks, calcium, and vitamin D were initiated postoperatively, with a plan for palliative radiation therapy (RT) of 20 Gy in 5 fractions to C1-2 and associated hardware to prevent disease progression. Discussion This report illustrates a unique complication of OM in EOC. Given the rare nature of these lesions, the literature is sparse. Four retrospective studies comment on OM in the context of other rare OC metastases . In these, the incidence of OM ranged between 1.2% and 4%. Deng et al. analyzed 1481 patients with stage 4 ovarian carcinoma using the Surveillance, Epidemiology, and End Results (SEER) database. OM was found in 3.74% of the entire cohort with a median survival time of 11 months for the patients with OM. Dauplat et al. examined 255 patients with EOC with stage 4 disease. Only four patients (1.6%) had OM with a median survival of 9 months. Gardner et al. used the SEER database to determine the pattern of the distant metastases at the initial presentation in patients with gynecological cancer and found that OM was present in 4% of the patients with ovarian carcinoma, vs 13% and 23% of patients with uterine and cervical cancer, respectively. Additionally, four retrospective studies looked specifically at OM in OC (Table 1). Table 1 Four retrospective studies examine osseous metastasis (OM) in ovarian carcinoma Publication - Author, Year Cohort - No OM - No (%) Overall Survival - Months Survival After OM Diagnosis - Months Most Commonly Involved Site Ak et al., 2021 (2) 736 19 (2.60) 38.1 13.6 Vertebral Sehouli et al., 2013 (5) 1,717 26 (1.50) 50.5 7.2 Vertebral Zhang, C. et al., 2019 (6) 32,178 352 (1.09) 50.0 5.0 Not Reported Zhang, M. et al., 2013 (7) 2,189 26 (0.82) Not Reported Not Reported Vertebral Ak et al. examined 736 OC patients and found OM in 2.6%; OM was mostly seen with clear cell histology similar to our case report. The vertebrae, as in our patient, were most commonly involved, though patients often had multiple sites of involvement. Pain was the most common presenting symptom, but was absent in over 50%. Unlike our case, out of the two patients presenting with pathologic fractures, one had neurologic deficit. Patients were managed with palliative RT and bisphosphonates. Only advanced, inoperable disease at presentation was associated with a shorter time to development of OM. Median overall survival in OC patients with OM was 38.1 months and median survival after OM diagnosis was 13.6 months. Patients who had OM at the time of diagnosis of their OC had a shorter median OS than those who developed OM later on, 6.1 vs 63 months, respectively. To note, although insignificant, overall survival was shorter in patients with clear cell histology after OM than in patients with a different histologic subtype ( 7 vs 22 months) . Sehouli et al. examined 1,717 patients and found OM in 1.5%. The vertebral column was the most common site, most frequently in the lumbar, followed by the thoracic and cervical regions. Multiple OM were seen in the majority of patients, as in our case. Pain was the presenting symptom in 66%; 9% had impaired mobility unlike our patient, and 4% had neurologic symptoms. Pathologic fractures were reported in 33%. Most patients were treated with bisphosphonates; of those treated, 26% went on to develop pathological fractures and required surgical intervention. RT of OM was performed in a minority of cases for pain control and for SRE prevention. OM was noted to progress in 75% of cases despite systemic and local therapy. The median overall survival of the entire cohort was 50.5 months; patients with early OM had significantly shorter overall survival than those with later OM, 11.2 vs 78.4 months; to note, the overall survival rates were calculated regardless of the histology of the disease. By far, the largest study on this topic, Zhang, C. et al. , examined 32,178 Surveillance, Epidemiology, and End Results (SEER) database OC patients and found the prevalence of OM was 1.09%. OM were more common in women over 65, Black and unmarried women. Similar to our patient, most of those patients had an advanced stage, poorly differentiated grade, non-serous type, elevated CA-125 and had concurrent distant metastasis. The median overall survival for the entire cohort was 50 months, whereas the median overall survival after OM diagnosis was 5 months only. Among examined variables, only surgery at the primary site was associated with significantly longer survival, 18 vs 3 months for primary site surgery versus no surgery. Survival was significantly shorter in patients with a non-serous histology without commenting specifically on the clear cell carcinoma histology . Lastly, Zhang, M. et al. found OM in 0.82% of 2,189 OC cases. The majority of OM were vertebral (12 cervical, 10 lumbar, seven thoracic), eight were pelvic, five were limb, two were sternal, and one was rib. Over half presented with pain, 35% with difficulty walking, and 15% were asymptomatic. Similar to our case report, the majority of cases with OM were in advanced disease and EOC, and most of them were managed with chemotherapy and RT. Cases that were managed with combined chemotherapy and RT had significantly longer survival than those treated with either agent alone, 14.2 versus 11 versus 8.4 months for combined therapy, RT alone, and chemotherapy alone, respectively . There is a paucity of data regarding the management of OM with or without SRE in OC, and the current management of lesions is based on that for other solid tumors. Diagnosis includes history and physical, and imaging options include radiographs, CT and MRI; MRI is the modality of choice for vertebral lesions. A multidisciplinary team approach is often needed for the management of such rare cases, including radiology, orthopedic surgery, neurosurgery, radiation oncology , gynecological oncology, palliative and pain medicine . All of these modalities were utilized as illustrated in this case. Conclusions In conclusion, we present a unique case of clear cell EOC with vertebral OM resulting in pathologic C1 fracture requiring surgical stabilization, further complicated by vertebral artery encasement and narrowing. OM secondary to OC are rare and often present with pain though rarely with neurologic deficit. The risk factors for the development of OM are poorly understood but may include clear cell EOC as in this case, and lesions are more commonly described in those with late-stage disease. Patients who present with OM at the time of diagnosis or early in their disease course may have shorter overall survival than those with later OM. However, survival after OM diagnosis is on the order of months. Surgery at the primary site and combination chemotherapy and RT may prolong survival. These findings are based on limited retrospective studies, and further examination of risk factors and prognostic implications of OM in OC is needed. Human Ethics The authors have declared that no competing interests exist. 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The increased attention drawn to the negative environmental impact of the cattle industry has fostered a host of research-driven initiatives among relevant actors. While the identification of some of the most problematic environmental impacts of cattle is seemingly more or less unanimous, solutions are complex and might even point in opposite directions. Whereas one set of solutions seeks to further optimize sustainability pr. unit produced, e.g., by exploring and altering the relations between elements kinetically moving one another inside the cow's rumen, this opinion points to different paths. While acknowledging the importance of possible technological interventions to optimize what occurs inside the rumen, we suggest that broader visions of the potential negative outcomes of further optimization are also needed. Accordingly, we raise two concerns regarding a focus on solving emissions through feedstuff development. First, we are concerned about whether the development of feed additives overshadows discussions about downscaling and, second, whether a narrow focus on reducing enteric gasses brackets other relations between cattle and landscapes. Our hesitations are rooted in a Danish context, where the agricultural sector mainly a large-scale technologically driven livestock production contributes significantly to the total emission of CO2 equivalents. critical kinetics planetary boundaries technical solutions feed additives livestock Jevons' paradox Denmark anthropology Independent Research Fund Denmark through the project Cattle Crossroads. Researching Danish Animal Production for the Future0217-00171B This research was funded by the Independent Research Fund Denmark through the project Cattle Crossroads. Researching Danish Animal Production for the Future accessed on 9 February 2023), Grant no. 0217-00171B. pmc1. A Commentary on Feed Additives as Solutions to Cattle's Climate Impact Since 2006, when the much-quoted FAO report Livestock's Long Shadow was published, increasing attention has been paid to the environmental challenges brought about by the cattle industry . Problems pile up. Today, agriculture occupies about 38% of Earth's terrestrial surface . Industrial livestock requires enormous amounts of feed, the production of which takes up more than three quarters of all agricultural land on the planet . This leads to massive deforestation, which proliferates into yet other problems such as soil erosion, nutrient leaching, and loss of biodiversity. Further, the gases emitted from the rumination processes of cattle make up a substantial portion of the greenhouse gases (GHG) that spread through the atmosphere, heating up our globe. In particular, enteric fermentation has been targeted and understood as key to controlling and potentially reducing the climate impact of cattle. In response, a host of research-driven initiatives among relevant actors has emerged. As this special issue suggests, the time has now come to collect knowledge on forage and feedstuff digestion kinetics in ruminants in order to meet the mounting pressures to reduce enteric methane production. The fact that domesticated animals produced around the world (mainly cattle, pigs, and poultry) now outnumber wild mammals and birds by a factor of ten no doubt adds pressure to this predicament . Yet, for all the weight this ratio puts on the world's ecosystems, the scientific knowledge base supporting the industry's transition towards more sustainable futures most often comes from very specific areas of the natural sciences. Nourishing this quantitatively large global production of a few domesticated animal species, then, is the continuous production of scientific knowledge and research related to issues such as feed intensification, genetics, and health. For cattle, the obvious aim is to further optimize and increase dairy and beef production industries that in Euro-American production systems are premised on principles of high cost efficiency, achieved by keeping large animal herds on small but intensively managed areas, with easy access to feed products that are often both nutritionally optimized and imported from overseas. While the identification of some of the most problematic environmental impacts of cattle is seemingly more or less unanimous, solutions are complex and might even point in opposite directions. As is clear from this special issue, one set of solutions points to interventions into the causal relations of elements kinetically moving one another inside the cow's rumen. More specifically, feed additives of various sorts are developed to decrease the generation of methane, thus targeting climate change. Surely, these interventions are valuable after all, in these critical, increasingly hot times, why oppose GHG reductions in whatever form and by whatever means? Nonetheless, in this short contribution, we raise two concerns regarding a focus on solving emissions through feedstuff development. Whereas knowledge about the possibilities of technological optimization is important, we suggest that broader visions of the possible negative outcomes of further optimization are also needed. Notably, we are concerned for two reasons: First, the development of feed additives may overshadow discussions about downscaling. Second, a narrow focus on reducing enteric gasses by manipulating a set of kinetic causal processes inside the rumen may bracket other relations between cattle and landscapes. Both of these consequences, we suggest, can potentially limit the scope of climate impact mitigation in relation to cattle. Below, we substantiate these reservations and go on to probe how the development of feed additives sit with ideas about absolute sustainability and safe operating spaces for humanity. Our approach to the issue of feed additives and cattle production is rooted in anthropology and cultural history. We thus work using a method of ethnographic fieldwork among stakeholders engaged in Danish cattle production, and we conduct document analysis of, e.g., policies and public discussions, just as we look to archival and historical literature to trace earlier connections between state making and livestock production in Denmark. 2. Intensified Danish Livestock Production With Feral Effects Within the agricultural sciences, an answer to the problematic climate impact of cattle has often been to further intensify animal production cf. . This response, however, rests on a modernistic assumption that more-than-human lives are essentially controllable by humans. The ecological crisis that we are presently witnessing does indeed testify to human activities and projects on a massive scale, but not to human control over causal relations in the more-than-human world. This is what we mean by feral kinetics in this opinion's title; we want to indicate that projects in which (causal) relations were once set in motion by humans through intentional projects often spur various unintended effects . Surely, no one set out to change the climate through animals. A brief historical look at the Danish context in which our research is rooted shows how intensification has come about gradually and in response to a host of societal, political, and historical circumstances that jointly make up what livestock came to be. In Denmark, the agricultural sector is responsible for 27.1% of national GHG emissions (excl. land use, land use change, and forestry (LULUCF)), of which intensive livestock production is a prominent contributor . Danish livestock production is often positively framed in public discourse as economically and environmentally cost-efficient when measured at the scale of singular products. Yet, there is reason to question the hidden costs of this mode of calculation, which often fails to include GHG emissions and global environmental impact derived from the livestock industry's dependency on feedstuffs, and thus, on land cultivation and deforestation both in Denmark and overseas, as scientists have also pointed out . In Denmark, as in other European countries, agricultural production has historically informed the organization of government, business, and civil society, and politicians still identify Denmark as "a farming country" see, for example, . It was through the workings and on-going development of the agricultural sector that Denmark as a nation underwent some of its most significant historical changes, not least that of industrial modernization . More specifically, 20th-century industrial modernization in the agricultural sector came about through the emergence of a strong, export-oriented livestock industry see, for example, . For instance, the number of pigs in Denmark has increased from 301,000 in 1860 to 12.2 million today, which is now more than twice the Danish population . The historical emergence of a strong livestock sector not only changed the welfare and fortuity of rural communities. It also changed the physical appearance of the animal bodies that would increase the reach of Danish industrial interests by yielding more meat and milk per animal than they ever had before, which was achieved, in particular, through the industry's adoption of scientific approaches to rational and optimized feeding . Our point is that during the same historical processes that have made Danish agriculture synonymous with a large livestock industry, the livestock industry has itself become synonymous with high export and feedstuff dependency, as both are integral to how cost efficiency is construed in the industry. However, if the purpose of novel feed additives is to mitigate the climate impact of cattle production, it seems pivotal to ask whether such a high dependency on feeds should itself become a site of scientific intervention in the industry. 