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15545859 | The role of psychosocial and family factors in adherence to antiretroviral treatment in human immunodeficiency virus-infected children. | The toxicity and complexity of antiretroviral therapy (ART) regimens are substantial challenges in the context of patients' lives. This study examines child psychosocial and caregiver/family factors influencing adherence to ART in perinatally human immunodeficiency virus (HIV)-infected children. Seventy-five children (ages 3-13 years) prescribed ART, and their primary caregivers were recruited from 2 urban pediatric HIV programs. A battery of psychologic assessments and self-report adherence data were collected from all caregivers and 48 children who were > or =7 years old. Forty percent of caregivers and 56% of children reported missed doses of medication in the past month. Families in which the caregiver or child reported missed doses (nonadherent) were compared with families who reported no missed doses (adherent). In univariate analyses, nonadherence was significantly associated with older child age (P < 0.05), worse parent-child communication (P < 0.017), higher caregiver stress (P < 0.002), lower caregiver quality of life (P < 0.003) and worse caregiver cognitive functioning (P = 0.033), and of borderline significance in its association with increased (1) child responsibility for medications (P < 0.07), (2) HIV disclosure to the child (P < 0.07) and (3) child stress (P < 0.08) In logistic regressions controlling for age, caregiver/family factors were the most strongly associated with nonadherence, including worse parent-child communication (P < 0.03), higher caregiver stress (P < 0.01), less disclosure to others (P < 0.05) and quality of life (P < 0.01). Our data suggest that efforts to improve children's adherence to complex antiretroviral regimens requires addressing developmental, psychosocial and family factors. |
15545858 | Otoscopic and tympanometric findings in acute otitis media yielding dry tap at tympanocentesis. | The value of tympanometry in detection of middle ear effusion (MEE) has been widely studied in otitis media with effusion. There has been no direct comparison of tympanometric and tympanocentesis (TAP) findings in acute otitis media (AOM). We compared otoscopic, tympanometric and TAP findings in AOM including cases of AOM without effusion. In a study of AOM treatment of 90 children, a tympanogram was obtained, and TAP was performed before and after 5 days of treatment. Subjects were followed with otoscopy and tympanometry every 2 weeks for 3 months or until the MEE cleared. In 130 AOM ears, otoscopic, tympanometric and TAP findings were available; MEE was obtained from 110 ears. Of 20 ears with a dry tap, 18 had abnormal tympanogram and otoscopic findings. With TAP findings as the standard, sensitivity and positive predictive value of type B tympanogram were 97 and 87%, respectively. Of 18 AOM ears yielding dry tap, 2 yielded MEE 5 days later, and 8 continued with evidence of MEE 5 days-12 weeks later. Five subjects with 8 AOM ears yielding dry tap were lost to follow-up; all had short duration of clinical symptoms. Although otoscopic and tympanometric findings suggested the presence of MEE in AOM, MEE was unobtainable by TAP in 14% of cases. Dry tap cases likely represent early AOM before accumulation of detectable MEE. However, technical difficulty in obtaining small amounts of or highly viscous MEE could not be excluded. Sensitivity and positive predictive value of abnormal tympanograms in detection of MEE in AOM cases are comparable with those in otitis media with effusion. |
15545857 | Serotype-specific pneumococcal antibodies in breast milk of Gambian women immunized with a pneumococcal polysaccharide vaccine during pregnancy. | In breast-feeding populations, immunization during pregnancy with pneumococcal polysaccharide offers a potentially useful approach to preventing pneumococcal disease in young infants. Breast milk samples were collected at 0, 2, 4 and 6 months after delivery from Gambian women vaccinated during pregnancy (24-32 weeks gestation) with Pneumovax II (n = 56) or Mengivax A&C (n = 57). Specimens were examined for secretory immunoglobulin A (s-IgA) concentration, subclass distribution and avidity specific to pneumococcal serotypes 4, 6B, 14, 19F and 23F and the antigen mixture in Pneumovax II by enzyme-linked immunosorbent assay. Colostral s-IgA and IgG concentrations in paired maternal sera were compared. Colostral s-IgA concentrations specific to all pneumococcal polysaccharide antigens investigated were significantly higher (P < 0.05) among Pneumovax II vaccinees. Titers specific to serotypes 4, 6B and 14 and the vaccine formula remained significantly higher during 6 months, and those for 19F were higher during 4 months. Significantly higher concentrations of vaccine antigen-specific s-IgA antibody were sustained for 6 months after delivery (P = 0.011). Comparison of colostral s-IgA and IgG in serum revealed a significant correlation only among Mengivax A&C vaccinees for pneumococcal polysaccharide 23F (rs= 0.68; P < or = 0.0001). Vaccination elicited trends toward increased s-IgA2, reaching significance for serotype 14 and the vaccine formula. Immunization elicited significantly higher s-IgA avidities specific to all pneumococcal polysaccharide antigens studied during 6 months. The public health value of immunization during pregnancy with pneumococcal polysaccharide vaccine in breast-feeding populations warrants further evaluation, particularly in populations with a high incidence of pneumococcal disease in early infancy. |
15545856 | Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates. | Seven valent pneumococcal conjugate vaccine (PCV7) was licensed and introduced in 2000 for universal administration of children younger than 2 years of age and for selective immunization of children 2-5 years of age. To identify changes in colonization and antimicrobial susceptibility among Streptococcus pneumoniae organisms after introduction of PCV7. Infants and children ages 2-24 months were enrolled in surveillance study of nasopharyngeal carriage of S. pneumoniae. Nasopharyngeal cultures for S. pneumoniae were performed at all well child visits and illness visits of children with acute otitis media. S. pneumoniae organisms were serotyped, and antimicrobial susceptibilities to penicillin, amoxicillin, trimethoprim-sulfamethoxazole and azithromycin were performed. During the 3-year period (October 2000 through September 2003), nasopharyngeal colonization with vaccine serotypes declined from 22% to 2%, and nonvaccine serotypes increased from 7% to 16%. Rates of antibiotic resistance of S. pneumoniae isolates to penicillin, amoxicillin, azithromycin and trimethoprim-sulfamethoxazole were 29.3, 2.2, 26.5 and 28.1%, respectively. PCV7 immunization produces a marked decline in vaccine serotypes carried in the nasopharynx of young children, with a coincident rise in the prevalence of nonvaccine serotypes. Important shifts in antimicrobial susceptibility have not been observed to date. |
15545855 | Immunogenicity and safety of the eleven valent pneumococcal polysaccharide-protein D conjugate vaccine in infants. | Development is ongoing to increase the serotype coverage of pneumococcal conjugate vaccines. We report here the immunogenicity and safety of a new 11-valent pneumococcal conjugate vaccine (Pn-PD) in infants. In a randomized, single blind study, 154 Finnish infants received 1 of 3 regimens: 4 doses of Pn-PD at 2, 4, 6 and 12-15 months; 3 doses of the Pn-PD at 2, 4 and 6 months and 1 dose of 23-valent polysaccharide vaccine (PncPS) at 12-15 months; or 3 doses of the hepatitis B vaccine at 2, 4 and 6 months and Pn-PD at 12-15 months. Serum IgG antibodies to vaccine serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F were measured with an enzyme immunoassay at the ages of 2, 7 and 12-15 months and at 4 or 28 days after the last vaccination. Local and systemic reactions were recorded by parents during 8 days after each dose. Serious adverse reactions were recorded during the entire study period. There was a significant increase in the IgG concentrations to vaccine serotypes after 3 doses of Pn-PD. Antibody concentrations after the primary series varied between 1.26 and 4.92 microg/ml depending on the serotype and study group. PncPS vaccine induced a better booster response than the Pn-PD, measured at 28 days after the fourth dose. IgG concentrations after the Pn-PD booster ranged between 1.60 and 9.63 microg/ml and after the PncPS booster between 4.24 and 40.54 microg/ml, depending on the serotype. The antibody concentrations after the first dose of Pn-PD administered at 12-15 months increased significantly but were lower than after the fourth dose at the same age. No significant antibody increase was measured 4 days after the vaccinations at 12-15 months. The safety profile of the vaccine was acceptable. The Pn-PD we tested was immunogenic and safe in infants. |
15545854 | Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections. | Viral lower respiratory tract infections are a leading cause of hospitalization for young children. We used polymerase chain reaction (PCR) and conventional methods of cell culture and antigen detection to establish the viral etiology of acute respiratory tract infections in 75 hospitalized children. One or more viral pathogens were detected in 65 (87%) children, with respiratory syncytial virus being the most commonly identified virus (36 children). Other viruses identified included influenza virus types A and B, parainfluenzavirus type 3, adenovirus, enterovirus, rhinovirus, coronavirus and human metapneumovirus. PCR increased the diagnostic yield significantly compared with antigen detection and culture, with 39 (21%) diagnoses identified by this method. Multiple infections were identified in 20 (27%) children. PCR-based methodologies offer increased sensitivity for the detection of most respiratory viruses in young children. The inclusion of PCR into diagnostic testing strategies is needed to broaden our understanding of the natural ecology of respiratory viruses and the significance of multiple infections. |
15545853 | Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis. | There is increasing evidence that rhinoviruses (RV) are able to cause lower airway infections and to induce wheezing in young children. There are few data on the clinical characteristics of RV infections in infants. The aim of the study was to compare clinical characteristics of infantile RV infection associated with wheezing and respiratory syncytial virus (RSV) bronchiolitis. During a 22-month study period in 1992-1993, 100 children younger than 24 months old were hospitalized with respiratory tract infection-associated wheezing. Viral etiology was originally assessed by antibody and antigen assays. Etiologic studies were later supplemented by polymerase chain reaction for RVs (in 2000) and for RSV (in 2002), studied in frozen respiratory samples. There were 81 children with adequate determinations for both RVs and RSV. Twenty-six children had RV and 24 had RSV infection, and these 50 cases form the material of the present study. Atopic dermatitis, oxygen saturation, respiratory rates and clinical scores based on wheezing and retractions and total serum IgE concentrations and blood eosinophil counts were studied in all cases on admission. The children with RV infection, compared with RSV patients, were older (median, 13 versus 5 months), presented more often with atopic dermatitis (odds ratio, 16.7; 95% confidence interval, 2.22-100) and blood eosinophilia (odds ratio, 2.22; 95% confidence interval, 1.04-50). The groups did not differ from each other with regard to total serum IgE. Oxygen saturation values were lower in children with RSV infection. There were no significant differences in respiratory rates or scores combining wheezing and retractions. RV-associated wheezing and RSV bronchiolitis, although having rather similar clinical characteristics, differ significantly with regard to age, presence of atopic dermatitis and eosinophilia during infection. |
15545852 | Risk of bacterial infection in previously healthy respiratory syncytial virus-infected young children admitted to the intensive care unit. | To evaluate the risk of bacterial infection and use of antibiotics in otherwise healthy children infected with respiratory syncytial virus (RSV) admitted to the intensive care unit (ICU). Demographics, clinical information, interventions and outcomes were extracted from the charts of consecutive patients with laboratory-confirmed RSV infection at Children's Hospital, Boston from October 1990 through April 2002. Patients born at <36 weeks gestational age or with preexisting medical conditions were excluded. The median age of the 165 previously healthy infants infected with RSV was 42 days. Almost all patients received supplementary FiO2, and 63 (38.2%) patients required mechanical ventilator support. No patients died. The median length of stay was 3 days in the ICU and 7 days in the hospital. Most patients had bacterial cultures sent: 155 (93.9%), blood cultures; 121 (73.3%), urine cultures; and 85 (51.5%) cerebrospinal fluid cultures. Only 1 blood culture was positive, and 1 potential urinary tract infection was identified in a patient with a negative urinalysis. All intubated patients and 80.4% of nonintubated patients received antibiotic therapy. In otherwise healthy infants admitted to the ICU with RSV infection, bacteremia, urinary tract infection and meningitis are uncommon. Although bacterial pneumonia in this cohort may be more prevalent, overdiagnosis is common. |
15545851 | Infant pertussis: who was the source? | In the United States in the 1990s, the incidence of reported pertussis in adults, adolescents and infants increased; infants younger than 1 year of age had the highest reported incidence. In 4 states with Enhanced Pertussis Surveillance, we examined the epidemiology of reported pertussis cases to determine the source of pertussis among infants. A source was defined as a person with an acute cough illness who had contact with the case-infant 7-20 days before the infant's onset of cough. The average annual pertussis incidence per 100,000 infants younger than 1 year of age varied by state: 22.9 in Georgia; 42.1 in Illinois; 93.0 in Minnesota; and 35.8 in Massachusetts. Family members of 616 (80%) of 774 reported case-infants were interviewed; a source was identified for 264 (43%) of the 616 case-infants. Among the 264 case-infants, mothers were the source for 84 (32%) and another family member was the source for 113 (43%). Of the 219 source-persons with known age, 38 (17%) were age 0-4 years, 16 (7%) were age 5-9 years, 43 (20%) were age 10-19 years, 45 (21%) were age 20-29 years and 77 (35%) were age > or =30 years. The variation in reported pertussis incidence in the 4 states might have resulted from differences in awareness of pertussis among health care providers, diagnostic capacity and case classification. Among case-infants with an identifiable source, family members (at any age) were the main source of pertussis. Understanding the source of pertussis transmission to infants may provide new approaches to prevent pertussis in the most vulnerable infants. |
15545850 | Respiratory syncytial virus: G gene genotype and disease severity. | In a hospital-based study by Martinello (2002), specific G gene genotypes of respiratory syncytial virus subgroup A virus were associated with an increased severity of illness. We sought to confirm the association of G genotypes with disease severity in a population-based study. Ninety-one type A respiratory syncytial viruses (identified in the 1999/2000 season by polymerase chain reaction and cell culture), collected in a German multicenter study (PRI.DE) were analyzed for G gene diversity (amino acids 1-165). Disease severity was classified according to World Health Organization criteria for pneumonia in outpatients and by a bronchiolitis score (Rodriguez, 1997) in inpatients. Multiple regression analysis was used to explain disease severity. Three clusters were identified (cluster 1, n = 35; cluster 2,n = 35; cluster 3, n = 21). Sixty-seven patients had severe disease. After controlling for other variables, illness severity was significantly greater for cluster 2 viruses (odds ratio, 7.0; 95% confidence interval, 1.6 49), compared with viruses in other clusters. Other known risk factors (male gender, age) were not associated with disease severity. Our cluster 2 is genetically distinct from the virulent genotype in Martinello's study. Previously reported associations between G genotypes and disease severity in hospitalized patients can be generalized across the spectrum of illnesses including outpatients. The association seems not to be linked to a specific G gene structure. Rather G gene diversity in combination with the susceptibility of the host cohort may form the basis of such associations. Because of the magnitude of the effect, the underlying mechanisms warrant further investigation. |
15545848 | Thyrotoxicosis presenting as hypogonadism: a case of central hyperthyroidism. | Herein, we present a case of central thyrotoxicosis with well-documented serial therapeutic interventions. Thyroid-stimulating hormone (TSH)-secreting pituitary tumors represent a rare cause of hyperthyroidism. It is being diagnosed more frequently with the third-generation TSH assay. Many conditions can produce normal or elevated TSH levels in combination with elevated thyroid hormone levels. The differential diagnosis includes resistance to thyroid hormone (RTH, Refetoff's syndrome), assay interference from anti-T4/T3 and heterophile antibodies, elevated or altered binding proteins, drugs affecting peripheral metabolism, and noncompliance with thyroid replacement therapy. In contrast to RTH, our patient presented had high alpha-subunit-to-TSH molar ratio, failed TSH response to thyrotropin-releasing hormone stimulation, and a large pituitary mass. Normal or high TSH in the presence of elevated T4 or T3 is a fairly common clinical scenario with many etiologic possibilities. This TSH-producing adenoma represents an unusual initial clinical presentation, as hypogonadism appeared before features of thyrotoxicosis were appreciated. This case represents the most modern therapeutic approach to the management of this rare disease. Our patient has done well on octreotide with control of thyrotoxicosis and an additional 30% shrinkage of his tumor mass. |
15545849 | Intrathoracic masses due to extramedullary hematopoiesis. | Extramedullary hematopoiesis often occurs in hemoglobinopathies, hemolytic anemias, leukemias, lymphomas, and myeloproliferative disorders. Liver, spleen, and lymph nodes are frequently involved. However, extramedullary hematopoiesis may also develop in other sites such as thymus, kidney, retroperitoneum, and paravertebral areas of the thorax. Extramedullary hematopoietic masses are often microscopic and asymptomatic, but sometimes they lead to tumor-like masses. We describe massive intrathoracic extramedullary hematopoiesis in a 41-year-old man with compound heterozygosis for beta-thalassemia and sickle cell anemia and functional asplenia. We also describe a 39-year-old man with beta-thalassemia intermedia, who was initially diagnosed as having tumor masses, but was later proved, by magnetic resonance imaging, to have extramedullary erythropoietic tissue. These observations provide further support to include extramedullary hematopoiesis among the differential diagnosis of tumor-like masses in patients with hematologic diseases. |