3. The Issue of Scale and Re-Bound Effects Indeed, to pinpoint our first reservation, focusing on greening the enteric digestion process by making 'enhanced' rumens less harmful, and politically prioritizing this effort, may engender a so-called rebound effect where decreased methane emission pr. cow is evened out by an increased scale of production a mechanism sometimes summarized as Jevons' paradox. In other words, addressing the issue of methane emission through conceptualizing the rumen as a discrete and singular site of intervention may occlude the concern both with a potential rise in scale and with other the well-known, environmentally harmful effects of maintaining present-scale livestock production . Inadvertently, we fear, the development of feed additives may contribute to the status quo, thus foreclosing difficult discussions about how we might best use arable land (for feed or food), and about the number of cattle the world's ecologies (including atmospheric greenhouse gasses) can actually support. Aspiring for sustainability as genuine change on a planet with limited resources and imminent tipping points requires that we think in absolute terms. Adjustment and improvement miss the mark. 4. The Issue of Other Ecological Relations Our second hesitation is that a narrow focus on kinetics inside the rumen may eclipse wider ecological relations put into motion by the altered processes in the rumen. As the many ecological crises we are witnessing make clear, humans can no longer be seen as being in full control of various processes on earth what we referred to above as the 'feral' nature of the non-human world in this day and age. Processes once perceived as controllable have proven not to be so, resulting in unintentional global effects that are both distributed and caused by human actions . With regard to feed additives specifically, these may work on other relations than those within the rumen, making it urgent to widen the scope of research. We must be careful not to make yet another potent feral product by limiting our view of what the problems and solutions are. 5. Thinking with Absolute Sustainability To summarize, our hesitations with regard to feed additives concern, first, how additives may maintain status quo in terms of the scale of cattle production, and second, how they may engender unanticipated ecological effects. On both accounts, we suggest, there is a need to consider how technological and natural scientific solutions to the methane issue relate to a planet with boundaries that limit a safe operating space for humanity . In short, we want to question how feed additives as a means of reducing methane emissions sit with ideas about absolute sustainability . If, as we suggest, technological solutions 'work back' on the identification of what the problem even is, the result is too easily a circular argument; we can only see the problems that we think we can solve by way of technology rather than by a just and green societal transition, sanctioned in progressive politics. In making this argument, and exploring how it works in a Danish context, we draw on the model of planetary boundaries originally suggested by Rockstrom et al. . In 2017, Campbell et al. further worked with the model, arguing that agricultural production is, indeed, a main driver for the eco-system changes occurring, particularly within spheres where the planetary boundaries are transgressed. Our point is simply this: If the impact of agricultural production already exceeds 'permissible' limits, something has to change fundamentally. Making things relatively better is just not enough. This is particularly important in agro-industrially intensified countries such as Denmark where livestock industries are (dis)proportionately large; we must question both issues of scale and of unintended side effects. Choices remain to be made that observe planetary boundaries. Now, the scientists and companies who develop feed additives would probably agree that this is just one tool among many others. We want to stress that it is not feed additive development per se that we take issue with. Rather, looking to the recent political work of pushing for a green transition of the Danish cattle industry, we are concerned with the way feed additives have emerged on the political stage. Here, additives are presented as the obvious solution to a universal problem. However, the problem that additives are key to solving i.e. a massive cattle industry, nourished by feed that causes deforestation and in a monocultural logic can remain untouched. Further, the wider effects of the additives have yet to be documented. 6. A Couple of Examples To substantiate our argument, below we will look at a couple of instances where feed additives are discussed in a Danish context. We do so via ethnographic fieldwork, where we engage with stakeholders such as researchers and politicians, as well as with various written sources. Our method is ethnographic in the sense that we trace relations and generate analyses in dialogue with the field; as such, we explore what feed additives may be as they are produced and discussed by people who develop, implement, or entrust them with positive effects for mitigating climate change see also . In 2021, all political parties but one represented in the Danish parliament signed an agreement on the green transition of agricultural production in Denmark . The agreement, launched as historic and ambitious, commits to reducing GHG emissions from agriculture by 55-65% by 2030 compared to 1990 levels, in addition to reducing nitrogen and phosphorous run-off into waterways in order to comply with EU regulation. To reach this binding target, curiously, the agreement starts with listing a number of caveats, all to the effect that the goal must be achieved without decreasing agricultural productivity, nor compromising public finances and Denmark's competitive edge with regard to agriculture. Instead, the agreement highlights the continued prioritization of developing and implementing new technologies. Indeed, trust in (near) future technological solutions is so great that the historically ambitious deal, as it is now, ensures less than a third of the promised reduction. More precisely, the agreement specifies a reduction of 1.9 tons of CO2e out of the 6.1-8 tons which is the overall target for the agricultural sector, equaling a reduction in GHG emissions of 55-65% from 1990 emission levels. The rest of the required reduction, the agreement states, will be brought about by new technologies that have yet to be developed and implemented. Two overall arenas for technological innovation are singled out in the political agreement: namely, the curbing of emissions from manure from all production animals and enteric fermentation in livestock. The agreement states as follows: "It will be a continued priority that new tools, such as feed additives, are transferred as quickly as possible to the implementation track, and that the demand [for reduced GHG emissions] is adjusted according to what can be realized" (p. 4). What we want to point to here is that the means for a very large proportion of the CO2 reduction that the agreement commits to have yet to be invented, and that reduction targets are adjustable. In other words, the binding and historic agreement on the green transition of Danish agriculture is highly negotiable, and, further, dependent on uncertain technologies. All the while, the agreement lists a number of other priorities that are not up for negotiation such as productivity, employment, public finances, and rural development. This leaves it up to innovative technologies to find the remaining (majority) of the promised GHG reduction. Accordingly, as we see it, there is a substantial risk that the agreement's limited focus on climate change mitigation will lead to so-called "burden-shifting" see as the negative impacts of feed production and consumption are only considered with regard to a single planetary boundary, as opposed to asking how feeds can become sustainable in an absolute sense, heeding all biospheres. This is to say that optimizing feeds as a means to mitigate GHG emissions specifically risks overlooking equally important and environmentally detrimental processes such as the eutrophication or acidification of waterbodies. If global feed production and consumption on the whole are largely left unchanged, the use of feed additives to mitigate GHG emissions risks relocating instead of actually solving the problems caused by livestock production. By leaving it up to hopeful investments in future technologies to reduce GHG, we are not forced to consider the number of cows, nor the other effects of an unchanged scale. Another example from our fieldwork sheds light on the potential unintended effects of implementing feed additive solutions. Below, we provide more detail regarding some of the ways that feed additives work in the practices and discussions of industrial agriculture stakeholders. At the annual Cattle Congress 2022, the head of the Cattle Section in SEGES Innovation the Danish agricultural interest organization's independent research unit together with a researcher from the same organization, gave a talk under the headline "Climate Requirements in the Agricultural Agreement" the same deal mentioned above. From her point of view, climate requirements can be answered by two distinct means of action: the handling of digestion and manure while not compromising another distinct theme, namely animal welfare. In this way, she framed the problems involved in having an agricultural sector accounting for over one fourth of Danish GHG emissions by setting a very particular triangular frame within which one should think, talk, research, and act in relation to climate requirements: welfare, digestion, and manure. She mentioned that feeding with additives could reduce 20% of the 0.17 million tons CO2 that needed to be reduced by 2025, but also expressed frustration with the limited amount of money reserved to introduce and implement a new product approved by the European Union in the spring of 2022. New routines on farms need to be developed and supported, and potentially skeptical farmers should be convinced that milk yields will not decrease on account of the new additive. The researcher assisted her and elaborated on the tools needed to reach the goals in the climate law and the agreement discussed above. These were tools that altogether confirmed the dictum of 'more for less' (higher yield and more efficiency in feed and in producing bodies) that has made Danish livestock production competitive on a global market despite high production costs. Just as important, the presentation repeated a dictum that has recently become a standard answer to green goals: optimization equals sustainability. The researcher then went on to talk about the possibilities of reducing methane by changing diets rapeseed and a handful of feed additives were mentioned, along with the possibilities and challenges these feeding options spurred. He singled out one new product and stated that the climate impact of milk will decrease by 17%, adding that if all conventional producers would implement the additive, the reduction targets for 2030 could be met. Thus far, he continued, the additive has only been tested on Holstein cattle. He wrapped up his presentation by saying that if any of the farmers present were interested in testing the product on their animals, they should feel free to get in touch. What interests us here is that the talk can be seen as combining the launch of a solution with calling for further tests, thereby mimicking the agreement above in its expectations for future effects of something yet to be fully developed and tested. Interestingly, a person in the audience raised his hand and questioned the manure from cattle fed with the approved additive, asking whether the emissions from it altered when distributed on the fields. In response, the researcher answered that the amount of product used is so small, and further that the product is processed so quickly in the cow that it was very unlikely that it would have an effect elsewhere, outside the rumen. However, he continued, researchers in Canada have recently conducted a study where they pointed to higher emissions from manure in the fields as an effect of the application of feed additives. Interestingly, this Canadian study or hesitation, we could call it did not seem to 'alter' the Danish researcher's hopes for feed additives once they have been further tested. Chatting with the researcher after the talk, it became clear that potentially increased emissions on the fields were understood as a problem for another research field namely, that which deals with manure handling. For him, it seemed, there were so many kinetic relations to be explored within the rumen, and understanding what happens later, out on the fields, would be a theme to be researched once processes in the rumen are more fully understood. Our point here is to highlight the decoupling of what goes on in the rumen upon applying feed additives from the 'afterlife' of such an intervention. 7. Conclusion: Heeding all Biosphere Domains at Once To conclude, what we argue and the reason for our reservations towards the prevalent kind of solutionism offered by the development of feed additives is that it takes a very particular perspective on the cow for its rumen to be the sole target of any intervention. From this perspective, the cow is a singular unit from within which technology can decrease methane emission. To the contrary, as anthropologists, we would see any cow as a set of relations, ranging from the microbial level to global issues of deforestation . While we do not oppose feed additives as such, we do hold that they risk building on and maintaining a tunnel vision, as also described above, that allows for a curious disconnection of cattle's rumen from other cattle-related processes and decisions, including the discussion of scale and other effects than GHG emissions. In Denmark, and elsewhere, other biosphere problems are also apparent as seen from the model of planetary boundaries. Not least, we have huge problems with the leaching of N and P severely affected waterways in Denmark, as a result of the scale of animal production, regardless of its climate efficiency when measured pr. kilogram of, e.g., milk. Put bluntly, as we see it, if we care about the immediate threats to the safe operating space for humanity, it makes little sense to assess the climate impact of cattle pr. singular rumen. One direct insight from the principle of absolute sustainability is that all agricultural resource activities impact many of the nine biosphere domains. Accordingly, solutions need to follow suit. We cannot afford the luxury of solving one problem at a time. Acknowledgments We are very grateful to Hanne Helene Hansen for inviting us to contribute to this special issue, and to the three anonymous reviewers for helpful feedback. We also want to thank Liza Rosenbaum Nielsen, Kari Eriksson, and Camilla Kirketerp Nielsen for sustained and challenging discussions. Author Contributions Conceptualization, N.B., S.B., and F.H.; methodology, N.B., S.B., and F.H.; formal analysis, N.B., S.B., and F.H.; investigation, N.B., S.B., and F.H.; data curation, N.B., S.B., and F.H.; writing original draft preparation, N.B. and F.H.; writing review and editing, N.B., S.B., and F.H.; project administration, F.H.; funding acquisition, F.H. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. The article builds on publicly available sources. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
A 13-year-old neutered, blue-eyed female Siamese cat with a bodyweight of 4.8 kg was admitted for enucleation of the right eye. An ultrasound guided retrobulbar block with 1 mL of ropivacaine was performed under general anaesthesia. When the tip of the needle was visualised inside the intraconal space, negative aspiration of the syringe before injection and no obvious resistance during injection were confirmed. Instantly, after ropivacaine was administered, the cat became apnoeic, and its heart rate and the blood pressure increased significantly for a short period of time. During surgery, the cat needed cardiovascular support to maintain blood pressure and was under continuous mechanical ventilation. Spontaneous breathing returned 20 min after the end of anaesthesia. Brainstem anaesthesia was suspected, and after recovery, the contralateral eye was examined. A reduced menace response, horizontal nystagmus, mydriasis, and absence of the pupillary light reflex were present. The following day, mydriasis was still present, but the cat was visual and was discharged. The inadvertent intra-arterial injection of ropivacaine was suspected to be the cause of the spread into the brainstem. To the current authors' knowledge, possible brainstem anaesthesia has only been reported in a cat 5 min after a retrobulbar block but never instantly. brainstem anaesthesia cat retrobulbar block intraarticular injection This research received no external funding. pmc1. Case Presentation A 13-year-old neutered, blue-eyed female Siamese cat with a bodyweight of 4.8 kg was scheduled for enucleation of the right eye due to panuveitis and secondary glaucoma. The menace response and dazzle reflex were normal on the left eye. Apart from being geriatric, the cat had no other comorbidities in her clinical history. Her preoperative clinical examination was normal without any nystagmus noticed or reported during her ophthalmological examination, and her biochemistry and haematological results were unremarkable. The cat's current medications included meloxicam and chloramphenicol ointment. For preanaesthetic medication, a combination of methadone (0.2 mg/kg) (Methadyne, Jurox, Leatherhead, UK), midazolam (0.3 mg/kg) (Hameln pharma Ltd., Gloucester, UK), and alfaxalone (1.5 mg/kg) (Alfaxan/Multidose, Jurox, Dublin, Ireland) was mixed in the same syringe and administered intramuscularly (IM). Anaesthesia was induced with a total of 1.8 mg/kg of alfaxalone administered through a right cephalic intravenous cannula. Intravenous fluid therapy was administered during anaesthesia at a rate of 3 mL/kg/h (Hartmann's solution; Aquapharm No. 11; Animalcare LTD; York, UK). Anaesthesia was maintained with sevoflurane (Sevohale, Chanelle, Galway, Ireland) in 100% oxygen administered through a Mapleson-D breathing system. Throughout anaesthesia, heart rate and rhythm with electrocardiography, haemoglobin oxygen saturation (SpO2), oscillometric blood pressure, oesophageal temperature, capnography, and spirometry were continuously monitored and recorded every 5 min using a multiparameter monitor (Datex-Ohmeda, GE, Helsinki, Finland). A retrobulbar block (RBB) was used as part of a multimodal analgesic plan. Following aseptic preparation of the periocular area and the area dorsal to the zygomatic process, an ultrasound (US)-guided RBB was performed using a 14 MHz linear transducer connected to a portable ultrasound device (Mindray bio-medical electronics Ltd., Shenzhen, China). Sterile ocular gel was applied to the globe, and the US transducer was placed over the cornea with the marker positioned laterally. The orientation was initially perpendicular to the transverse plane and parallel to the dorsal plane of the globe, and then it was oriented with an angle of 30deg approximately relative to the dorsal plane in order to position the US marker towards the junction between the zygomatic arch and the orbital ligament laterally. The depth and focus of the US were adjusted to achieve a good view of the retrobulbar space, the cone, and the optic nerve. The retrobulbar compartment was identified as a conic shape formed by the extraocular muscles positioned caudally to the eyeball. A 22 gauge, 50-mm ultrasound needle with extension tubing (USB 50 EVOLUTION, Temena GmbH) was introduced using a supra-temporal approach . The needle was inserted perpendicularly to the skin and oriented latero-medially behind the orbital ligament, dorsally to the zygomatic process of the temporal bone and ventral to the frontal bone, through the temporal muscle. When the tip and part of the needle were identified ultrasonographically using an oblique in-plane approach, the needle was advanced latero-medially to reach the intraconal space by crossing the extraocular muscles. In this case, the needle was visualised to go through the cone and appear in the medial aspect of it; therefore, it was slightly retracted until it was inside the cone again. At this level, negative pressure was applied to the syringe to exclude blood vessel penetration, and 1 mL of ropivacaine 0.75% (Naropin, Apen Pharma Trading Limited 0.75%, Dublin, Ireland) was injected without obvious resistance. The maximum recommended dose of ropivacaine of 2 mg/kg was calculated to be 1.28 mL . Immediately after the injection and before the needle had been removed, the cat became apnoeic. After a minute of apnoea, manual ventilation was initiated. At the same time, there was an immediate rise in the cat's heart rate (HR) from 102 to 140 bpm with a sinus rhythm. Unfortunately, there is no record of the concurrent blood pressure (BP), but we recall that it increased in parallel with the heart rate. Twenty minutes later, the cat was transferred to the operating theatre, and continuous mechanical ventilation (CMV) on a volume control mode was initiated using a veterinary ventilator (Merlin, Vetronic Services LTD, Devon, UK). During this time, no parameters were recorded on the monitoring sheet as the anaesthetist was involved in providing manual ventilation, but when the cat was moved to theatre, the blood pressure could not be measured with oscillometry or the flow Doppler technique. By that time, it was suspected that the administration of the local anaesthetic (LA) in the retrobulbar space could have been responsible for the occurrence of apnoea and the instability of the HR and BP. When the surgery started, the mean BP (MBP) was 50 mmHg, and the HR was 75 bpm. A dose of 0.01 mg/kg of glycopyronium (Accord Healthcare Limited, Durham, UK) was administered intravenously (IV) and was repeated after 5 min as there was no effect. Due to the lack of response to the anticholinergic, a dose of 0.1 mg/kg of ephedrine (MaCarthys Laboratories, Martindale Pharma, Brentwood, UK) was administered IV, and this was repeated again after 10 min, after which the MBP increased to 80 mmHg but only temporarily. The HR remained at levels >100 bpm after the above interventions, while the MBP increased again only after a dopamine (Martindale Pharma, UK) IV infusion at a dose of 5 mg/kg/min was initiated. During the whole anaesthetic, the SpO2 and the EtCO2 were maintained within the acceptable limits, while the oesophageal temperature was 34-36 degC. Anaesthesia ended at 75 min after induction, and the cat remained apnoeic. Twenty minutes following inhalant discontinuation, the cat was still apnoeic, and a decision was made to reverse the midazolam with 0.01 mg/kg of flumazenil IV (Hamlen Pharma gmbh, Gloucester, UK). The cat responded immediately and started breathing spontaneously following the administration of flumazenil. Dopamine was discontinued after extubation, as the cat was able to maintain MBP > 80 mmHg. During surgery, the cat lost approximately 29 mL of blood, which was 10% of her estimated total blood volume (4.8 kg x 60 mL/kg = 288 mL). On recovery, the cat remained on Hartman's solution at a rate of 3 mL/kg/h until the volume lost was replaced. After the cat had fully recovered, an ophthalmological examination of the left eye revealed a reduced menace response, horizontal nystagmus, mydriasis, and absence of the pupillary light reflex (PLR). The rest of the clinical examination was normal. She was responsive to stimulation and had a good appetite. The Glasgow Feline Composite Measure Pain Scale scores were between 0 and 2 postoperatively. The following day, she had a normal menace response, subtle horizontal nystagmus, mydriasis, and the PLR was present. The cat returned home on the day after surgery. One week later, at the follow-up examination, the left eye had a normal menace response, no nystagmus, a slightly larger than normal resting pupil size but was less mydriatic than postoperatively and within the normal limits for a blue-eyed Siamese cat, and with the PLR present. The owner reported no concerns, and the patient was discharged. 2. Discussion Regional anaesthesia of the eye is commonly applied in veterinary patients to provide analgesia during painful procedures, such as enucleation, or for akinesia of the extraocular muscles, which results in the globe maintaining a central position . Additionally, it reduces the incidence of the oculocardiac reflex during enucleation surgery by blocking the ophthalmic branch of the trigeminal nerve and the ciliary ganglion, as has been described in horses . The RBB and peribulbar blocks (PBB) are two different types of regional anaesthesia techniques in which the LA is either deposited in the retrobulbar or in the peribulbar space, respectively, with the final aim being for the LA to reach the intraconal space. The intraconal space is within the retrobulbar cone, and in the dog, the latter is formed by the ocular extrinsic muscles: the dorsal, ventral, lateral, and medial rectus muscles, the retractor bulbi with its four fascicles, and more superficially and medially, the dorsal oblique muscle . There is no fascia surrounding the muscles that form the cone. Within the retrobulbar cone are the ophthalmic nerve, the ciliary nerves, the optic nerve, the oculomotor nerve, and the abducens nerves. Additionally, the internal ophthalmic artery and the ciliary arteries run in the same space . Different techniques have been described for both blocks . In dogs, among other blind approaches to the RBB, the inferior-temporal-palpebral and the supra-temporal approaches have been described in cadavers. In one study with sedated dogs, the peribulbar technique was shown to be more reliable for producing anaesthesia than the RBB when using a bent needle inserted through the inferior eyelid . However, both methods produced adverse effects such as exophthalmos, chemosis, and anterior uveitis, which had resolved 14 h later . In cats, Shilo-Benzamini et al. described a superior-nasal approach for the retrobulbar block through the upper eyelid at the dorsomedial orbit using a curved needle. This was found to have a 70% success rate in cadavers, but this was only 50% when tested in sedated cats . Ultrasound-guided ophthalmic regional anaesthesia has been used recently in human ophthalmology, as it has the advantage of allowing visualisation of the retrobulbar structures and the needle at the same time as well as confirmation that the LA has been administered in the correct space. According to our knowledge, thus far, only extraconal deposition of the LA has been described in dog cadavers with US guidance . An US-guided PBB was shown to be as effective as a blind technique in anaesthetised dogs, although the dogs receiving the blind technique had a higher incidence of increased intraocular pressure (IOP) due to the possible wrong positioning of the needle, as the authors hypothesised . In cats, an US-guided RBB with a trans-palpebral approach, as mentioned above, was effective in only 50% of the animals , possibly due to "the difficulty in identifying the curved needle tip", as commented by the author in a review article on regional ophthalmic anaesthesia . More recently, the authors of a case report on a cat with microphthalmia described the use of an US-guided RBB using a modified technique similar to the supra-temporal approach, but in this case, the needle was introduced into the retrobulbar space from the subzygomatic area . Advocates of the PBB highlight the reduced risk of complications, such as the distribution of the LA in the central nervous system (CNS), retrobulbar haemorrhage, and globe penetration, compared to the RBB, as the needle is inserted further away from these structures . Indeed, the reported incidences of CNS complications in humans after a RBB are 0.09%, 0.27%, and 0.9% , whereas a much lower incidence of 0.007% has been reported with the PBB; however, the authors concluded that this incidence is probably underestimated . In veterinary patients, the incidence of complications is unknown. Only one case has been reported in a cat with suspected brainstem anaesthesia that occurred 5 min following the injection of LA into the retrobulbar space using a blind technique . The technique routinely performed at our hospital is the US-guided RBB using a supra-temporal approach with intraconal deposition of the LA. This preference is due to the perceived greater success rates when an US-guided technique with an in-plane approach is used and the correct deposition of the LA can be visualised. Additionally, a smaller volume of LA is necessary, as it is injected inside the cone. Humans receive regional ophthalmic blocks while awake, and the side effects vary from contralateral pupil dilation to amaurosis, convulsions, grand-mal seizures, hypertension/hypotension, tachycardia/bradycardia, and cardiopulmonary arrest . In veterinary medicine, the side effects reported in one cat following RBB were apnoea, increased HR and systolic blood pressure initially, and a reduction in blood pressure below normal values during surgery . A delay in recovery was also noticed, and after extubation, the cat presented with nystagmus, absence of the menace response, mydriasis, a lack of dazzle, and a negative PLR in the contralateral eye. There are three main potential mechanisms whereby a RBB or PBB may lead to CNS complications. First, these can occur due to penetration of the sheath of the optic nerve and the entry of LA into the subarachnoid space of the brainstem . If this occurs, symptoms appear 5 to 10 min after injection, depending on the onset of action of the LA. The second mechanism is through the inadvertent injection of the LA into the internal ophthalmic artery. The pressure of the injectate forces the LA to flow back into the internal carotid artery and into the brain. In such cases, clinical signs appear rapidly . Thirdly, complications can occur due to the systemic absorption of the LA . In the case presented here, tachycardia, hypertension, and apnoea appeared instantly before the removal of the needle, and the cat remained mechanically ventilated until recovery. No obvious resistance was noticed during the injection, and the needle did not seem to have penetrated the optic nerve on the US image. Given the rapid onset of the clinical signs, CNS spread of the local anaesthetic exclusively through penetration of the sheath of the optic nerve is less likely. Unfortunately, there are no saved images to corroborate this, as it is not common practice to save images for every patient, especially in routine cases. Similar to our case and to the other case report from a cat, the first manifestations of CNS spread in humans are often hypertension and tachycardia. This can be explained as a parasympathetic blockade through a combined vagal and carotid sinus reflex block . Although the immediate onset of symptoms in our case is in favour of inadvertent intra-articular injection, no blood appeared during the application of negative pressure to the syringe. Additionally, one would expect the duration of the symptoms to be transient due to the rapid redistribution of blood out of the brain, but this was only the case for hypertension and tachycardia. However, the cat remained apnoeic during the whole anaesthetic procedure and for 20 min after the end of anaesthesia. In dogs, the internal ophthalmic artery runs on the dorsal surface of the optic nerve . To the best of our knowledge, there is no published description of the ophthalmic vasculature in cats that mentions the exact pathway of the internal ophthalmic artery. In humans, because of an anatomical variation in the inferior ophthalmic artery in 15% of the population, there is a higher risk of inadvertent intra-arterial injection . The use of colour-flow Doppler could have helped us to identify the artery and avoid a possible intra-arterial injection of the LA, but this was omitted before the administration of ropivacaine. The rapid systemic absorption through the local capillaries could also explain this clinical presentation. However, the total dose administered (1 mL) was less than the maximum recommended dose in cats . The possibility that some of the LA was injected intra-arterially and some reached the subarachnoid space through penetration of the sheath could explain the quick onset of symptoms in combination with the increased duration of apnoea. In a similar case report in a human, an intra-arterial injection was suspected due to the instant occurrence of CNS toxicity. The same patient remained apnoeic for 40 min after seizures had resolved. The authors speculated that systemic absorption from the local capillaries or the spread of the LA in the subdural space along with the optic nerve could explain the sustained respiratory arrest . Following recovery from anaesthesia, the cat in the present case report had symptoms in the contralateral eye that could potentially be explained by brainstem exposure to the LA . Although nystagmus may be present during recovery from anaesthesia and opioids cause mydriasis in cats, the above symptoms were still present the following morning, although to a lesser degree. In contrast with humans, where convulsions or seizures are common, the cat in this report did not show any twitches, probably because general anaesthesia was masking this response. It is not clear why, upon administration of flumazenil, the cat started breathing spontaneously immediately, as midazolam causes minimal respiratory depression, and it did not compromise ventilation after administration in our case. However, when diazepam is administered with buprenorphine in rats, respiratory depression has been reported to be greater . Potentially, the impact of benzodiazepines on central ventilatory control after CNS dysfunction, as occurred in our case, is more pronounced compared with in a normal CNS. Additionally, the use of flumazenil has been reported to reduce the recovery time from anaesthesia in humans when no benzodiazepines have been administered . It is unknown as to whether it was the pharmacological action of flumazenil or the time that had elapsed since the retrobulbar block that caused the return to spontaneous breathing. Lipid emulsion therapy has been proven to be effective for treating local-anaesthetic-induced systemic toxicity , including a case of local-anaesthetic-induced seizures after a peribulbar block in humans . When brainstem anaesthesia was suspected in our case, the administration of a lipid emulsion could have potentially helped to resolve the cardiovascular and respiratory complications. 3. Conclusions We have presented a case report of a potential exposure of the CNS to ropivacaine after an US-guided RBB in a cat that showed sustained apnoea, cardiovascular instability, as well as nystagmus, mydriasis, and an absent PLR postoperatively in the contralateral eye. The early onset of symptoms, prior to needle withdrawal, indicates that an inadvertent intra-arterial injection of the LA was the possible cause, although we cannot exclude subarachnoid injection or a combination of the two. Although an US-guided technique was used and negative pressure was applied before the injection, this complication could not be avoided, and we highlight the importance of using colour-flow Doppler for better visualisation of the vasculature. Any medications that can be reversed could be beneficial for similar cases. Author Contributions Conceptualisation, A.P. and E.R.; writing original draft preparation, A.P.; writing review and editing, E.R.; supervision, E.R. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement The presented case is not a prospective study and for that reason does not require ethical approval. The owner of the animal in the presented case gave consent to anonymously share the details of the case for publication purposes. Please see a blank consent form attached to the nonpublished materials section. Informed Consent Statement Informed consent was obtained from the owner of the animal involved in the case report. Data Availability Statement The presented case report is not a study, and no data were collected. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Animals (Basel) Animals (Basel) animals Animals : an Open Access Journal from MDPI 2076-2615 MDPI 10.3390/ani13050805 animals-13-00805 Editorial Editorial: Role of Non-Coding RNAs in Animals Do Duy Ngoc 12* Suravajhala Prashanth 34* 1 Faculty of Veterinary Medicine, Viet Nam National University of Agriculture, Hanoi 100000, Vietnam 2 Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N 5E3, Canada 3 Bioclues.org, Hyderabad 500072, India 4 Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana 690525, India * Correspondence: [email protected] (D.N.D.); [email protected] (P.S.) 23 2 2023 3 2023 13 5 80526 12 2022 10 1 2023 21 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcThe importance of non-coding RNAs (ncRNAs), such as microRNAs (miRNA), long non-coding RNAs (lncRNA), and circular RNAs (circRNA), in gene regulation is increasingly being appreciated in many species. Thanks to the next generation of sequencing methods, thousands of ncRNAs have been identified in different livestock species and their functions are undergoing characterization. Clearly, ncRNAs are involved in many gene regulation processes and pathways related to economically important traits in livestock species . In addition, ncRNAs are also considered to be potential biomarkers for infectious diseases in different farm animal species . This Special Issue contains 13 articles summarizing the diverse roles of ncRNAs in livestock . In particular, we report on different species of animal that have been used to study the functions of ncRNAs. These include chicken , pigs , goats , sheep , cattle , mice , and insects . Exploring the expression of ncRNAs in different biological conditions is an important step in understanding their function. Bo et al. identified 20,269 lincRNAs, including 16,931 novel lncRNAs, expressed in the testes of Yiling goats. The authors also suggested that ENSCHIT00000000777, ENSCHIT00000002069, and ENSCHIT00000005076 were the key lincRNAs in the process of testis development, a fact derived via co-expression analyses. Gan et al. used RNA sequencing to identify 302 miRNAs expressed in pig umbilical venous blood (UVB) and umbilical arterial blood (UAB). As a result, 106 and 22 miRNAs were specifically expressed in the UVB and UAB, respectively. The authors also suggested that miR-423 and miR-122-5p can be used as characteristic miRNAs of UVB and UAB, respectively. Hao et al. performed RNA-Seq to study the roles of lncRNAs in the mammary glands of lactating Small-Tailed Han (STH) ewes and Gansu Alpine Merino (GAM) ewes. The authors identified 1894 lncRNAs that were differentially expressed, among which 31 and 37 lncRNAs were up and downregulated respectively, when comparing STH ewes with GAM ewes. In addition, the authors also found that the development and proliferation of mammary epithelial cells via the enrichment of the target genes, followed by the morphogenesis of the mammary gland, ErbB signaling pathway, and Wnt signaling pathway could be important for mammary gland and milk yield regulation. To explore the function of lncRNAs in pig spleens at different stages of development, Li et al. profiled the systematic characters of mRNA and lncRNA repertoires in three groups of spleens from nine Yorkshire pigs, with three aged seven days, 90 days, and 180 days, respectively. The authors identified 19,647 genes in addition to 219 known and 3219 putative lncRNA transcripts; 1729 genes and 64 lncRNAs therein were found to express differentially. The authors also found that differentially expressed genes and the potential target genes of differentially expressed lncRNAs both performed the crucial roles of up-regulation in immune activation and hematopoiesis, and down-regulation in cell replication and division, in 180-day-old pigs compared to seven-day-old pigs. MiRNAs are the most well-studied molecules in the ncRNAs. Several studies contained within this Special Issue attempt to validate their functions. Guo et al. indicated the potential roles of miR-149-5b in the regulation of bovine adipocyte differentiation . Xu et al. show that, by targeting PTEN, MicroRNA-148a can regulate the proliferation and differentiation of ovine preadipocytes. Qiao et al. provided evidence of the role of miR-F4-C12 50 in the regulation of adipose accumulation, finding that it performed this role by targeting PIK3R1 in castrated male pigs . Wang et al. identified 852 known miRNAs and 179 novel miRNAs in female ICR mice mammary glands at the virgin stage, day 16 of pregnancy, day 12 of lactation, day 1 of forced weaning, and day 3 of forced weaning. The authors also discovered a novel miRNA (novel-mmu-miR424-5p) involved in regulating the expression of the CSN2 gene. Other studies also validated the function of circRNAs and lncRNAs . Regarding the circRNA function, Wang et al. indicated that circEZH2 can sponge miR-378b to regulate milk fat metabolism , while Shen et al. showed that circular PPP1R13B can target miR-9-5p to promote chicken skeletal muscle satellite cell proliferation and differentiation . Lastly, via RNA sequencing and the follow-up validation, Jian et al. confirmed that the roles of lncPGC in the regulation of primordial germ cell formation in chickens were mediated by TCF7L2. This Special Issue focused not only on livestock species but also on the roles of lncRNAs in insects. Choudhary et al. provided an updated review of the functions and molecular mechanisms of the mode of action of different insect lncRNAs. Taken together, these contributions enlighten the research community on contemporary breakthroughs and suggest approaches for performing future functional studies of the regulatory roles of ncRNAs in animals. We anticipate that both expert scientists and readers can benefit from the state-of-the-art studies addressing the roles of ncRNAs contained within this Special Issue. Acknowledgments We would like to thank all the authors who contributed their papers to this Special Issue. Author Contributions D.N.D. and P.S. wrote and edited the original draft of the manuscript. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Williams A. Functional aspects of animal microRNAs Cell. Mol. Life Sci. 2008 65 545 562 10.1007/s00018-007-7355-9 17965831 2. Weikard R. Demasius W. Kuehn C. Mining long noncoding RNA in livestock Anim. Genet. 2017 48 3 18 10.1111/age.12493 27615279 3. Miretti S. Lecchi C. Ceciliani F. Baratta M. MicroRNAs as biomarkers for animal health and welfare in livestock Front. Vet. 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As one of the most abundant game species in Europe, European wild boar (Sus scrofa) populations prove highly adaptable to cultivated landscapes. The ongoing process of climate change and the high agricultural yields seem to further optimize the living conditions for this species. In long-term reproduction monitoring, we collected data on the body weight of wild boar females. Over an 18-year period, the body weight of wild boar females increased continuously, then stopped and decreased. It was possible to detect differences between the body weights of animals from forest and agricultural areas. For these areas, differences in body weight development also led to a significant distinction in the onset of puberty. We conclude that, even in a highly cultivated landscape, forested areas provide habitat characteristics that may strongly influence reproduction. Second, with dominant agricultural areas in Germany, wild boar reproduction has been favored in recent decades. Sus scrofa reproduction weight increase habitat climate factors Ministry of Food, Agriculture and Consumer Protection of Lower Saxony, Germany (Niedersachsisches Ministerium fur Ernahrung, Landwirtschaft und Verbraucherschutz)Verein der Forderer der Wildtierforschung an der Stiftung Tierarztliche Hochschule Hannover e. V.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)491094227 University of Veterinary Medicine Hannover, FoundationThis research was funded by the Ministry of Food, Agriculture and Consumer Protection of Lower Saxony, Germany (Niedersachsisches Ministerium fur Ernahrung, Landwirtschaft und Verbraucherschutz) and by "Verein der Forderer der Wildtierforschung an der Stiftung Tierarztliche Hochschule Hannover e. V." This Open Access publication was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) 491094227 "Open Access Publication Funding" and the University of Veterinary Medicine Hannover, Foundation. pmc1. Introduction The wild boar (Sus scrofa) is a popular and widely abundant game species , and populations have increased throughout Europe in recent decades . It is an opportunistic omnivore with a high adaptability to changing environmental conditions . The wild boar has by far the highest reproductive potential and fecundity of all ungulate species worldwide in relation to its body mass . Combined with a low natural adult mortality rate in temperate climates , it can achieve high population densities in a very short time period . Due to its increasing population, it has become a very important species from an economical point of view . It can transmit diseases (like the African swine fever) to livestock and cause damage to agriculture . Several aspects that contribute to wild boar population growth have been studied and discussed. Among them, the most important factors are a reproductive success or lower juvenile mortality due to optimal feeding and mild climatic conditions . Several parameters of wild boar reproductive biology, such litter size , sex ratio and parturition time (unpublished own data) are positively related to maternal body weight. A body weight increase in free-living wild boar populations was reported from different European habitats , arising the question if similar developments could be observed from study areas situated in parts of Germany that were dominated by a high extent of cultivated landscape. Therefore, the aim of this research was to investigate whether the body weight of female wild boars in some areas of northern Germany increased over an 18-year period and whether the increase in body weight was different among age classes and habitats. Here, the influence of external (e.g., climate and mast) and internal (e.g., age and maturity) factors on body weight was tested, and, in addition we also tested for a possible effect on the onset of puberty. We hypothesized that body weight increased in all age classes over the years and that comparisons between forest and agricultural habitats showed a greater weight increase in the latter. 2. Materials and Methods 2.1. Study Area The study area was situated in the East of the federal state of Lower Saxony (northern Germany) (52.36deg N, 10.35deg E) and comprised about 5500 km2 with altitudes ranging from 60 to 130 m asl . Based on data from the German Meteorological Service, the average annual temperature since 2000 was 9.7 degC, and the average annual precipitation was about 800 mm. The trend of mean temperature is increasing, and mean precipitation is decreasing . The study area comprised either forestal-agricultural habitats (fah) or represented a large contiguous forestal habitat . Within the total area, one large block of forest (430 km2) was interpreted as a separate territory, containing only 3% of agricultural areas, and thus, agricultural food was available for wild boars only to a limited amount. Forest composition was almost the same as in the total area, while the forested area additionally comprised 2% of heathland and 5% of settlement and infrastructure. This area could be interpreted as forestal habitat , while the agriculturally dominated part of the study area was about 5500 km2, with 61% auf agricultural areas and 22% of forest. The remaining 17% were buildings and infrastructure. The agricultural land was characterized by 80% of energy-enriched products (e.g., grain, sugar beets, oilseed, rape, maize, leguminoses and potatoes) in 2020. The remaining 20% consisted of heathland, fallow land and horticultural products . Since 2007, only slight changes within the different field crops were reported . The forest consisted of 18.9% oak (Quercus spp.), 11.2% beech (Fagus sylvatica), 7.6% other deciduous trees (e.g., Betula spp, Acer spp., Tilia spp., Sorbus aucuparia), 45.5% pine (Pinus spp.) and 16.6% other coniferous trees (Larix spp., Picea abies, Pseudotsuga menziesii). 2.2. Data Collection Data were collected from 3517 free-ranging hunted wild boar females in the study area during the hunting years from 2003 until 2020. Each hunting year (indicated as "year" in the following text) started in April and ended in March. Since the majority of samples derived from November-January, we focused our analyses on these months of the hunting year (n = 3.367, Table 1). The age of the wild boar females was identified by tooth determination . Following the age identification, female wild boars were grouped into three classes (n = 2024 piglets: <=12 months; n = 866 yearlings: >=13-24 months; n = 477 adults: >=25 months, Table 1). Their dressed body weight (without digestive system, heart, lungs, liver, reproductive tract, and blood, hereafter "bw") was recorded. Dissection and examination of the reproductive tract (uterus and ovaries) was performed according to our own protocols . Consequently, the onset of sexual maturity was assumed when ovaries had follicles >=0.4 cm in diameter. 2.3. Statistical Analysis We described with Tukey's Honest Significance Difference (HSD) test differences between mean bw in the three age classes both overall and within the two habitat types. Then, we used generalized linear models (GLM, ) with identity link to analyze the development of bw over the hunting years, including age class, habitat type, tree crop and weather variables (Table 2). Explanatory variables were checked for correlations among each other , but multicollinearity did not affect our analyses, as checked by correlations and variance inflation. Testing for both linear and unimodal relationships with the dependent variable (bw), we used the AIC (Akaike Information Criterion) from univariate models with each numerical weather variable to decide about their inclusion in the GLM. We stopped when adding a new variable did not result in a lower AIC value. We also included the hunting index as a measure of hunting intensity for each hunting year. We used a GLM with logit link and binomial error structure to find predictors of wild boar puberty. All analyses were performed using R software version 4.1.0 . 3. Results 3.1. Overall Body Weight Tukey's HSD test revealed highly significant differences between age classes in the whole sample. Mean bw for piglets, yearlings, and adults was 27.6 kg [sd 8.6, n = 2024], 54.0 kg [sd 10.5, n = 866] and 66.7 kg [sd 12.9, n = 477], respectively. In all age classes, we found an increase in bw that resulted in significant differences between some months, following a seasonal pattern during autumn and winter. A bw difference (diff) between November and January was significant in yearlings (Tukey's HSD test: p = 0.05, diff = -2.3 kg) and adults (Tukey's HSD test: p < 0.01, diff = -4.2 kg). In piglets, there was a significant bw difference between November and December (Tukey's HSD Test: p < 0.0001, diff = 3.1 kg) and, like in the other two age classes, between November and January (Tukey's HSD Test: p < 0.0001, diff = -3.9 kg). The weight increase in piglets from November to December was especially pronounced in the fh (diff = 5.0 kg) and, to a lesser extent, in the fah (diff = 2.3 kg). 3.2. Effect of Habitat on Body Weight Mean bw was higher in fah compared to fh habitats . The difference of 2.8 kg was significant (Tukey's HSD p > 0.01). Differences between habitat types were particularly pronounced in yearlings. In this age class, the mean bw of animals from the agricultural habitat was 8.0 kg higher than that from forest habitat (Tukey's HSD p > 0.01). In piglets and adults, the weight difference between habitats was 5.2 kg and 5.5 kg, respectively. 3.3. Temporal Trends in Body Weight and External Factors Bw differed per age class and habitat, but the overall trend was similar in both factor variables. In all models, the relationship of bw with hunting year was best described by a fourth-order polynomial that visually suggested a slight increase until about 2017, followed by a decrease until 2020 . Fluctuations in bw were more pronounced for wild boar in fh. Strong beech mast benefited especially adult animals in fh , while oak mast did result in differences in bw without any significance. Among all age classes, climate factors such as frost periods in February negatively affected bw, while higher precipitation in May and July had a positive impact . The inclusion of the hunting index further improved the final model, with the bw being negatively correlated with this predictor of hunting pressure , which was again true for all age classes. 3.4. Predictors of Wild Boar Puberty In our data, piglets reached puberty approximately at a bw of 30 kg, and in fh, this was achieved at an age of 11 months, whereby piglets of fah seemed to achieve the crucial body weight at a lower age, i.e., about 8-9 months . As a result, in fah, 80 percent of the 8-month-old piglets had already reached puberty, while in forest areas, only 64 percent did. In years with beech masts, the probability of puberty was slightly higher than in years without mast . 