15545847 | Plasmapheresis as an adjuvant therapy for hypertriglyceridemia-induced pancreatitis. | Hypertriglyceridemia is an uncommon cause of pancreatitis. A serum triglyceride level of more then 1000 to 2000 mg/dL is an identifiable risk factor. Interestingly, serum pancreatic enzyme levels may be normal or only minimally elevated in such cases. The reduction of triglyceride level to below 1000 mg/dL effectively prevents further episodes of pancreatitis. The mainstay of treatment for the hypertriglyceridemia associated with pancreatitis includes dietary restriction of fat and administration of lipid-lowering agents. It is thought that within 24 to 48 hours of the onset of pancreatitis, in the majority of patients, triglyceride levels fall rapidly as a result of fasting status, as the absorption of chylomicrons to the blood is cut off. Experiences with plasmapheresis are limited. We report a case of hypertriglyceridemic necrotizing pancreatitis with mildly elevated amylase and lipase, treated successfully with plasmapheresis. |
15545846 | Metastatic pure small-cell carcinoma of prostate. | Extrapulmonary small-cell carcinoma arising in the prostate gland has been described in several case series and case reports. However, pure small-cell carcinoma of the prostate is rare, and there are only a few reports in literature describing the clinical features and management of this neoplasm. These tumors are highly aggressive and commonly manifest with visceral metastasis at the time of diagnosis. We report a case of metastatic pure prostatic small-cell carcinoma and an associated paraneoplastic polyneuropathy. |
15545845 | Quadricuspid aortic valve: report of three cases. | Quadricuspid aortic valve (QAV) is a very rare congenital malformation. We have encountered three patients with QAV, of whom one patient may be the eldest reported patient with this particular anatomical abnormality. In another of our patients, there was aortic regurgitation, aortic stenosis, and healed infective endocarditis, with adhesion of the tips of the cusps. In all three patients, the cusps were all of equal size. Until now, there has been very little documented evidence about the anatomical variations in QAV or its relationship with infective endocarditis. From the available literature, we conclude that the anatomical variations in patients with QAV are similar to those in patients with quadricuspid pulmonary valve, and infective endocarditis may not be an uncommon complication. |
15545844 | A comparison of bedtime insulin glargine with bedtime neutral protamine hagedorn insulin in patients with type 2 diabetes: subgroup analysis of patients taking once-daily insulin in a multicenter, randomized, parallel group study. | Basal insulin is frequently administered once daily. This subgroup analysis of a multicenter, randomized, parallel study compared insulin glargine (Lantus Aventis Pharmaceuticals, Bridgewater, NJ) with neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes, evaluating only patients treated previously with once-daily NPH insulin. Patients received bedtime insulin glargine or NPH insulin, with preprandial regular insulin. One hundred patients (mean age, 57.9 years; mean glycohemoglobin, 8.4%; mean fasting blood glucose, 167 mg/dL) were treated for up to 28 weeks. Patients treated with insulin glargine (n = 52) and NPH insulin (n = 48) achieved similar reductions from baseline in glycohemoglobin (-0.41% versus -0.46%) and fasting blood glucose (-22 mg/dL versus -22 mg/dL) at week 28. The proportion of patients reaching target fasting blood glucose (<120 mg/dL) at 28 weeks was 34.2% with insulin glargine and 24.4% with NPH insulin. Similar proportions of patients achieved glycohemoglobin less than 7% and less than 8% in both groups. Baseline and week-28 mean daily doses of insulin glargine (27.3 IU versus 36.4 IU) were similar to NPH insulin doses (25.5 IU versus 30.2 IU). However, significantly fewer patients reported one or more episodes of hypoglycemia with insulin glargine (46.2%) versus NPH insulin (60.4%; P < 0.05). Significantly fewer patients also reported one or more symptomatic episodes confirmed by blood glucose less than 50 mg/dL with insulin glargine (17.3%) versus NPH insulin (31.3%; P < 0.005). Bedtime insulin glargine is as effective as bedtime NPH insulin in improving glycemic control, with significantly less hypoglycemia. |
15545843 | Multiple Polymorphisms in the renin- angiotensin-aldosterone system (ACE, CYP11B2, AGTR1) and their contribution to hypertension in African Americans and Latinos in the multiethnic cohort. | When compared with other U.S. populations, African Americans have excess hypertension. Genetic variants in elements of the renin-angiotensin-aldosterone system (RAAS), namely the angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2), and angiotensin II type 1 receptor (AGTR1) genes, have been associated with risk of hypertension in some populations. We genotyped the D/I polymorphism in the ACE gene, the C(-344)T polymorphism in the CYP11B2 gene, and the C(-535)T polymorphism in the AGTR1 gene among African American and Latino members of the Multiethnic Cohort Study (MEC) to determine their association with hypertension. We observed no significant increase in the risk of hypertension for either African Americans or Latinos homozygous or heterozygous for the D allele of the ACE gene. Among African Americans we observed carriers of the (-344)T allele of CYP11B2 to be at increased risk of hypertension (versus CC genotype: TC genotype, OR = 1.66 [95% CI: 1.01-2.72]; TT genotype, OR = 1.74 [95% CI: 1.07-2.82]). There was also an increase in risk of hypertension associated with the AGTR1 T allele for African Americans (versus CC genotype: TC genotype, OR = 2.62 [95% CI: 1.46-4.72]; TT genotype, OR = 2.67 [95% CI: 1.51-4.74]). The associations observed with CYP11B2 and AGTR1 genotypes were not observed among Latinos. These data suggest that the (-535)T allele of AGTR1 and (-344)T allele of CYP11B2 may increase hypertension risk among African Americans but not among Latinos. Characterization of the linkage disequilibrium and haplotype patterns in the RAAS pathway genes will be crucial to understanding differences in hypertension susceptibility in these ethnic populations. |
15545832 | Effects of sesame oil on oxidative stress after the onset of sepsis in rats. | The aim of this study was to investigate effects of sesame oil on oxidative stress after the onset of sepsis in rats. Effects of sesame oil on lipid peroxidation, superoxide anion, superoxide dismutase, catalase, glutathione, and nitrite after the onset of endotoxin intoxication were determined. To further examine the protective effect of sesame oil on sepsis, a mortality study was also conduced in cecal ligation and puncture-induced sepsis in rats. Sesame oil was given orally 6 h after endotoxin administration and cecal ligation and puncture, and parameters were then measured in another 6 h. Data demonstrated that a single dose of sesame oil reduced lipid peroxidation 6 h after endotoxin intoxication. Superoxide anion counts were decreased, glutathione levels were increased, and activities of superoxide dismutase and catalase, as well as nitrite levels, were not altered in lipopolysaccharide plus sesame oil-treated groups compared with lipopolysaccharide-treated groups. Furthermore, sesame oil given 6 h after cecal ligation and puncture significantly increased survival rate. Thus, we suggested that sesame oil could be used as a potent antioxidant to reduce oxidative stress after the onset of sepsis in rats. |
15545831 | De novo synthesis of ubiquitin carboxyl-terminal hydrolase isozyme l1 in rostral ventrolateral medulla is crucial to survival during mevinphos intoxication. | Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) is a deubiquitinating enzyme that is responsible for making ubiquitin, which is required to target proteins for degradation by the ubiquitin-proteasome pathway in neurons, available. We investigated whether UCH-L1 plays a neuroprotective role at the rostral ventrolateral medulla (RVLM), the origin of sympathetic neurogenic vasomotor tone in the medulla oblongata where the organophosphate insecticide mevinphos (Mev) acts to elicit cardiovascular toxicity. In Sprague-Dawley rats maintained under propofol anesthesia, Mev (960 microg/kg, i.v.) induced a parallel and progressive augmentation in UCH-L1 or ubiquitin expression at the ventrolateral medulla during the course of Mev intoxication. The increase in UCH-L1 level was significantly blunted on pretreatment with bilateral microinjection into the RVLM of a transcription inhibitor, actinomycin D (5 nmol), or a translation inhibitor, cycloheximide (20 nmol). Compared with aCSF or sense oligonucleotide (100 pmol) pretreatment, microinjection of an antisense uch-L1 oligonucleotide (100 pmol) bilaterally into the RVLM significantly increased mortality, reduced the duration of the "pro-life" phase, blunted the increase in ubiquitin expression in ventrolateral medulla, and augmented the induced hypotension in rats that received Mev. These findings suggest that de novo synthesis of UCH-L1, leading to an enhanced disassembly of ubiquitin-protein conjugates in the RVLM, is essential to maintenance of the "pro-life" phase of Mev intoxication via prevention of cardiovascular depression, leading to neuroprotection. |
15545830 | TSC for hemorrhagic shock: effects on cytokines and blood pressure. | Previous studies have shown that administering trans-sodium crocetinate (TSC) as a treatment of hemorrhagic shock leads to increased whole-body oxygen consumption and survival as well as protection of the liver and kidney. It has been suggested that TSC increases oxygen delivery by increasing the diffusivity of oxygen through plasma. However, as with any novel mechanism of action, there are always questions about whether the results could also be ascribed to other, previously described mechanisms of action. This study was designed to look at some aspects of that by examining the effect of different TSC dosing regimens on the blood pressure and the production of cytokines after hemorrhage because both responses have been reported with compounds that act via other mechanisms. In a constant-pressure rat model of hemorrhagic shock, it was seen that a singe bolus injection of TSC results in an immediate but transient increase in the arterial blood pressure. This is similar to the effect reported previously for using 100% oxygen. It was also found that if the TSC injections were repeated periodically over an hour, a sustained increase in the blood pressure would occur. Because inflammatory cytokines have been implicated in mortality and tissue damage, it has been suggested that TSC may affect the production of cytokines. Thus, the effect of TSC on the production of TNF-alpha and IL-10 was also examined. The data show that treatment with TSC results in lower concentrations of TNF-alpha in the liver and spleen as well as lower concentrations of IL-10 in the spleen. Again, similar effects on other cytokines have been seen with 100% oxygen. These results support the hypothesis that the effects of TSC on hemorrhagic shock are mediated via an effect on oxygen. |
15545829 | Impact of the indigenous flora in animal models of shock and sepsis. | Septicemia is currently the 10th leading cause of death in the United States, and shock and trauma patients are the source of much of the morbidity and mortality associated with septicemia. There is substantial evidence that the composition of the indigenous flora plays an important role in modulating outcome variables in animal models of shock and sepsis. Germ-free animals that lack an indigenous flora are not as susceptible to shock as their conventionally reared counterparts. And, in conventionally reared animals, the composition of the intestinal flora can also modulate outcome in shock and sepsis. For example, certain bacterial species/strains disseminate from the intestinal tract more easily than others, antibiotic-induced alterations of the flora can modulate the incidence of systemic spread, and a certain threshold number of intestinal bacteria facilitates extraintestinal dissemination. The composition of the intestinal flora can also affect intestinal permeability, the production of inflammatory mediators, and the responses of immune cells in extraintestinal sites. And, there is evidence that prior exposure to endotoxin, via either the oral or systemic route, can influence outcome in animals challenged with parenteral endotoxin, a widely used model of endotoxin shock. The general composition of intestinal flora of experimental animals can be characterized with relative ease. This knowledge can aid data interpretation, either to help explain irreproducible or expected results or to verify that observed differences are likely related to the dependent variable studied rather than the composition of the indigenous flora. |
15545828 | The peroxisome proliferator-activated receptor-gamma ligand 15-deoxyDelta12,14 prostaglandin J2 reduces the organ injury in hemorrhagic shock. | The cyclopentenone prostaglandin 15-deoxyDelta12,14PGJ2 (15d-PGJ2) exerts potent anti-inflammatory effects in vivo, which are in part caused by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Here we investigate the effects of 15d-PGJ2 on the multiple organ injury/dysfunction associated with severe hemorrhage and resuscitation. Male Wistar rats were subjected to hemorrhage (to lower mean arterial blood pressure to 45 mmHg) for 90 min and subsequently resuscitated with shed blood for 4 h. Rats were treated with either 15d-PGJ2 (0.3 mg/kg i.v.) or its vehicle (10% dimethyl sulfoxide) at 30 min before the hemorrhage. In some experiments, the selective PPAR-gamma antagonist GW9662 (1 mg/kg i.v.) or its vehicle (10% dimethyl sulfoxide) was given 45 min before the hemorrhage. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) urea and creatinine and, hence renal dysfunction; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and, hence, hepatic injury. The potent PPAR-gamma agonist 15d-PGJ2 abolished the renal dysfunction and largely reduced the liver injury caused by hemorrhagic shock. In addition, 15d-PGJ2 also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. The specific PPAR-gamma antagonist GW9662 reduced the protective effects afforded by 15d-PGJ2. 15d-PGJ2 did not affect the delayed fall in blood pressure caused by hemorrhage and resuscitation. The mechanisms of the protective effect of this cyclopentenone prostaglandin are, at least in part, PPAR-gamma dependent, as the protection afforded by 15d-PGJ2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-PGJ2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with hemorrhagic shock. |
15545827 | Diminished ERK 1/2 and p38 MAPK phosphorylation in skeletal muscle during sepsis. | Sepsis induces weight loss and the loss of skeletal muscle proteins, in part through an inhibition of protein synthesis secondary to an inhibition of the key steps controlling mRNA translation in skeletal muscle. We have previously shown that sepsis decreases the phosphorylation of eIF4E. The present study examines the phosphorylation of Erk 1/2 MAPK and p38 MAPK in skeletal muscle of rats with a chronic (5-day) intra-abdominal septic abscess. Mnk1 catalyzes the phosphorylation of eIF4E, and Mnk1 is activated by phosphorylation via Erk1/2 MAPK and p38 MAPK. Sepsis resulted in a significant decrease in the steady-state phosphorylation of Erk 1/2 and p38 MAPKs compared with sterile inflammation. To examine the mediators responsible for decreased phosphorylation of Erk 1/2 and p38 MAPKs, rats were treated with TNF binding protein (TNFbp) or infused for 24 h with TNF. Treatment of septic rats with TNFbp resulted in an increase in the phosphorylation of both Erk 1/2 and p38 MAPKs in skeletal muscle. This was associated with enhanced phosphorylation of eIF4E. In contrast, constant intravenous infusion of TNF-alpha for 24 h resulted in a complete inhibition of p38 MAPK phosphorylation while Erk 1/2 MAPK phosphorylation was increased. The net effect was a modest increase in eIF4E phosphorylation. The results suggest altered regulation of Erk 1/2 and p38 MAPK signal translation pathways by endogenously produced TNF, or some compound dependent on TNF may modulate, in part, the phosphorylation state of eIF4E in skeletal muscle during sepsis. |
15545826 | Platelet-activating factor receptor-deficient mice show an unaltered clearance of nontypeable Haemophilus influenzae from their respiratory tract. | Platelet-activating factor (PAF), a glycerophospholipid with proinflammatory properties, exerts its biological effects by interacting with the PAF receptor (PAFR) expressed on many different cell types. The PAFR specifically binds phosphorylcholine, the biologically active component of PAF. However, phosphorylcholine is also a component of the cell wall of nontypeable Haemophilus influenzae (NTHi). In recently published in vitro experiments, the invasion of respiratory epithelial cells by NTHi was mediated by the PAFR. To determine the role of the PAFR in host defense against pneumonia induced by NTHi, PAFR-deficient (PAFR-/-) and normal wild-type mice were intranasally inoculated with NTHi. The absence of a functional PAFR was associated with a normal innate immune response as indicated by similar bacterial counts, myeloperoxidase activity, and inflammation within the pulmonary compartment of PAFR-/- and wild-type mice. These data indicate that the PAFR does not interfere with the clearance of NTHi from the respiratory tract. |
15545825 | Cd40 but not CD154 knockout mice have reduced inflammatory response in polymicrobial sepsis: a potential role for Escherichia coli heat shock protein 70 in CD40-mediated inflammation in vivo. | The CD40-CD154 system controls various aspects of the host inflammatory response in models of cellular and humoral immunity. Recently, we described a role for CD40 in the innate immune response in polymicrobial sepsis. However, recent data suggests that CD40 maybe activated by CD154 or directly via bacterial heat shock protein (HSP) 70. Therefore, we decided to test the mechanism of CD40 activation in murine polymicrobial sepsis. Wild-type (WT), CD40, and CD154 underwent cecal ligation and puncture (CLP). Compared with WT mice, CD40 had improved survival in association with attenuated production of IL-12, TNF-alpha, and IL-6. In contrast, CD154 mice behaved similar to WT mice with regard to mortality and cytokine production. The differential response of CD40 and CD154 mice to CLP was not due to a general attenuated response to inflammatory stimuli, as all three strains had similar survival after LPS administration, and CD40 macrophages had normal production of IL-12 in response to lipopolysaccharide. In contrast, CD40 macrophages had attenuated IL-12 production in response to Escherichia coli HSP70 (DnaK). Furthermore, intraperitoneal administration of DnaK resulted in a 4-fold increase in IL-12 in WT mice, which was absent in CD40 mice. This data demonstrates CD154-independent CD40 activation in polymicrobial sepsis and suggests that bacterial HSP70 is capable of stimulating CD40 in vitro and in vivo. |