4. Discussion During the last years, a permanent weight increase in female wild boars of all age classes in Lower Saxony culminated in 2017 and decreased from thereon for unknown reasons, therefore, partly supporting our hypothesis on a permanent weight increase of the species in the wild. The unexpected halt and decrease in body weight might be in line with extremely arid summers occurring since 2018 in the region . By highlighting a significant distinction of body weight between animals from forestal (fh) vs. agricultural (fah) habitats, our second hypothesis proved right. In Poland, a similar increase of wild boar body weight has been reported, and the distance to forestal areas also turned out to be a significant factor . Interestingly, the difference in body weight has an additional impact on puberty achievement, and here, mast seeding events significantly improve the condition of animals situated in forestal habitats. This is supporting our results from earlier studies, indicating that the occurrence of splendid masts of oak or beech result in a higher reproductive outcome, especially in forestal areas . Additionally, the precocious puberty of female and male wild boars in our study area supports the theory of a high share of piglets in reproduction. Anyway, the proven distinction of habitats longs for discussion. Various studies reflect that wild boars' spatial behavior is highly adaptive and diverse , especially among different European countries . In our study, we focused on adjacent areas of agricultural habitats and woodland, where the woodland was characterized by its consistency. We assume that wild boar populations inhabiting agricultural areas near the edge of the forest habitat do enter it and vice versa but that the majority of the animals inhabiting the pure forest area is concentrating on the forest, which is also providing enough forage, especially under climate change conditions . This is supported by the fact that puberty is reached by piglets inhabiting agricultural dominated areas at lower ages, while mast occurrence influences the onset of puberty, especially among forest-inhabiting animals. While the hybridization of domestic pigs and wild boars might lead to an adjustment in reproductive traits in the latter, there is no indication that hybridization might be responsible for the habitat-dependent differences we found in this study. In Europe, hybridization mainly occurred during the outside feeding of domestic pigs in the Roman Empire and Middle Ages , and in some countries, it was also observed after World War II or even recently . A wide variation in the degree of ongoing hybridization in European countries is stated, referring to the type of pig farming as one explaining factor . In this context, Germany is one of the countries where industrial pig farming is most common and, therefore, ongoing hybridization is less likely. Nevertheless, the differences in the reproductive performance of wild boars between Northern and Southwestern Germany that were found in former studies were not tested for differences in hybridization with domestic pigs so far , and studies that precisely perform German wild boar genome analyses would certainly be helpful to interpret reproduction in this species more accurately. While both sexes of wild boars seem to reach puberty on highly weight-dependent conditions and have gained weight continuously over the last years, it was surprising to observe that mast seeding events in forestal habitats appear to additionally influence the onset of puberty. The meaning of mast seeding events for wild boar reproduction is controversially discussed, and although, e.g., wild boars in France also seem to respond to mast seeding events positively through a higher breeding proportion, the effect seems to be caused mainly by their weight increase . This could be due to the difference in habitats, with the French Mediterranean forest seemingly serving as a main feeding source for wild boars , while our study area has been dominated by agricultural land use from the beginning of the monitoring. The high adaptability of wild boars might lead to aligned feeding strategies, in which the occurrence of mast seeding events might not provoke an imminent increase of body weight but resolve in a short-time adjustment of body fat and fatty acids, discussed as "flush feeding" in pigs , that also seems to have different outcomes depending on the timing and reproductive status of the animals . Few large contiguous forestal habitats are situated in Northern Germany, and with climate change, the persistence of comparable forests is threatened . Whether additional reproductive parameters, such as the time of farrowing and litter size of wild boars, will also prove to be habitat-dependent in our study areas will, therefore, be part of our future research. An additional impact could be shown for various external factors, such as precipitation in June and frost periods in February, leading to diminished body weights, whereas higher temperatures in March and April, as well as precipitation in May, were improving body weight. It seems reasonable that cold periods in February, with possibly farrowing females or piglets among the rut, lead to a reduced body weight of a high percentage of animals. Potentially, animals will search for shelter and be less active in foraging . Likewise, it can be assumed that strong precipitation in June may lead to crop failure or at least poor harvests as a consequence and thus also results in a decrease in body weight. The meaning of seasonality in wild living species is an important topic in wildlife research , and in the wild boar, questions about reproductive seasonality still remain unsolved . Additionally, little is known for weight development of wild boars in other European habitats, and further research can be helpful to evaluate the importance of these factors in Europe's future climate. 5. Conclusions Within a long-term study on the reproduction of female wild boars, we were able to gain outstanding results on basic features such as body weight development and received valuable insights on the impacts of external and internal factors on puberty. We, therefore, explicitly propose to establish long-term monitoring of wildlife species to a far greater extent. Acknowledgments We would like to thank The Forestry Seeds Advisory Board (FSB) at Oerrel, Lower Saxony, the Forestry Commission Offices in Lower Saxony, the state office for statistics (NLS), and the German Meteorological Service (DWD) for providing their data. We want to further thank all the hunters for their cooperation and help in collecting data, especially the Forestry Commission Offices Oerrel, Unterluss and Wolfenbuttel as well as the "Verwaltung Gunther Graf v. d. Schulenburg". Special thanks belong to Angelika Niebuhr for her support and care of the database and to all the volunteers, students and ITAW staff who helped to collect samples throughout all the years. Author Contributions Conceptualization, F.G. and O.K.; methodology, F.G.; software, T.L.; validation, T.L., O.K. and F.G.; formal analysis, F.G.; investigation, F.G. and C.M.; resources, U.S.; data curation, F.G.; writing original draft preparation, F.G.; writing review and editing, C.M. and O.K.; visualization, T.L.; supervision, U.S.; project administration, F.G. and O.K.; funding acquisition, F.G. and O.K. All authors have read and agreed to the published version of the manuscript. Institutional Review Board Statement Ethical review and approval were waived for this study due to animals' origin from regularly performed hunting. Informed Consent Statement Not applicable. Data Availability Statement Data for land use and climate are available online via and (accessed on 1 February 2023). Conflicts of Interest The authors declare no conflict of interest. Figure 1 Map of Germany (left), indicating the site of the study area in Lower Saxony, Germany (right part of the figure), showing forestal-agricultural habitat (fah, outlined in orange) around the large contiguous forestal habitat (fh, outlined in green) where wild boar females of this study were sampled. Figure 2 Bw (weight) of wild boar females (all ages) increased with hunting year until about 2017, followed by a decline that was less pronounced in agricultural dominated habitat fah (n = 2837). Figure 3 Strong beech mast (numbers represent levels according to categorization from forestry commission office Oerrel, Lower Saxony; 1 = no, 2 = part, 3 = half, 4 = full mast) resulted in (significantly) positive effects on bw only for adult wild boar females in fh (n = 680, p = 2.77 x 10-7 for beech = 4, age = adult, habitat = fh). Figure 4 Bw (weight) of wild boar females of all ages was negatively influenced by days of frost in February (FrostFeb), lower precipitation in May (Nmai, precipitation in mm) and July (Njuli, precipitation in mm) and strong hunting pressure (HI, ratio of hunting bag/hunting area). Figure 5 Different probabilities of puberty in the two landscape types (forest = fh, agriculture = fah), as described by age of piglets. Figure 6 Probability of puberty slightly decreased with increasing overall bw over years (left) and slightly increased with beech mast (right; numbers represent levels according to categorization from forestry commission office Oerrel, Lower Saxony; 1 = no, 2 = part, 3 = half, 4 = full mast). animals-13-00898-t001_Table 1 Table 1 Distribution of wild boar females according to age and habitat. Habitat Piglets Yearlings Adults Habitat Total fh 306 184 103 593 fah 1718 682 374 2.774 total 2024 866 477 3.367 animals-13-00898-t002_Table 2 Table 2 Predictors of wild boar body weight used in this study. Variable Measure/Explanation Year numerical (2003-2020) Age class three nominal levels: piglets, yearlings, adults Habitat two nominal levels: forested (fh), agricultural (fah) Oak crop four ordinal levels: (1-4) Beech crop four ordinal levels: (1-4) Precipitation monthly sum in mm Temperature monthly average (degC) Hunting Index wild boar annually shot per km2 Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
The thermal environment is a major factor influencing amphibians. For example, amphibian reproduction occurs in specific temperatures, and minor changes in this aspect could have negative impacts on this biological process. Understanding the potential effects of temperature on reproductive output is important from both an ecological and captive breeding colony point of view. I examined temperature effects on reproduction in axolotl reared from egg to adult at 4 temperatures (15 degC, 19 degC, 23 degC, and 27 degC) These adult axolotls (n = 174) were measured and weighed, dissected, and their gonads were removed and weighed to obtain an individual's reproductive allocation. Female axolotls reared at 23 degC had a greater Gonadosomatic Index (GSI) compared to axolotl reared at each of the other temperatures with axolotls reared at 27 degC having the lowest reproductive output. Moreover, all GSI pair-wise comparisons in the four temperature treatments were significantly different from each other (ANOVA, F (3, 66) = 61.681, p < 0.0001). Additionally male rearing temperature significantly influenced GSI (ANOVA, F (3, 89) = 10.441, p < 0.0001). Male axolotls reared at 19 degC had significantly greater GSI compared to males reared at the three other temperatures. There were no statistical differences among each of the other pair-wise comparisons. As seen in this experiment, axolotls may be especially sensitive to climate-driven warming due to their highly permeable skin and paedomorphic life history. Understanding how axolotls and other amphibian species adjust to the challenges of climate change is important in the management of this imperiled taxa. Gonadosomatic Index gametogenesis climate change amphibian This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. pmc1. Introduction Caudates are especially sensitive to changing temperatures due to their lack of thermal regulation. Aquatic temperatures influence growth and development during the larval period and may impact sexual development and induce sex reversal . Two literature reviews examined the influence of temperature on the developmental plasticity of amphibian larvae and determined that age and size at the onset of metamorphosis were generally lowest at the warmest temperatures. Amphibian larvae that develop faster and metamorphose at a smaller body potentially impact fitness-related traits . Further, larval amphibians may be more vulnerable than adults to temperature variations and are likely to encounter higher variation in temperature living in the aquatic environment. Larval amphibians often prefer specific temperatures in lab experiments and this behavior can change depending on developmental stage . Temperature preference also occurs in adult obligatory aquatic salamanders (Amphiuma tridactylum) , and acclimation temperature can influence larval and adult preferred temperature. For example, aquatic salamanders, Cryptobranchus alleganiensis (hellbenders) and Necturus maculosus (mudpuppies), selected the lower temperatures in a gradient when acclimated at 5 degC and avoided warmer temperatures . In hellbenders, water temperature can impact the pH and PCO2 , and in Ambystoma texanum (small-mouth salamanders), water temperature can influence physiological immune function , and metabolic rates , Rearing temperature can reduce growth and survival of Andrias davidianus (the Chinese giant salamander) and play an important role in the initiation of reproductive cycles , with low temperatures inducing early timing of female gamete maturation, as shown in Siberian salamanders (Salamandrella keyserlingii) captured during breeding migrations . Thus, seasonal temperatures may affect spermatogenesis and ovulation in temperate salamander species and their endocrine e and exocrine control and constraints . Notwithstanding these studies, little is known whether and how water temperature affects gonads growth in urodeles. This information is of importance for the development of temperature regimes for rearing amphibians in captive colonies (including germplasm repository development), and in understanding the effects of climate induced changes on life histories traits including reproduction. The present study examines the effect of water temperature on the Gonadosomatic Index (GSI) in the Axolotl, Ambystoma mexicanum. These salamanders are imperiled and near extinction in nature because of invasive predatory fish, pollution, and urbanization . Axolotls are thriving in domestication as exotic pets, or in laboratory colonies where they are used as model organisms for biological research. This species has been cultured in the lab as surrogates for wild Ambystoma species on the research of cold storage and cryopreservation of spermatophores and for examining temperature influence on reproductive physiology . Axolotls possess features typical of salamander larvae, including external gills, and are paedomorphic (i.e., retaining juvenile characteristics as adults), which allows them to exploit water throughout their entire lifespan. By living in water, however, the species may be more vulnerable to changes in water temperature or quality compared to amphibians that are both land and water dwelling. Thus, it is important to know how the effects of temperature can influence reproduction of this species and other cold-blooded vertebrates. 2. Materials and Methods 2.1. Animals This study took place at the Warm Springs Fish Technology Center, U. S. Fish and Wildlife Service, in Warm Springs, Georgia. Male and female adult axolotl originally obtained from the University of Kentucky's Ambystoma Genetic Stock Center (AGSC) were paired together in 20 degC water in three containers to obtain eggs for this experiment. Approximately 75 larvae (three weeks old) from each of three clutches were mixed and divided into four groups and put in four tanks (244 cm x 61 cm x 24 cm) that were filled with artesian spring water (pH x = 6.8 +- 0.2) and recirculated through a chiller/heater which maintained temperatures at 15 degC, 19 degC, 23 degC, and 27 degC. Temperatures were checked using a YSI Pro 20i digital meter every other day and thermostat was adjusted if needed. Rearing temperatures were within the range of temperatures (10 degC to 28 degC) that axolotl have been successfully cultured . Axolotls were exposed to a 12 h light and 12 h dark photoperiod and fed brine shrimp daily until larvae were approximately 5-6 cm in total length and thereafter fed ad libitum rations of a prepared pellet diet obtained from the AGSC. This feed was broadcast haphazardly throughout the tank 5-6 days a week and larvae ate freely. Periodically, the four systems were tested for ammonia (x < 0.1), nitrite (x = 0.05), and alkalinity (x = 15 mg/L). 2.2. Gonads Collection As axolotls matured in culture tanks, individuals were sampled starting at 12 months of age (starting in March 2022) those not sampled remained exposed to culture temperatures until collected at a later date (up to 15.5 month of age). When collected, individuals were euthanized by adding 10.0 g of Tricaine Methane-Sulfonate (MS-222) and two parts of sodium bicarbonate to 1 L of water. Salamanders were placed in the solution and 10 min after visible breathing stopped, Snout-Vent-Length (SVL, distance from the tip of the snout to the anterior angle of the vent)) (mm) was measured, then individuals were dried with a paper towel, and weighed (body mass: BM) to within 0.1 g using an electronic balance. Individuals were dissected, testis or egg masses removed, and these were weighed to 0.1 g and photographed. All axolotls were subsequently frozen individually. 