15545824 | Circulating levels of macrophage migration inhibitory factor are associated with mild pulmonary dysfunction after cardiopulmonary bypass. | Macrophage migration inhibitory factor (MIF) is a central mediator of inflammatory response and acute lung injury that is secreted in response to corticosteroids. A rise in systemic MIF levels was described after cardiac surgery in steroid-treated patients. This study aimed to investigate the circulating levels of MIF and the possible relationship of this cytokine to pulmonary dysfunction after cardiopulmonary bypass (CPB). We included 74 patients without previous organ dysfunction undergoing elective coronary artery bypass surgery (CABS). The same team performed all CABS via a standard technique adding methylprednisolone (15 mg/kg) to the CPB priming solution (Group MP, n = 37). In the remaining patients (Group NS, n = 37), methylprednisolone was withdrawn from the CPB priming. MIF, C-reactive protein (CRP), and total C3 were assayed in peripheral blood sampled immediately before anesthesia induction and 3, 6, and 24 h post-CPB. Preoperative risk scores and peri- and postoperative variables were documented. Postoperative kinetics of MIF and C3 were similar for both groups. Levels of CRP 24 h post-CPB were higher in Group MP (P = 0.003). Higher MIF levels were detected 6 h post-CPB, and returned to preoperative levels 24 h after CPB. MIF levels 6 h post-CPB were inversely related to the postoperative PaO2/FiO2 ratio (P = 0.0021) and were directly related to the duration of mechanical ventilation (P = 0.014). Perioperative use of methylprednisolone did not modify the MIF response to CPB, but it was related to an enhanced acute phase response. Higher circulating MIF levels 6 h post-CPB were associated with worse postoperative pulmonary short-course outcome. |
15545823 | Initial posttraumatic translocation of NF-kappaB and TNF-alpha mRNA expression in peripheral blood monocytes of trauma patients with multiple injuries: a pilot study. | Post-traumatic inflammation is connected to monocyte dysfunction characterized by reduced NF-kappaB translocation during the first post-traumatic days. Because the exact dynamic of monocytic NF-kappaB translocation in patients directly after trauma remains unclear, the aim of this pilot study was to measure the intranuclear presence of NF-kappaB in monocytes from patients with multiple injuries initially after the trauma and during the early post-traumatic period and to compare these results with downstream-placed mRNA expression alteration of TNF-alpha, as well as with clinical data. Eleven patients were enrolled with an Injury Severity Score of 16 to 66 points, and blood samples were drawn on admission within 90 min and at 6, 12, 24, 48, and 72 h after trauma. NF-kappaB translocation of monocytic nuclear protein was analyzed by electrophoretic mobility shift assay and was quantified by densitometry as arbitrary units. In addition, monocytes of healthy volunteers were analyzed either native (-, control) or after LPS stimulation (+, control). For determination of downstream mRNA encoding for TNF-alpha, quantitative reverse transcriptase-PCR was performed. For both parameters, the negative control values were set as baseline (=1) and results from positive controls and patients were given as a relative alteration ratio without unit. Initial post-traumatic NF-kappaB translocation was significantly increased in trauma patients on admission (88 +/- 37) and 6 h after trauma (59 +/- 28) compared with the baseline level. In contrast, TNF-alpha mRNA was not increased on admission (1.7 +/- 0.9) and decreased even below baseline after 12 h. The substantial information of our study arises from the analysis of the dynamic of NF-kappaB translocation of monocytes. Enabled by closely matched sequential blood sampling strictly standardized to the traumatic event, an essential increase of monocytic signal transduction and transcription could be elucidated in the very early post-traumatic period, which precedes the down-regulation of the innate immune system. |
15545822 | Histocompatibility leukocyte antigen-D related expression is specifically altered and predicts mortality in septic shock but not in other causes of shock. | Although the expression of monocyte histocompatibility leukocyte antigen (HLA)-DR has been shown to be decreased during human sepsis, its level of expression in other nonseptic critical conditions is unclear. The aim of this study was to compare the level of HLA-DR expression on circulating monocytes among patients with septic, hemorrhagic, and cardiogenic shocks and severe sepsis without shock. At admission, HLA-DR expression was exclusively decreased in patients with septic shock (n = 30; P < 0.001), whereas the expression was similar between the other studied groups: cardiogenic shock (n = 16), hemorrhagic shock (n = 11), severe sepsis without shock (n = 18), and healthy volunteers (n = 8). HLA-DR expression was not predictive for overall mortality, but at day 1, an HLA-DR expression of less than 14 of mean fluorescence intensity (that corresponds to 40% labeled monocytes) was predictive of mortality exclusively in patients with septic shock (odds ratio, 11.4 and 95% confidence interval, 1.7; 78.4; P < 0.008). Catecholamine infusion, mechanical ventilation, positive blood culture, and number of units of blood or plasma transfused did not correlate with decreased HLA-DR expression. Thus, the decrease in HLA-DR expression is specific to septic shock and is associated, in septic shock patients, with increased mortality risk. |
15545821 | CXC-chemokine stimulation of neutrophils correlates with plasma levels of myeloperoxidase and lactoferrin and contributes to clinical outcome after pediatric cardiac surgery. | Several CXC-chemokines, of which interleukin (IL)-8 is the prototype, are potent neutrophil chemotactic and activating cytokines, inducing the secretion of granule proteins and the generation of reactive oxygen intermediates that may cause tissue damage and amplify inflammatory responses. Here, we investigated whether chemokines play a key role in the inflammatory process following cardiac surgery with cardiopulmonary bypass (CPB) in children. We performed an observational prospective clinical study of 40 pediatric patients before, during, and after open heart surgery with CPB. Plasma levels of chemokines, myeloperoxidase (MPO), and lactoferrin were measured by immunoassays. Cell surface receptors were detected by flow cytometry. Plasma levels of IL-8 were increased after CPB, correlating strongly with a reduction of expression of the CXC-chemokine receptors (CXCR) 1 and 2 on neutrophils indicating in vivo activation of neutrophils by IL-8. Other CXC-chemokines with Glu-Leu-Arg motif showed no correlation with CXCR1 or CXCR2 expression. Two components of neutrophilic granules, MPO and lactoferrin, were strongly elevated postoperatively, and the levels of both were correlated with IL-8. Levels of monocyte chemoattractant protein (MCP)-1 were increased postoperatively, correlating with a reduction of CCR2 expression and an increase of CD11b expression on monocytes, suggesting monocyte activation by MCP-1. The early postoperative course was complicated in patients with an increase of these inflammatory parameters. Impaired cardiovascular function correlated with increased levels of IL-8 and activation of neutrophils and was most prominent in patients with a long time on CPB and in those with cyanotic heart lesions. In conclusion, MCP-1 is involved in the regulation of chemotaxis and function of monocytes during and early after the end of CPB. Activation of neutrophils and down-regulation of CXCR1 and CXCR2 were predominantly caused by IL-8. This activation implies release of components of neutrophilic granules and correlates with the need for inotropic support. |
15545816 | The recovery of posterior cornea and anterior lens radii by a novel ray-tracing method. | Methods for estimating ocular surface radii are typically based on paraxial vergence calculations, need to account for finite source positions, and require refocusing of the camera. This article describes (1) a telecentric ray-finding method; and (2) its application to the problem of determining posterior cornea (R2) and anterior lens (R3) radii by a regression procedure that addresses these issues. The ray-finding algorithm simulates Purkinje image heights Pj(h) (for j = 2, 3; for the Le Grand eye) for the expected range of Rj. A two-step cubic regression procedure fits this image data globally and then over a refined interval to estimate Rj locally. The goodness of fit is measured by the R statistic. A standard method is compared with the new method in simulation. Mean absolute errors and SD's are recorded for 10 randomly chosen R2 and R3. The effect of errors caused by (1) axial shift of the posterior cornea and anterior lens (axially up to +/-0.1 mm); and (2) camera digitization (pixel sizes of 20 microm) are simulated. The method can make use of general surface height information; therefore, it is tested on an eye with nonspherical cornea shape (a toroidal surface). The time to generate Rj is no more than 45 s (R3), with R > 0.9999. The errors for the unmodified eye are (1.3 +/- 2.1) x 10 mm (R2) and (2.4 +/- 1.6) x 10 mm (R3) (new) vs. (5.6 +/- 0.9) x 10 mm (R2) and (1.1 +/- 1.0) x 10 mm (R3) (standard). Digitization increases errors to 0.32 +/- 0.16 mm (R2) and 0.10 +/- 0.10 (R3) (new) vs. 0.45 +/- 0.33 mm (R2) and 0.48 +/- 0.13 mm (R3) (standard). Axial shift error for R2 is similar between methods, with a tendency toward lower error for the new method given digitization error. This trend is found for R3, although the new method now does consistently better with digitization error. Shift contributes the smaller proportion of total error (approximately 10 mm) compared with digitization (approximately 10 mm). The errors for the toroidal surface are (5.7 +/- 7.6) x 10 mm (R2) and (1.1 +/- 0.7) x 10 mm (R3) (new) compared with errors of 0.18 +/- 0.01 mm (R2) and 0.44 +/- 0.07 mm (R3) (standard). The new method produces better results in this case. A telecentric image-computing algorithm produces accurate image positions. A two-step cubic regression produces accurate estimates of R2 and R3 (errors approximately 10 mm). This error increases with axial shift (approximately 10 mm) and digitization (approximately 10 mm). The new method does better than a standard method ignoring all the errors and tends to handle digitization error better. The new method works well on a toroidal anterior cornea. Testing on model/real eyes is required. Efforts are continuing to refine methods for videophakometry. |
15545815 | Tolerating vertex distance changes for spherocylindrical corrections. | Prescriptions depend on the vertex distance. Although weak prescriptions are insensitive to a vertex distance change, stronger ones must be adjusted if the vertex distance is modified by an appreciable amount. The tolerable amount can be specified for pure spherical powers. For spherocylindrical corrections, the concept of dioptric distance is invoked in this article and applied to the propagation of an astigmatic wavefront. This leads to a simple rule that is well suited to decide on the necessity of modifying a prescription. |
15545814 | Critique of claims of improved visual acuity after hypnotic suggestion. | Psychological approaches to improving vision present an enticing alternative to invasive procedures and corrective lenses; hypnotic suggestion is one such technique. During the past 60 years, multiple studies have documented improvements in the vision of myopic individuals after hypnotic interventions. Given the increasing interest in behavioral and alternative approaches, we have reviewed the pertinent studies to evaluate their validity. We delineate various shortcomings in these reports, including potential methodological caveats, problems with experimental controls, and controversial data interpretation. Overall, the data do not seem to support hypnosis as a viable option for significant long-term improvement of myopia. However, hypnosis can increase one's subjective feeling of enhanced visual acuity by affecting higher cognitive functions, such as attention, memorization, and perceptual learning, which could influence performance on visual tasks. |
15545813 | A novel low-order method for recovery of the corneal shape. | To describe a novel low-order method for the recovery of the corneal height from videokeratographically obtained images. The method uses an iterative cubic approach with implicit continuous curvature. Convergence is easily established for a particular videokeratograph. The effect of skew rays is treated in a postprocessing step. Four simulated model corneas are tested: (1) an asphere; (2) an ellipsoid; (3) a radially keratotomized cornea; and (4) a simulation of photorefractive keratectomy (PRK). The corneal height, slope, and tilt are compared against theory and a 2nd order Taylor series method using root mean square error measures. The effect of lateral and axial shifts (up to 0.1 mm) is examined. The two methods are tested (experimentally) on an 8-mm spherical calibration ball, in which the image data are processed using a least-squares calibration procedure. The lowest height errors are found for the asphere and PRK models (4.5 x 10 microm and 3.6 x 10 microm). The maximum height error is 0.38 microm (ellipsoid), with 0.14 microm average overall error and 0.45 microm error for the 8-mm calibration ball. The comparison method has an average error of 0.92 microm, with maximum error of 1.5 microm (PRK) and 0.55 microm error for the 8-mm calibration ball. Shift induces larger (approximately 200 microm/mm) height errors than axial shift (approximately 2 microm/mm), but the errors are similar between methods. A demonstration on additional ellipsoids suggests the new algorithm (without skew ray compensation) is not as effective as the comparison method for increasingly nonspherical surfaces. The method has a short completion time of 2.3 s in seven iterations using MATLAB version 5.0 (The MathWorks, Inc., Natick, MA), running on a Pentium III 667-MHz processor with 128 MB RAM, and running the Windows 2000 operating system (Microsoft, Redmond, WA). An accurate, simple, robust, iteratively stable and fast method for estimating the corneal shape is described. A recovery with continuous curvature and skew ray compensation suggests a potential improvement within the context of current standard corneal shape recovery algorithms. |
15545812 | Corneal endothelial cell morphometry and corneal thickness in diabetic contact lens wearers. | To assess corneal endothelial cell morphometry and corneal thickness in diabetic patients who wear contact lenses. Images of the central corneal endothelium were analyzed quantitatively and qualitatively and corneal thickness was measured in a group of diabetic patients (type 1, N = 26; type 2, N = 4) who wear soft contact lenses and in a group of nondiabetic age-matched control subjects who were also contact lens wearers. Endothelial cell characteristics and corneal thickness values were similar for the two groups (p > 0.05). Four of the diabetic patients (and none of the nondiabetic patients) displayed folds in the endothelial mosaic. The morphometry of corneal endothelial cells and central corneal thickness values in diabetic patients who wear soft contact lenses were not appreciably different from those found in lens-wearing control subjects. |
15545811 | Measurements of ocular aberrations and light scatter in healthy subjects. | To report and validate an optical imaging system that provides measurements of higher order ocular aberrations and light scatter in human eyes. An optical imaging system has been established that provides for combined measurements of ocular aberrations and light scatter. A laser beam was expanded and focused to a point on the retina by the optics of the eye. Wavefront sensing was performed with a Shack-Hartmann aberrometer to determine the wavefront aberration function and calculate the point spread function, giving information on ocular aberrations. A cylindrical lens was placed in the path of the incident laser beam path, and the line spread function was derived from the laser slit, giving information on combined ocular aberrations and light scatter. A relative index for ocular light scatter was determined by subtracting the area under the two line spread functions. Measurements were performed in one eye of 20 normal healthy subjects. The subjects' ages ranged between 21 and 78 years, and the average for all the eyes was 43 +/- 17 years (mean +/- SD). Higher order ocular aberrations were correlated with subjects' ages (r = 0.6; p = 0.01; N = 20). Combined higher order ocular aberrations and light scatter were correlated with age (r = 0.7; p = 0.0002; N = 20). Light scatter was correlated with age (r = 0.6; p = 0.002; N = 20). A method was established to measure age-related changes in ocular higher order aberrations and light scatter. Differentiating the contribution of ocular aberrations and light scatter to the retinal image quality has potential value for anticipating the outcome of procedures that attempt to compensate for ocular aberrations and for providing information on factors that degrade the optical performance of the eye in health and disease. |
15545810 | Simulated impairment of contrast sensitivity: performance and gaze behavior during locomotion through a built environment. | An experimental study investigated the effects of simulated impairment of contrast sensitivity (CS) on performance and eye gaze patterns during locomotion through a library. Normally sighted participants with simulated CS impairment (diffusive blur) walked two routes, one entailing limited change in direction (simple) and the other entailing several changes in direction (complex), while eye movements relative to the scene were recorded. Performance variables included walking speed in completing the route, pauses during travel, and collisions with objects on the route. For eye movements, dwell time and saccades were determined for each of three object classes: (1) objects on the route below eye level; (2) objects on the route extending above eye level; and (3) elsewhere-objects not on the route. Walking speed was significantly affected by CS level and by route; pauses and collisions were rare. Dwell times and saccades suggested limited attention directed to low-level objects, except for CS impairment on the complex route. In the complex route, saccades and dwell times in the object class "elsewhere" were also reduced. The results for the simple route suggest ballistic strategies: the participant appraises the scene and follows a more or less predetermined path. For the complex route, CS impairment appears to adversely affect information processing and locomotion. The results have implications for the design of built environments, especially with regard to the safety of visually impaired occupants during emergency scenarios. |