2.3. Statistical Analysis Gonadosomatic index (GSI) was obtained by the dividing testis or eggs mass versus the body mass (in grams). GSI is widely used in studies of reproductive cycles of different groups of animals . These data were arcsine square root transformed to minimize the heterogeneity of variances among treatments . Body size data were log-transformed before analysis. An ANOVA was performed on these data using the Excel2016.lnk software package (Microsoft, Redmond Washington, DC, USA) to analyze the effect of rearing temperature on the GSI (p = 0.05 level of significance). If the p-value from the ANOVA was less than the significance level, a Tukey-Kramer post hoc test was done to examine which groups are different from each other. 3. Results 3.1. Females Female body size was significantly affected by rearing temperature. Axolotls reared at 15 degC and 23 degC and had a greater SVL and body mass compared to axolotls reared at 19 degC and 27 degC temperatures (Table 1). These body size differences were statistically different. SVL: ((ANOVA, F (3, 65) = 13.625, p < 0.0001), Body mass: (ANOVA, F (3, 65) = 31.907, p < 0.0001). Additionally, female axolotls reared at 23 degC had a greater GSI compared to axolotl reared at each of the other temperatures . All pair-wise comparisons in GSI in the four temperature treatments were significantly different from each other (ANOVA, F (3, 66) = 61.681, p < 0.0001, Figure 1), with axolotls reared at 27 C having the lowest reproductive output. 3.2. Males Male body size was significantly affected by rearing temperature. Axolotls reared at 23 degC had a greater SVL (115.4 mm) and body mass (93.4 g) compared to axolotls reared at other temperatures (Table 1). These body size differences were statistically different. SVL: ((ANOVA, F (3, 86) = 4.572, p = 0.0052), Body mass: (ANOVA, F (3, 86) = 14.143, p < 0.0001). Rearing temperature significantly influenced GSI (ANOVA, F (3, 89) = 10.441, p < 0.0001). Male axolotls reared at 19 degC had significantly greater GSI compared to males reared at the three other temperatures . Males in the warmest water temperature (27 degC) had the smallest GSI compared to axolotls reared at 15 degC and 23 degC temperatures, but these differences were not statistically different. 4. Discussion 4.1. Females Body size of females and the growth development of gonads depended strongly on temperature regime. Axolotls were larger both in length and weight when reared at 15 and 23 degC. Interestingly, gonads size of axolotls reared at the coldest temperature (15 degC) did not increase in proportion to body mass. These salamanders may have the capacity to allocate food energy to growth rather than to reproduction as temperature conditions at 15 degC may not be ideal. Alternatively, if temperature environments are optimal, females will growth larger and produce more eggs. This likely occurred in females reared at 23 degC as axolotls were larger and the GSI was significantly greater compared to females at the three other temperatures. 4.2. Males Similar to females, male body size was greatest at 15 degC and 23 degC, however males reared at 19 degC had a significantly greater GSI compared to males reared at the three other temperatures. Again, the potential for an energy trade-off between growth and reproduction is likely for males reared at different temperatures. 4.3. Effects of High Rearing Temperature and Climate Warming Both females and males were smaller in body size and produced relatively a smaller percentage of gonads when reared at 27 degC. This was particularly true for females. High temperatures may influence not only gonads production but may also affect gamete maturation or increase gamete mortality as seen in fish and mammals . Seasonal temperature variation can influence spermatogenesis and ovulation is some salamander species . I4 nature, axolotl growth and reproduction could be affected by increased water temperatures that arise from climate change. This species originated in cold water (<16 degC) lakes in Mexico and ideal water temperatures for rearing axolotls in the lab is 16-18 degC. Water temperatures above 24 degC can put stress on the animals and result in a loss of appetite (personal observation) and may make axolotls more vulnerable to parasites. A previous study suggested that maintaining axolotl at 24 degC or below can accelerate growth without serious detrimental effects but rearing temperatures above that would reduce axolotl developmental rates. This occurred in the present experiment as rearing temperatures of 27 degC resulted in axolotl reduced body size and decreased the relative mass of testis and the number of eggs. It is possible that the 27 degC water temperature affected hormonal function in these salamanders and suppressed gametogenesis. Future studies are needed to address the role of temperature on hormones, gamete quality, and paternal investment in offspring. 5. Conclusions These results suggest that the reintroduction and translocation of axolotls into former and new habitats should identify water temperature as an important component in conservation efforts. Previous research that examined axolotl distribution found this species in water temperatures ranging between 16 to 23 degC . As seen in this experiment, males and females should be reared at different temperatures to optimize reproductive output and may be especially sensitive to high temperatures. Whether temperature influences other maternal contribution to offspring, i.e., input into other fitness-related qualities (e.g., egg or hatching size) is presently unknown. While this study examined the effects of constant temperatures on axolotl reproduction, additional research should focus on the consequences of variable thermal environments. The ability of species to adapt to this extrinsic factor behaviorally or physiologically is little known. Understanding how axolotls and other amphibian species adjust to the challenges of temperature variation is important in the management of this imperiled taxa. Acknowledgments I thank William Wayman for the construction of systems for rearing axolotls and thank William Wayman, Jackie Zelco, and Isabel Veith for their help in feeding animals. I especially thank Sam Figiel and Aria Foster for assistance in dissecting axolotls and Yue Liu for reviewing an earlier version of the manuscript. I gratefully acknowledge the AGSC which received financial support (P40-OD019794) from the Office of Research Infrastructure Programs at the National Institutes of Health. Institutional Review Board Statement All procedures involving animals were reviewed and approved by the Animal Care and Use Committee of the U.S. Fish and Wildlife Service Warm Springs Fish Technology Center. All the animals used in this study were cared for in accordance with the Institutional Animal Care and Use Committee guidelines at the Warm Springs Regional Fisheries Center that conformed to standards established by the United States Office of Lab Animal Welfare and the United States Department of Agriculture. Approval code: WSFC 2021-05. Informed Consent Statement Not applicable. Data Availability Statement The data presented in this study are available upon request from the corresponding author. Additionally, data files have been uploaded to FigShare on Gonadosomatic Index (GSI) of female axolotls, Ambystoma mexicanum. Different letters indicate statistically significant differences among temperatures. Mean +- standard deviation. Figure 2 Effects of rearing temperature (15 degC, 19 degC, 23 degC, and 27 degC) on Gonadosomatic Index (GSI) of male axolotls, Ambystoma mexicanum. Different letters indicate statistically significant differences among temperatures. Mean +- standard deviation. animals-13-00874-t001_Table 1 Table 1 Effects of rearing temperature (15 degC, 19 degC, 23 degC, and 27 degC) on snout-vent-length (SVL) (mm) and body mass (g) of female and male axolotls, Ambystoma mexicanum. Different letters indicate statistically significant differences among temperatures. Mean +- standard deviation. Females 15 degC 19 degC 23 degC 27 degC n 25 21 16 21 SVL 110.6 +- 12.6 a 103.8 +- 5.4 b 114.4 +- 5.4 a 101.6 +- 8.9 b Body Mass 95.9 +- 12.6 a 70.6 +- 7.9 b 93.1 +- 12.7 a 57.0 +- 18.3 b Males 15 degC 19 degC 23 degC 27 degC n 27 30 20 12 SVL 111.1 +- 4.1 a 109.5 +- 5.6 a 115.0 +- 6.1 b 109.2 +- 8.6 a Body Mass 86.5 +- 7.8 a 72.3 +- 12.3 a 92.1 +- 17.8 b 72.1 +- 13.1 a Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
Cancers (Basel) Cancers (Basel) cancers Cancers 2072-6694 MDPI 10.3390/cancers15051354 cancers-15-01354 Editorial Editorial: Autologous and Allogeneic Stem Cell Transplant in Cancer Therapy Sharma Nidhi 1* Efebera Yvonne A. 2* 1 Division of Hematology, The Ohio State University, Columbus, OH 43210, USA 2 Department of Hematology, Blood and Marrow Transplant, OhioHealth, Columbus, OH 43214, USA * Correspondence: [email protected] (N.S.); [email protected] (Y.A.E.) 21 2 2023 3 2023 15 5 135413 2 2023 15 2 2023 19 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcOver the last 10 to 20 years, there have been significant improvements in the fields of both autologous and allogenic transplantation. The upper age limit for hematopoietic stem cell transplantation continues to increase for both autologous SCT (ASCT) and allogeneic HCT (allo-HCT). The improvement in supportive management and development of novel agents has led to increases in survival outcomes in patients undergoing ASCT for multiple myeloma and lymphoma. Advances in conditioning regimens, the expanding use of alternative donor stem cell sources such as haploidentical stem cells and cord blood, and the use of modern T-cell depletion strategies such as post-transplant cyclophosphamide have led to better survival outcomes and a reduced incidence of graft versus host disease in patients undergoing allo-HCT. This special issue, which comprises 12 papers, addresses various aspects outlining the roles of ASCT and allo-HCT in the treatment of hematological malignancies, new advancements pertaining to their use and the challenges they pose when deciding on the optimal practice. The paper by Jiang et al. was a retrospective analysis on patients who underwent allo-HCT to better understand how survival has changed over the years. The authors divided the patients into groups based on the year of transplant. The data showed that both progression free and overall survival increased over the years. Five-year graft-versus-host disease/relapse-free survival (GFRS) also increased from 6% to 14% in the latter years. The authors attributed this change to advances in supportive care and treatments focused on the mitigation of graft versus host disease (GVHD) and relapse . For allogenic transplantation, tacrolimus, a calcineurin inhibitor that prevents T-cell activation, is often used for GVHD prophylaxis. However, there is variability in the serum concentrations of tacrolimus (TAC), and little is known on the impact of early TAC levels on acute GVHD (aGVHD). The retrospective study (2002-2016) by the same group studied the effect of early post-transplantation tacrolimus concentration on the risk of acute GVHD. It was reported that achieving >=10 ng/mL during the first week of allo-HCT may mitigate the risk of aGVHD. However, levels of >11 ng/mL beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse . Graft versus host disease is a serious but common complication associated with allo-SCT as a result of donor T-cell mediated stem cells that attack immunocompromised host tissues. The treatment of aGVHD involves a high dose of corticosteroids, which suppress the immune system and put patients at an even greater risk of infectious complications , and potential viral reactivation complications. Despite this increased risk, there are little published data focused on the efficacy of cytomegalovirus (CMV) prophylaxis for patients who develop aGVHD. Wolfe et al. reported on the efficacy of letermovir to prevent clinically significant CMV infection (CS-CMVi) among allo-HCT patients who developed aGVHD in a single center retrospective study. Among aGVHD patients, letermovir prophylaxis decreased CS-CMVi in patients with aGVHD (p < 0.001), reduced non-relapsed mortality (p = 0.04) and improved overall survival (p = 0.04), suggesting that letermovir prophylaxis improves outcomes by preventing CS-CMVi in patients with aGVHD. Dybko et al. aimed to identify predictive and risk factors associated with the increased occurrence of the BK virus-related hemorrhagic cystitis (HC) following hematopoietic stem cell transplantation (HCT). A significant correlation was observed between HC incidences after HCT, BK viremia and viruria, and aGVHD occurrence. Furthermore, the level of BK virus DNA in serum at day +21 (>0.75 x 103) significantly impacted the patients' survival time . Allo-HCT therapeutic efficacy is mainly dependent on immune alloreactivity mediated by donor lymphocytes infused with the stem cell graft, the so-called graft versus leukemia (GVL) effect. Disease recurrence is the major obstacle to the success of allo-HCT, as patients with high-risk acute leukemia and MDS have a high risk of relapse after allo-SCT . Prophylactic donor lymphocyte infusion (DLI) has been shown to reduce the relapse rate but at the cost of increased GVHD . Tsirigotis et al. tested the safety and efficacy of a novel method of prophylactic DLI based on prolonged repetitive administration of low lymphocyte doses. When extended for up to 3 years, low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia (AL). The data showed that repeated and prolonged DLI administration resulted in relapse prevention, perhaps by inducing a long-lasting anti-leukemic effect . Gutierrez et al., in a retrospective analysis, showed that it may be a curative option in relapsed/refractory (R/R) mantle cell lymphoma with a low cumulative incidence of relapse (CIR). They showed that it might be a better option for fit patients, using human leukocyte antigen (HLA)-identical (related or unrelated) or haploidentical related donors and without previous transplantation. In another study, Tsai et al. compared the outcomes of post cyclophosphamide with or without anti-thymoglobulin and GCSF-primed bone marrow plus peripheral blood stem cells (GIAC). They showed that the mGIAC approach may be a preferential choice for patients with low/intermediate-risk diseases in the view of non-relapse mortality (NRM), CIR, or overall survival (OS) . For multiple myeloma (MM), ASCT is more commonly used compared to allo-HCT. In this issue, three papers were published (two original article and one review). Jordan et al. performed a retrospective survival analysis on newly diagnosed MM (NDMM) patients receiving ASCT from 1992 to 2016 . Patients were split into five groups based on historic changes in novel agents for the treatment of MM. Across the years, there was a statistically significant improvement in both progression-free-survival (PFS) and OS, which was primarily attributed to the inclusion of novel therapies and post-transplantation maintenance. Importantly, significant survival improvements were seen in patients <=65 years and >65 years old. Baertsch et al. reported on the outcome after salvage high-dose chemotherapy (HDCT)/ASCT following re-induction treatment with carfilzomib/lenalidomide/dexamethasone (KRD). The authors conducted a retrospective analysis of patients that had previously undergone frontline HDCT/ASCT and reported that KRD followed by salvage ASCT were associated with favorable PFS and the response was enhanced by maintenance treatment. Deep remissions achieved with KRD followed by salvage autologous transplantation were associated with favorable PFS and were enhanced by maintenance treatment . In the past years, the therapeutic approaches for patients diagnosed with MM and their respective prognoses have decisively changed with the development of highly efficient new anti-myeloma drugs, such as protosome inhibitors (PI), immunemodulatory drugs (IMID), monoclonal antibodies and CAR-T cells. The review by Greil et al. addresses the role of allo-HCT in MM. The authors discuss data showing that a decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Salvage allo-HCT is recommended, preferentially within clinical trials, for patients with early relapse after first-line therapy including ASCT, and in high risk (HR) constellations according to cytogenetics and stage . Severe acute or chronic GVHD, systemic signs of inflammation and endothelial dysfunction with fluid overload are relatively common posttransplant conditions that are associated with an adverse prognosis and decreased survival due to increased NRM in allotransplant recipients. Previously, it has been shown that there is an association between systemic metabolic profiles and the risk of GVHD, and fluid retention post allo-HCT . Hatfield et al. studied the potential associations between lipidomic profiles and pretransplant inflammation, early fluid overload and later development of aGVHD. Ninety-two consecutive patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were included in the analysis. The results showed that the pretransplant lipidomic profiles differed significantly when comparing patients with and without the risk factors: (i) pretransplant inflammation, (ii) early fluid overload, and (iii) patients with and without later steroid-requiring aGVHD . The pediatric population treated with allo-HCT most frequently develop endocrine complications. The treatments given, consequently, lead to impaired fitness, including exercise-induced shortness of breath, fatigue and reduced participation in physical activity . These symptoms may indicate frailty . Suominen et al. evaluated the physical fitness and prevalence of frailty in male long-term survivors of pediatric allo-transplant. Low muscle strength and a high incidence of frailty were observed in survivors of pediatric allo-HCT. There is a predominant risk of cardiovascular and metabolic diseases in the long-term . We hope that this Special Issue has responded to the clinical demand for up-to-date and in-depth information about the optimal management of patients undergoing hematopoietic stem cell transplantation for hematological malignancies. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Jiang J. Sigmund A.M. Zhao Q. Elder P. Benson D.M. Vasu S. Jaglowski S. Mims A. Choe H. Larkin K. Longitudinal Survival Outcomes in Allogeneic Stem Cell Transplantation: An Institutional Experience Cancers 2022 14 5587 10.3390/cancers14225587 36428678 2. Sharma N. Zhao Q. Ni B. Elder P. Puto M. Benson D.M. 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Physical Fitness and Frailty in Males after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Long-Term Follow-Up Study Cancers 2022 14 3310 10.3390/cancers14143310 35884371 |