15545809 | Gain and movement time of convergence-accommodation in preschool children. | Convergence-accommodation is the synkinetic change in accommodation driven by vergence. A few studies have investigated the static and dynamic properties of this cross-link in adults but little is known about convergence-accommodation in children. The purpose of this study was to develop a technique for measuring convergence-accommodation and to study its dynamics (gain and movement time) in a sample of pre-school children. Convergence-accommodation measures were examined on thiry-seven normal pre-school children (mean age = 4.0 +/- 1.31 yrs). Stimulus CA/C (sCA/C) ratios and movement time measures of convergence-accommodation were assessed using a photorefractor while subjects viewed a DOG target. Repeated measures were obtained on eight normal adults (mean age = 23 +/- 0.2 yrs). The mean sCA/C ratios and movement times were not significantly different between adults and children (0.10 D/Delta [0.61 D/M.A.], 743 +/- 70 ms and 0.11 D/Delta [0.50 D/M.A.], 787 +/- 216 ms). Repeated measures on adults showed a non-significant mean difference of 0.001 D/Delta. The results suggest that the possible differences in crystalline lens (plant) characteristics between children and adults do not appear to influence convergence-accommodation gain or duration. |
15545808 | Repeatability of IOLMaster biometry in children. | This study compares the repeatability of IOLMaster (Zeiss, Oberkochen, Germany) axial dimension measurements and conventional ultrasonography in children. A series of IOLMaster (partial coherence interferometry, optical pachometry) and Echoscan (US 800, Nidek, Tokyo, Japan) (ultrasound) measurements were taken on 179 Chinese children (mean age, 10.6 +/- 0.8 years) taking part in a longitudinal study of myopia development, and the measurements were repeated on 37 of these subjects. IOLMaster axial length measurements showed better repeatability (95% limits of agreement for repeatability, -0.047 to 0.038 mm) than Echoscan axial length measurements (95% limits of agreement for repeatability, -0.85 to 0.67 mm). IOLMaster anterior chamber depth measurements also showed better repeatability (95% limits of agreement for repeatability, -0.053 to 0.073 mm) than Echoscan anterior chamber depth measurements (95% limits of agreement for repeatability, -0.57 to 0.49 mm). IOLMaster measurements were, on average, slightly larger than Echoscan measurements for axial length (by 0.14 mm) and anterior chamber depth (0.09 mm). Partial coherence interferometry techniques, such as that used by IOLMaster, should be considered as the standard technique for axial length measurement in children because they are noninvasive, highly precise, and easy to use. |
15545807 | Normal eye growth in emmetropic schoolchildren. | The purpose of this report is to describe the normal growth pattern of the optical components of the eye in a cohort of emmetropic, school-aged children. Emmetropia was defined as refractive error (measured by cycloplegic autorefraction) in the vertical and horizontal meridians of the right eye between +1.00 D and -0.25 D at all the visits. This definition resulted in a sample of 194 children enrolled in the Orinda Longitudinal Study of Myopia (OLSM) between ages 6 and 14 years with at least 2 years of follow-up evaluation (across three annual visits) between 1989 and 2000. The optical components measured included corneal power, anterior chamber depth, crystalline lens thickness, Gullstrand lens power, calculated lens power, crystalline lens index, vitreous chamber depth, and axial length. Corneal power and anterior chamber depth were best modeled as quadratic functions of ln (age). The model involving the square of the inverse of age best described calculated lens power and crystalline lens index. The relationship between age and crystalline lens thickness was best described using a linear function of age with a point of inflection. A linear function of ln (age) with a point of inflection best described the relationship between age and axial length, Gullstrand lens power, and vitreous chamber depth. For five of the eight components (crystalline lens thickness, Gullstrand lens power, calculated lens power, corneal power, and crystalline lens index), the line modeling the data was negative in overall direction, indicating that the component value decreased with age. The upward trend of the line modeling axial length, anterior chamber depth, and vitreous chamber depth reflected the continued growth of the eye from age 6 years to age 15 years. A picture of normal eye growth in emmetropes from ages 6 to 15 years is provided based on a combination of cross-sectional and longitudinal data. Axial elongation, crystalline lens flattening and thinning, and decrease in lens power are its hallmarks. |
15545791 | Relation between climacteric symptoms and ovarian hypofunction in middle-aged and older Japanese women. | To gain insight into the characteristics and current status of climacteric symptoms reported by middle-aged and older women in Japan, we surveyed women presenting at our menopause clinic. The participants included 1,069 women, ranging in age from 40 to less than 60 years (mean age, 50.2 y). Climacteric (indefinite) symptoms were objectively assessed with the use of the Keio questionnaire, which grades the severity of 40 types of symptoms classified into 20 subgroups. The total scores obtained for the 40 symptoms were used to calculate symptom prevalence and severity. To evaluate ovarian function, concentrations of estradiol and follicle-stimulating hormone (FSH) in sera were measured. The most frequent symptom was general fatigue, reported by 88.2% of the women. Shoulder stiffness was the symptom rated to be severe by the highest percentage of women (38.1%). The prevalence and severity of hot flushes (and sweats) were slightly higher in perimenopausal and early postmenopausal women than in premenopausal and late postmenopausal women. The prevalence and severity of hot flushes and sweats were higher in women with estradiol < 25 pg/mL and FSH > 40 mIU/mL than in those with estradiol > or = 25 pg/mL and FSH < or = 40 mIU/mL. General fatigue and shoulder stiffness, symptoms with low hormone dependence, are the two most frequent climacteric symptoms in our clinic. Hot flushes and sweats, symptoms with high hormone dependence, are also common symptoms. |
15545790 | Changes in bone density and turnover after alendronate or estrogen withdrawal. | To compare bone mineral density (BMD) and bone turnover changes after therapy withdrawal in postmenopausal women treated with alendronate or estrogen-progestin. In this randomized, blinded, multinational, placebo-controlled trial, 1,609 healthy postmenopausal women ages 45 to 59 years were assigned to receive alendronate, placebo, or open-label estrogen-progestin (conjugated equine estrogens plus medroxyprogesterone acetate or a cyclic regimen of 17 beta-estradiol, norethisterone acetate and estradiol). Of the original women, one third after year 2 and one third after year 4 were switched from alendronate to placebo, while remaining blinded to treatment assignment. The women taking estrogen-progestin in years 1 to 4 were followed off therapy in years 5 and 6. BMD at the lumbar spine and hip and biochemical markers of bone turnover were measured. The treatment groups described in the current report represent 860 women at baseline; 481 women entered year 5, and 430 completed 6 years. BMD steadily decreased in the placebo group during all 6 years. In contrast, spine and hip BMD increased during the first 4 years in the groups receiving daily continuous alendronate 5 mg and estrogen-progestin. During years 5 and 6, BMD decreased at the lumbar spine -2.42% (95% CI = -4.10, -0.74) and total hip -1.09% (-2.60, 0.41) in the group previously treated with alendronate 5 mg for 4 years. In comparison, large BMD decreases were observed at the spine [-7.69% (-8.96, -6.41)] and total hip [-5.16% (-6.30, -4.01)] among women who had received estrogen-progestin for 4 years. Alendronate produces greater residual skeletal effects than estrogen-progestin after therapy discontinuation. |
15545789 | Osteoarthritis and osteoporosis in postmenopausal women: clinical similarities and differences. | Osteoarthritis and osteoporosis are two major health problems affecting more than 60% of post-menopausal women in the United States. The promotion of healthy aging and the prevention and reduction of morbidity and mortality is a main concern for healthcare providers. The similarities and differences in pathophysiology, diagnosis, and treatment for osteoarthritis and osteoporosis are often not clear for clinicians. Some osteoporosis treatments, including bisphosphonates and vitamin D, seem to have a beneficial effect on osteoarthritis as well. A review of these two conditions in terms of bone mineral density, bone turnover, hormonal effects, and treatment options will be discussed. |
15545788 | Antral follicle counts are related to age at natural fertility loss and age at menopause. | The variability in ultrasound-based antral follicle counts sized 2-10 mm after allowing for age-related decline is considerable. This may represent differences in actual reproductive age among women. This hypothesis was tested by cohort comparison for distribution of age at occurrence of reproductive events. A model with a nonlinear mean decline with age was fitted to antral follicle counts (AFC) obtained in 163 regularly cycling fertile volunteers. Ages at last child birth and menopause were predicted from the individual AFC by using thresholds to represent these events and the model for decline with age. Distributions of the observed ages at last childbirth (proxy variable for loss of natural fertility) and ages at menopause were obtained from the BALSAC demographic database and the Prospect-EPIC study, respectively. The observed distributions were compared with the predicted distributions by using visual comparison and quantile-quantile plots. Predictions of age at last child and age at menopause were done using percentiles of the modeled AFC distribution for given age, and corresponding percentiles of the predicted distributions of age at these reproductive events, with predictions following from the position of a woman's AFC relative to these percentiles. The predicted distributions of age at last child and age at menopause showed good agreement with the observed distributions in the BALSAC and EPIC cohort. Compared with age alone, antral follicle counts gave some additional information for individual prediction of age at last child and menopause. The link between declining antral follicle counts and reproductively significant events like loss of natural fertility and menopause is strengthened by the high degree of similarity among the predicted and observed age distributions. Predictive usefulness of this relationship in a clinical setting may be more marginal, except in the case of women who have low AFCs for their age. |