Energy security concerns require novel greener and more sustainable processes, and Paris Agreement goals have put in motion several measures aligned with the 2050 roadmap strategies and net zero emission goals. Renewable energies are a promising alternative to existing infrastructures, with solar energy one of the most appealing due to its use of the overabundant natural source of energy. Photocatalysis as a simple heterogeneous surface catalytic reaction is well placed to enter the realm of scaling up processes for wide scale implementation. Inspired by natural photosynthesis, artificial water splitting's beauty lies in its simplicity, requiring only light, a catalyst, and water. The bottlenecks to producing a high volume of hydrogen are several: Reactors with efficient photonic/mass/heat profiles, multifunctional efficient solar-driven catalysts, and proliferation of pilot devices. Three case studies, developed in Japan, Spain, and France are showcased to emphasize efforts on a pilot and large-scale examples. In order for solar-assisted photocatalytic H2 to mature as a solution, the aforementioned bottlenecks must be overcome for the field to advance its technology readiness level, assess the capital expenditure, and enter the market. The 2050 roadmap strategies and net zero emission goals are made possible through the adoption of novel greener and more sustainable processes. In this regard, exploiting solar irradiation (a plentiful energy source) is advantageous for developing green hydrogen technologies. Photocatalytic devices are suited for large-scale plants proliferation. Three case studies from France, Spain, and Japan are presented. hydrogen net zero emissions photocatalysis roadmap technological development source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:10.03.2023 M. Isaacs , J. Garcia-Navarro , W.-J. Ong , P. Jimenez-Calvo , Is Photocatalysis the Next Technology to Produce Green Hydrogen to Enable the Net Zero Emissions Goal?. Global Challenges 2023, 7 , 2200165. 10.1002/gch2.202200165 pmc1 Introduction Today, humankind is confronted by a series of global challenges: energy/environmental crises, population growth, pandemics, and geopolitical wars, that simultaneously promote the depletion of natural resources and accelerate the contamination of sources of life: water, air, and soil. Among these challenges, energy production, and demand deserve special attention by the research and development communities who urgently need to devise tangible solutions. Notably, the continuous conversion of fossil fuels, such as oil, gas, and coal continue to contribute to greenhouse gases emissions, such as carbon dioxide (CO2). Ideally, certain criteria for selecting the future energy sources should be observed, namely, these sources should be abundant, easy to recycle or regenerate at the large scale, and their conversion should be CO2-free. The world's total net CO2 emissions, from 1850 to 2019, were 2400 +- 240 Gt(CO2). Between 2010 and 2019 alone, roughly 17% of the total cumulative net CO2 emissions (410 +- 30 GtCO2) were released, supporting Hubbert's predictions from 1970. The concentration of CO2 in the atmosphere has been directly measured by the Mauna Loa Observatory, exhibiting 417 ppm Figure 1 . Such CO2 increases result in damning and imminent consequences to the natural world. For example, increases to the surface temperature of the Earth consequently impact the average rate of sea levels (e.g., 20 cm rise between 1901 and 2018), desert dryness, melting of glaciers and ice caps, heat content and acidification of the ocean, and other negative effects to various ecosystems. Figure 1 a) Measurements of atmospheric CO2 since 1958 from the Mauna Loa Observatory in Hawaii (black) and from the South Pole (red) show a steady annual increase in atmospheric CO2 concentration. Reproduced with permission. Copyright 2022, Scripps CO2 Program. b) Illustrative scheme to represent the technological transfer from laboratory setups, pilot scale devices, and large-plants. For these reasons, an assessment of existing processes must be carried out to replace them with more efficient and sustainable technologies. For that, a shift from fossil fuels to clean energy has been suggested by the roadmap 2050 (the European Commission (EU)) and Net Zero by 2050 (the EU Green Deal and International Energy Agency). At the present time, fossil fuels still supply 80% of the world's energy. In this context, the use of solar energy is an appealing alternative due to the primary energy source being an effectively unlimited supply of great power. The diversity of emitted photons with different energies that can be selectively captured and thus used for chemical conversion to obtain solar clean fuels makes this a unique source. Nevertheless, the capture of solar photons is a challenge due to the day-night cycle, seasonal change, cloud presence, and geographical local distribution. Among several solar-driven fuels currently under investigation, hydrogen is primarily unlocking the potential of renewables as an energy source, and moving carbon neutrality toward a reality rather than a myth. The attractiveness of H2, as an energy vector, lies in three arguments: a) Its high energy content per unit mass (142 kJ mol-1), twofold to threefold increase compared with classical fossil fuels, such as gasoline, methane, propane, and natural gas, b) versatile energy storage medium because it can be used in electric only or combined heat and power fuel cells in stationary applications, internal combustion engines, and fuel cell vehicles, and c) despite its low self-discharge rate, regenerative hydrogen fuel cells may be cheaper than batteries in an optimized energy arbitrage system. H2 integration into the economic model became a serious consideration following the signing of the Paris agreement by the members of United Nations (UN). One of the goals of this agreement is to decarbonize heavy industry and, for that, reinviting or shifting existing technologies for optimized, greener, and more sustainable processes is a must. Thus, the European Commission, the World Economic Forum, the UN, Mission Innovation, and established industries are implementing new strategies to support net zero emissions and update their portfolio of technologies. With this integration scenario, emerging H2 technologies are achieving historical technology readiness levels (TRL), ranging from laboratory setups into pilot devices and large-plants . However, storage, transport, and safety hindrances must be addressed and refined to enable fully widespread integration into the socio-economical context. H2 safety is undoubtedly a topic to be addressed for a broader implementation and social acceptance. Briefly, the ignition energy of H2 mixed with air (0.017 mJ) is lower than natural gas (0.24-0.31 mJ). As natural gas is already handle in a large scale making a proof-of-concept. Thus, the ignition energy difference points out that theoretically H2 would cause lower flame propagation from the ignition point, thus is safer. Therefore, an ignition endanger will be consider when a source is close (e.g., spark or over heated contact). Experiments have shown that H2 does not ignite in cases where it was expected under specific circumstances, namely in presence of friction or energized devices. Still, more maturity in ignition tests is needed to mitigate and minimize inherent risks (essentially ignition), as reached for natural gas. 2 Hydrogen Production Context Worldwide political and scientific consensus have defined a color nomenclature for H2 in function of its source of production. There are eight different colors but for this article we limit the introduction of the three extreme cases, from the most and least contaminant and neutral sources. Please refer to Ajanovic et al. for details. Grey H2 is made with fossil-fuel-based technology, blue H2 is climate-neutral and made with carbon capture and storage technology, and green H2 is made with renewable energy (using renewables). To date, H2 is produced by mostly fossil fuels (98%) emitting nearly 900 million metric tons (Mt) of CO2 per year. By 2020 H2 production reached 90 Mt. It is forecasted, however, that H2 production may surpass 200 Mt in 2030. Steam methane reforming (76%) is the leading H2 production technology in the market, followed by coal gasification (22%), two energy-intensive and highly polluting methods. Electrolysis, a clean but relatively adolescent technology is already in the loop of existing technological processes contributing to 2% of total production, evidencing the need to decentralize H2 production to facilitate the integration with downstream processes to foster a sustainable energy transition. The output stream of electrolyzers is a mixture of H2 and O2. Thus, a common practice consists in using gas separation processes, (also in fuel cells and steam methane reforming with the equivalent or other by-product gases) in the end production point with possible recirculation for increasing the efficiency itself and obtained a higher H2 purity. The high-quality H2 with the desired low impurity levels is achievable with either adsorption and diffusion purification processes. The commercial technology widely used for adsorption-based H2 purification is Pressure Swing Adsorption (PSA), where porous solid adsorbents (e.g., zeolites and activated carbons) preferentially adsorb particular components from a gas stream in a pressurized vessel, later to be released after depressurization, that is, pressure cycles. Besides PSA, there are other methods based on temperature (TSA) and/or vacuum (VSA) but purities and cost differ. The amount of H2 made from renewable sources, like water or biomass, is a small part of the total amount produced. Fortunately, there are several methods to obtained H2 and O2 via water splitting (WS), namely electrolysis, electrocatalysis, photocatalysis (PC), photoelectrocatalysis, photovoltaic-electrochemical, solar thermochemical cycles, photothermal catalytic, or photobiological processes. WS is an uphill reaction that requires a significant Gibbs free energy, that is, 237 kJ mol-1. Interestingly, WS requires a very similar amount of energy as natural photosynthesis, with plants needing 1.24 eV (energy required per electron driven through the photosynthetic system) to make glucose, whereas to split water artificially requires 1.23 eV per electron. This thermodynamic requirement of PC H2 production is defined primarily by the water oxidation (oxygen evolution reaction) and then the proton reduction (hydrogen evolution reaction, HER) half-reactions requiring 1.23 and 0 V versus normal hydrogen electrode (pH = 0), respectively. On top of H2 production via WS, PC is an appealing approach for other energy applications, such as CO2 reduction and nitrogen fixation. As heterogeneous catalysis type, PC is particularly simple, requiring only light to activate the solid semiconductor (SC) and transform either a liquid or gas reactant. Unlike, typical electrolyzer connected with a photovoltaic panel, PC simplifies in its unassisted electricity possibility, potentially lowering costs in an operating expenses (OPEX) viewpoint. 3 Photocatalytic Water Splitting Principle PC WS is a heterogeneous surface catalytic reaction and possesses an attractive simplicity, requiring only light, a catalyst, and water to function. For that reason, PC WS is an appealing prospect, and considered one of the "holy grail" reactions in physical chemistry because can directly produce H2 from water. Should the technical barriers be removed whilst maintaining even a moderate capital expenditure (CAPEX), then one can presume it to challenge competitor methods, perhaps eventually reaching an even more attractive cost. Typically, PC WS starts when a SC is irradiated with a photon with equal or higher energy than its band gap. This generates an exciton: excited electron (e-) and a positive hole (h+). These two charge carriers dissociate and migrate to the surface of the catalyst. Some e-/h+ partners face undesirable recombination on the surface or in the bulk, but the e-/h+ pairs reaching the surface may undertake one of the two WS half-reactions. Figure 2 a) Photocatalyst scheme of activation, generation, and reactional water splitting steps. b) Summary of general photocatalytic steps. Successful h+ moieties avoiding recombination can oxidize water to create O2 and H+, while on the other hand, available can reduce the H+ to obtain H2. Therefore, the HER consumes 2 molecule of H2 formed. The four steps of the process (activation, exciton formation, recombination, redox) all involve different time scales, which are well-described by Takanabe et al. Figure 2b summarizes PC WS sequential steps: a) Activation of the catalyst (critical), b) generation of the charge carriers, and c) redox reactions in the interface between the catalyst and the substrate. Prior to catalyst activation there are two pre-reaction steps, first the reactant molecules must diffuse to the liquid-gas/solid interface to be adsorbed onto the catalyst surface. Once on the surface, they then wait to encounter a photo-generated charge carrier and react. Furthermore, after the catalyst's activation, two analogous post-reaction steps then happen. They initially desorb from the catalyst surface and then diffuse back into the reaction media. The critical step (activation of the catalyst) defines the overall efficacy of the material, which occurs mostly in the interior of the catalyst, but some sub-steps may proceed at its surface. Many leading scientists are currently improving the reaction medium/catalyst interface contact with sophisticated advanced material strategies (Z-scheme, Schottky junctions, and co-polymerization, among others) to tune key properties and increase efficiencies. 4 Photocatalytic Technological Developments This section will showcase three photocatalytic systems develop in Asia and Europe. One recently automated laboratory scale reactor, and two pilot devices: A panel photocatalytic array and a compound parabolic collector (CPC). The reasoning is to highlight the international efforts toward improving laboratory photocatalytic systems and the transition into pilot and large-scale processes. The first step toward large-plants, however, is the development and refinement of effective PC devices capable of promising performance on the pilot scale. Considerations of the complexities of benchmarking and effective engineering challenges in developing lab-scale PC materials was addressed in our recent work designing and constructing a compact automated stainless steel reactor, of 40 cm3 of volume. H2 photoproduction and quantum yields exhibited twofold increases when compared to literature equivalent materials. This result emphasizes that reactor geometry and configuration setup play a key role in the performance of PC materials and reveals insights into ideal (minimal losses) heat/mass/photonic profiles. An unprecedented 100 m2 arrayed panel system led by Professor Domen, comprising 1600 units has been recently launched at Kakioka Research Facility at the University of Tokyo. This system design has achieved 0.76% solar-to-hydrogen (STH) conversion, similar to ideal lab scale efficiency, 1% STH. The configuration attractiveness relies in being simple, cheaper, and more amenable to scale-up compared with solar cells and/or electrolysis systems. Each panel plate was sprayed with a modified aluminum-doped strontium titanate photocatalyst layer, one of the most efficient photocatalysts to date. The highlight of this panel array is its H2 recovery after several months of continuous operationality, starting with a moist gas product mixture, and H2 capture with a polyimide membrane. Another pilot device for solar H2 generation and removal of wastewater pollutants was tested at Plataforma Solar de Almeria. This setup consists of a CPC, which is a reactor type enabling highly efficient solar photon collection. Two materials were tested, Pt/(TiO2-N) and Pt/(CdS-ZnS), with the former outperforming the latter in combination with two sacrificial electron donors: formic acid and glycerol. This system evidences other proof-of-concept of H2 production, though this time using municipal wastewaters, enabling simultaneous waste water depollution and energy vector generation. Though several photocatalytic WS prototypes are available, their efficiency is still low (<1%). From a photochemical process perspective, reactor design and process optimization are needed to make this technology viable and feasible on a relevant scale. Furthermore, from a materials science perspective, higher-performing photocatalysts with better stability and H2 production efficiency (5-10% STH) are needed for economic viability. Public and private partnerships are proliferating internationally to tackle these bottlenecks; The Green Deal (European Union) in particular is investing a significant amount into finding tangible renewable solutions. 5 Conclusions and Outlook By maturing solar-assisted photocatalytic H2 technologies on a pilot scale, like in the three case studies, the proof-of-concept stage can be bypassed and thus enable the new chapter of TRL acceleration. The innovation of advanced H2 pilot devices in the next half-decade will be key to unlocking new engineering advances for large-scale that may foster both the commercialization of H2 from solar-fueled photocatalysis across the global market and the circular economy (while decarbonizing with clean energy). For solar scale up reactor design and dimensional technological transfer analysis, we propose a (non-exhaustive) list of parameters extracted from the selected case studies to implement in higher TRL projects, essentially in four axes: operational, photonic, mass, and heat transfer profiles. We suggest such considerations with the intention that WS PC pilot devices proliferate and unlock further technological barriers. Operational considerations include quantification of H2 (data acquisition) within an integrated on-line analytical equipment (gas chromatography) to reduce operational costs in human resources which is essential for scaling up to TRL >=3 (pilot prototypes). Reactor components should have resistance to pH, corrosion, and exposed environmental conditions. Furthermore, components must be easy to handle and accessible (with a modular assembly design providing an optimal solution to this point), and finally low-cost (low CAPEX and OPEX). Photonic considerations for catalyst activation focus on efficient photon capture and distribution, with suitable geometry to maximize collected light, suitable light absorbing materials, and maximizing use of the solar spectrum. Mass transfer considerations facilitate adsorption-desorption interactions, for example the reactor must guarantee minimal pressure from the gas flow, ensure suspended particle homogeneity in the contained volume, and avoid creation of pronounce vortexes of sufficient agitation to disrupt processes. Heat transfer considerations include the use of recirculating chillers directly in the path of the light source or inside the reactor (but not in contact with the particle dissolution) to guarantee a constant temperature, ideally of 20 degC, to avoid thermal catalysis contributions. Ultimately, for large-scale setups, the inclusion of wastewater and or organic pollutants as for substrate source and electron or proton donors or so-called sacrificial agents, respectively, should not be negligible while planning of building the plant. Contrarily, optimal processes envisage the simultaneous reuse of one of source (wastewater) resulting in the production of decontaminated (of organic pollutants) water and concomitant generation of energy solar carriers. Conflict of Interest The authors declare no conflict of interest. Acknowledgements Prof. Dr. Markus Antonietti is acknowledged for his support. The Max Planck Society supported this research financially. M. A. Juan Rodriguez is acknowledged for his graphical design contribution. The acknowledgements section was added and corrections made to references 19, 41 and 43 after initial online publication, on March 10, 2023. Open Access funding enabled and organized by Projekt DEAL. |
Cells Cells cells Cells 2073-4409 MDPI 10.3390/cells12050779 cells-12-00779 Editorial Rho GTPases in Model Systems Filic Vedrana * Weber Igor * Division of Molecular Biology, Ruder Boskovic Institute, Bijenicka 54, HR-10000 Zagreb, Croatia * Correspondence: [email protected] (V.F.); [email protected] (I.W.) 01 3 2023 3 2023 12 5 77922 2 2023 27 2 2023 (c) 2023 by the authors. 2023 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ). pmcSince the discovery of their role in the regulation of actin cytoskeleton 30 years ago, Rho GTPases have taken center stage in cell motility research. Over time, it has become clear that these "molecular switches" are also involved in the regulation of other cellular processes, such as cell polarization, cell differentiation and growth, membrane trafficking, and transcriptional regulation. The biological importance of Rho GTPases is exemplified by the fact that mammalian cells invest more than 150 genes that encode their direct regulators. Rho GTPases are essential signaling molecules in mammals and across the whole eukaryotic domain. This Special Issue of Cells represents a collection of review articles and original research papers covering Rho GTPases in model organisms and cell culture systems. It can be roughly divided into sections devoted to evolutionary aspects, screening and mechanistic approaches, and the roles of Rho GTPases in mammalian physiology and pathology. Evolutionary insight into the functional roles of Rho GTPases in simple model organisms can provide an invaluable perspective on their universal biological importance. Current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes, such as morphogenesis and polarity, cellular integrity, cytokinesis, and cellular differentiation, are presented by Vicente-Soler et al. . Although the genetic tools available in yeast are still unrivaled, the physiology of the actin cytoskeleton in these organisms is quite specific and distinct from metazoan cells. A much closer match is provided by the highly motile cells of amoebozoan protists, which share the composition and dynamics of the transient actin-based structures, in particular with mammalian cells of the hematopoietic lineage. Filic et al. provide an overview of the Rho signaling pathways that regulate the actin dynamics in Dictyostelium and compare them with similar signaling networks in mammals . Interestingly, although phylogenic algorithms do not identify strict homologies between Rho GTPases in the two groups, comprehensive functional studies established that canonical mammalian representatives, Rho, Rac and Cdc42, obviously have their functional analogues in Dictyostelium. Moving on into the realm of multicellularity, a review by Beljan et al. represents a compilation of the current knowledge concerning Rho-family GTPases in non-bilaterian animals, the available experimental data regarding their biochemical characteristics and functions, and an original bioinformatics analysis of their relationship with metazoan counterparts . Their findings provide a general insight into the evolutionary history of Rho-family GTPases in simple animals and support the notion that the ancestor of all animals probably contained Rho, Rac and Cdc42 homologs. Rho proteins of plants (ROPs) form a specific clade of Rho GTPases, which are involved in plant immunity and their susceptibility to diseases. In their review, Engelhard et al. summarize central concepts of Rho signaling in disease and immunity of plants and briefly compare them to important findings in the mammalian research field . Interesting similarities emerge, as follows: while invasive fungal pathogens may co-opt the function of ROPs for manipulation of the cytoskeleton that promotes pathogenic colonization, mammalian bacterial pathogens also initiate effector-triggered susceptibility for cell invasion via Rho GTPases. Zebrafish, as model vertebrates, offer a unique opportunity to explore the spatial and temporal dynamics of Rho GTPases within a complex environment at a level of detail unachievable in any other organism. Boueid et al. present a compilation of examples where the roles of Rho, Rac and Cdc42 in cell motility, developmental processes, angiogenesis, neural system and pathological processes in zebrafish were investigated using a set of powerful tools to follow and locally modulate Rho GTPases signaling and their function in real time, combined with rapidly evolving imaging and genetic techniques . Given the large complexity involved in the signaling networks centered on Rho GTPases, system-level research is required to fully grasp the extent of their biological roles and regulation. In their review article, Dahmene et al. highlight the recent large-scale studies, including proteomic approaches to map the full repertoire of Rho GTPases and Rho regulators protein interactions and high throughput screening strategies that unraveled new roles for understudied family members by using cell culture models and mouse embryos . An example of the high throughput screening approach is provided by Long et al., who developed and applied an image-based high-content screen using RNA interference to systematically perturb each of the 21 Rho family members and assess their importance to the overall organization of the Golgi complex . Their analysis revealed previously unreported roles for two atypical Rho family members, RhoBTB1 and RhoBTB3, in the endomembrane traffic events. In addition to their localization at the plasma membrane and endomembranes, recent research demonstrates that active pools of different Rho GTPases also localize to the nucleus. Navarro-Lerida et al. discuss how the modulation of Rho GTPases driven by post-translation modifications provides a versatile mechanism for their compartmentalization and functional regulation . They stress that understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is will contribute to the exploration of Rho GTPases as important therapeutic targets in cancer and other disorders. Indeed, it is becoming increasingly clear that small Rho GTPases play essential roles in human physiology and pathology. In their review article, Sarowar and Grabrucker discuss the role of three archetypical Rho GTPases in the modulation of dendritic spine morphogenesis in the amygdala, the core brain region associated with fear learning and conditioning . Dendritic spines are tiny, dynamic, and heterogeneous actin-rich protrusions on the surface of neuronal dendrites that receive input from an axon at the synapse. RhoA inhibits dendritic growth and dynamics, while Cdc42 and Rac1 promote them. By doing so, Rho GTPases and some of their modulators expressed in the amygdala play an important role in fear-related processes. Another example of the influence of Rho signaling on synaptic plasticity is provided by Figiel and colleagues . Synaptic remodeling mediated by matrix metalloproteinase 9 (MMP-9) is essential for long-term memory formation. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Rho GTPases seem to be downstream effectors of MMP-9, and the authors review current knowledge on their roles in MMP-9-dependent signaling pathways in the brain, with emphasis on the influence of their post-translational modifications. Mao et al. explored the function of Rho GTPases during phagocytosis of spent photoreceptor outer segment fragments by retinal pigment epithelial (RPE) cells, which is essential for visual function . This process is mediated by Mer tyrosine kinase (MerTK) receptor signaling, and MerTK mutations cause complete blindness in early adulthood, for which widely applicable therapy is still unavailable. In their research, the authors show that efficient RPE phagocytosis requires the activation of Rac1 and the simultaneous suppression of RhoA activity downstream from MerTK. In MerTK-deficient RPE cells, elevated RhoA activity blocks phagocytic cup formation. However, inhibition of RhoA downstream effector ROCK is sufficient to restore the phagocytic capacity of MerTK-deficient RPE. Since ROCK inhibitors are already approved for common, long-term use for ocular disease, this study supports future efforts toward their use in simple therapy, possibly as eye drops. Veluthakal and Thurmond systematically summarize the role of different Ras superfamily GTPases in the normal functioning of pancreatic islet b-cells . Pancreatic islet b-cells take up glucose and initiate glucose metabolism that, via a plethora of signaling events, induces insulin granule exocytosis. The authors review the roles of Rho, Arf and Rab family members in the islet insulin secretory process and describe how the altered activity of GTPases can lead to b-cell dysfunction. Considering the important roles that Rho GTPases play in the regulation of physiological processes, it is no surprise that their altered activities significantly contribute to numerous pathological conditions. Humphries et al. provide an overview of the current understanding of the regulation and functions of Rho GTPases specifically in breast cancer . They show that, similarly to findings in other tumors, there are conflicting data concerning the role of Rho GTPases in breast cancer. However, the prevalent notion is that increased activation of Rho GTPases has tumor-promoting roles in breast cancer initiation, metastatic progression, chemoresistance, and radioresistance. Furthermore, Rho GTPases have important roles in diseases whose major contributor is chronic inflammation. Kilian et al. summarize the role of RhoA in stress-induced signaling from damaged cardiomyocytes to immune cells, which leads to immune cell activation, chronic inflammation and cardiac disease progression . They discuss the possible roles of RhoA signaling in cardiomyocytes, macrophages, neutrophils, and dendritic cells, which are important in the pathogenesis and progression of cardiac dysfunction. Atherosclerosis is another example of a chronic inflammatory immune-mediated condition implicated in the pathogenesis of coronary artery disease, a major cause of mortality worldwide. Lee et al. highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification . They also discuss the off-target effects of statins, the most widely used therapy for hypercholesterolemia, on Rac immune signaling. Inflammation also has a crucial role in the development of gastrointestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer. IBD is marked by the uncontrolled activation of immune cells and alterations to intestinal epithelial cells (IECs), characterized by increased tight junction permeability and altered cytoskeletal rearrangements. Pradhan et al. summarize the current knowledge on the roles of classical Rho GTPases in the context of intestinal homeostasis and disease, focusing on IECs and T cells . Finally, Hahmeyer and da Silva-Santos provide a comprehensive overview of the current knowledge about the role of Rho signaling pathways in sepsis, a life-threatening organ dysfunction caused by a dysregulated response to infection . They describe how Rho proteins, mainly Rac1 and RhoA, are involved in the development of sepsis-specific symptoms in different systems and cells, including the endothelium, vessels, and the heart. Author Contributions Conceptualization, V.F. and I.W.; writing original draft preparation, V.F. and I.W.; writing review and editing, V.F. and I.W. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest The authors declare no conflict of interest. Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. References 1. Vicente-Soler J. Soto T. Franco A. Cansado J. Madrid M. The Multiple Functions of Rho GTPases in Fission Yeasts Cells 2021 10 1422 10.3390/cells10061422 34200466 2. Filic V. Mijanovic L. Putar D. Talajic A. Cetkovic H. Weber I. Regulation of the Actin Cytoskeleton via Rho GTPase Signalling in Dictyostelium and Mammalian Cells: A Parallel Slalom Cells 2021 10 1592 10.3390/cells10071592 34202767 3. Beljan S. Herak Bosnar M. Cetkovic H. Rho Family of Ras-Like GTPases in Early-Branching Animals Cells 2020 9 2279 10.3390/cells9102279 33066017 4. Engelhardt S. Trutzenberg A. Huckelhoven R. Regulation and Functions of ROP GTPases in Plant-Microbe Interactions Cells 2020 9 2016 10.3390/cells9092016 32887298 5. Boueid M. Mikdache A. Lesport E. Degerny C. Tawk M. Rho GTPases Signaling in Zebrafish Development and Disease Cells 2020 9 2634 10.3390/cells9122634 33302361 6. Dahmene M. Quirion L. Laurin M. High Throughput strategies Aimed at Closing the GAP in Our Knowledge of Rho GTPase Signaling Cells 2020 9 1430 10.3390/cells9061430 32526908 7. Long M. Kranjc T. Mysior M. Simpson J. RNA Interference Screening Identifies Novel Roles for RhoBTB1 and RhoBTB3 in Membrane Trafficking Events in Mammalian Cells Cells 2020 9 1089 10.3390/cells9051089 32354068 8. Navarro-Lerida I. Sanchez-Alvarez M. del Pozo M. Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases Cells 2021 10 1990 10.3390/cells10081990 34440759 9. Sarowar T. Grabrucker A. Rho GTPases in the Amygdala A Switch for Fears? Cells 2020 9 1972 10.3390/cells9091972 32858950 10. Figiel I. Kruk P. Zareba-Koziol M. Rybak P. Bijata M. Wlodarczyk J. Dzwonek J. MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity Cells 2021 10 166 10.3390/cells10010166 33467671 11. Mao Y. Finnemann S. Acute RhoA/Rho Kinase Inhibition Is Sufficient to Restore Phagocytic Capacity to Retinal Pigment Epithelium Lacking the Engulfment Receptor MerTK Cells 2021 10 1927 10.3390/cells10081927 34440696 12. Veluthakal R. Thurmond D. Emerging Roles of Small GTPases in Islet b-Cell Function Cells 2021 10 1503 10.3390/cells10061503 34203728 13. Humphries B. Wang Z. Yang C. Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses Cells 2020 9 2167 10.3390/cells9102167 32992837 14. Kilian L. Frank D. Rangrez A. RhoA Signaling in Immune Cell Response and Cardiac Disease Cells 2021 10 1681 10.3390/cells10071681 34359851 15. Lee C. Carley R. Butler C. Morrison A. Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis Cells 2021 10 2808 10.3390/cells10112808 34831028 16. Pradhan R. Ngo P. Martinez-Sanchez L. Neurath M. Lopez-Posadas R. Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases Cells 2021 10 66 10.3390/cells10010066 33406731 17. Hahmeyer M. da Silva-Santos J. Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research Cells 2021 10 1844 10.3390/cells10081844 34440613 |
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