15545787 | Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. | Age at menopause and age at the start of the preceding period of cycle irregularity (menopausal transition) show considerable individual variation. In this study we explored several markers for their ability to predict the occurrence of the transition to menopause. A group of 81 normal women between 25 and 46 years of age visited the clinic two times (at T1 and T2) with an average interval of 4 years. All had a regular menstrual cycle pattern at T1. At T1, anti-mullerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B and estradiol (E2) were measured, and an antral follicle count (AFC) was made during the early follicular phase. At T2, information regarding cycle length and variability was obtained. Menopause transition was defined as a mean cycle length of less than 21 days or more than 35 days or as a mean cycle length of 21 to 35 days, but with the next cycle not predictable within 7 days during the last half year. A logistic regression analysis was performed, with the outcome measure as menopause transition. The area under the receiver operating curve (ROCAUC) was calculated as a measure of predictive accuracy. In 14 volunteers, the cycle had become irregular at T2. Compared with women with a regular cycle at T2, these women were significantly older (median 44.7 vs 39.8 y, P < 0.001) and differed significantly in AFC, AMH, FSH, and inhibin B levels assessed at T1. All parameters with the exception of E2 were significantly associated with the occurrence of cycle irregularity; AMH, AFC, and age had the highest predictive accuracy (ROCAUC 0.87, 0.80, and 0.82, respectively). After adjusting for age, only AMH and inhibin B were significantly associated with cycle irregularity. Inclusion of inhibin B and age to AMH in a multivariable model improved the predictive accuracy (ROCAUC 0.92). The novel marker AMH is a promising predictor for the occurrence of menopausal transition within 4 years. Adding inhibin B improved the prediction. Therefore, AMH alone or in combination with inhibin B may well prove a useful indicator for the reproductive status of an individual woman. |
15545774 | In situ depth profiling of 137Cs contamination in soils at the Idaho National Engineering and Environmental Laboratory. | Preremediation characterization of Cs contamination in soils was conducted at the Auxiliary Reactor Area (ARA)-23 Comprehensive Environmental Response, Compensation, and Liability Act site, located at the Idaho National Engineering and Environmental Laboratory (INEEL). Characterization activities included verification of the lateral extent of the contaminated area using the INEEL vehicle-mounted Global Positioning Radiometric Scanner. The vertical extent of the contamination in select areas of the site was evaluated with an in situ gamma-ray spectrometer, and depth discrete samples were collected at 5-cm depth intervals down to a depth of 20.3 cm. A comparison was made between the depth distribution data from the in situ spectrometric measurements and the physical, depth discrete samples. The results of the study and of the aforementioned comparison indicate that use of in situ high-purity germanium (HPGe) detectors during the remediation of the ARA-23 site will aid in directing the depth of excavation, thereby helping to (a) minimize the amount of soils excavated and removed for disposal, and (b) reduce overall project costs. |
15545773 | Uranium in hot water tanks: a source of TENORM. | Uranium deposits were detected inside hot water tanks using gamma-ray spectroscopic techniques and corroborated by the difference in the uranium concentration of the groundwater entering and leaving the hot water tanks. In-situ gamma-ray spectroscopy was performed using a transportable high-purity germanium (HPGe) gamma-ray spectrometer to estimate the mass of uranium in the hot water tanks. Gamma-ray spectroscopic analyses of hot water tanks in four residences with groundwater uranium concentration between 732 and 7,667 mug L revealed an estimated 3.5 to 69 g of uranium in each hot water tank. The uranium deposit within the tanks was indicated by the 143.8, 163.4, and 185.7 keV gamma rays of U and confirmed with the 63.3, 92.3, and 92.8 keV gamma rays of Th as well as the 1,001 keV peak of Pa. An average decrease in uranium concentration of 23% was observed in the groundwater that passed through the hot water tanks. Additionally, once "uranium free" water entered the hot water tanks, the uranium deposits within the tanks resulted in an increase in the uranium concentration in the effluent water. The groundwater had an alkalinity in the range of 46-96 mg L as CaCO3 and a pH range of 7.3-8.1. The accumulation of uranium in these hot water tanks results in them being classified as technologically enhanced naturally occurring radioactive materials (TENORM). |
15545771 | Residential radon exposure and lung cancer risk: commentary on Cohen's county-based study. | The large United States county-based study () in which an inverse relationship has been suggested between residential low-dose radon levels and lung cancer mortality has been reviewed. While this study has been used to evaluate the validity of the linear nonthreshold theory, the grouped nature of its data limits the usefulness of this application. Our assessment of the study's approach, including a reanalysis of its data, also indicates that the likelihood of strong, undetected confounding effects by cigarette smoking, coupled with approximations of data values and uncertainties in accuracy of data sources regarding levels of radon exposure and intensity of smoking, compromises the study's analytic power. The most clear data for estimating lung cancer risk from low levels of radon exposure continue to rest with higher-dose studies of miner populations in which projections to zero dose are consistent with estimates arising from most case-control studies regarding residential exposure. |
15545770 | Sample bottle design improvements for radon emanation analysis of natural waters. | The "radon emanation" method of analysis for Rn and Ra in natural waters has been used by scientists for more than 30 years. We have examined the use of a new plastic bottle design as a viable option and improvement to traditional glass designs. The advantages of the new design over that used previously in our laboratory include a larger volume, lower blank, less fragile nature, and ease of handling in the field. Extensive calibration of the new design yielded an average efficiency of 70.9 +/- 1.7% and showed that an accurate blank value can be determined for each sample based on its specific holding time. Based on a 5-L sample and a 60-min count time, minimum detectable activities (MDA) range from 1.0 to 1.2 mBq L for Rn and Ra, respectively. Memory effect experiments have shown that activity artifacts are negligible when reusing the sampling containers. In addition, intra- and inter-laboratory comparisons show that the new design gives reliable results. |
15545769 | The application of retrospective luminescence dosimetry in areas affected by fallout from the semipalatinsk nuclear test site: an evaluation of potential. | Luminescence retrospective dosimetry techniques have been applied with ceramic bricks to determine the cumulative external gamma dose due to fallout, primarily from the 1949 test, in populated regions lying NE of the Semipalatinsk Nuclear Test Site in Altai, Russia, and the Semipalatinsk region, Kazakhstan. As part of a pilot study, nine settlements were examined, three within the regions of highest predicted dose (Dolon in Kazakshstan; Laptev Log and Leshoz Topolinskiy in Russia) and the remainder of lower predicted dose (Akkol, Bolshaya Vladimrovka, Kanonerka, and Izvestka in Kazakshstan; Rubtsovsk and Kuria in Russia) within the lateral regions of the fallout trace due to the 1949 test. The settlement of Kainar, mainly affected by the 24 September 1951 nuclear test, was also examined. The bricks from this region were found to be generally suitable for use with the luminescence method. Estimates of cumulative absorbed dose in air due to fallout for Dolon and Kanonerka in Kazakshstan and Leshoz Topolinskiy were 475 +/- 110 mGy, 240 +/- 60 mGy, and 230 +/- 70 mGy, respectively. The result obtained in Dolon village is in agreement with published calculated estimates of dose normalized to Cs concentration in soil. At all the other locations (except Kainar) the experimental values of cumulative absorbed dose obtained indicated no significant dose due to fallout that could be detected within a margin of about 25 mGy. The results demonstrate the potential suitability of the luminescence method to map variations in cumulative dose within the relatively narrow corridor of fallout distribution from the 1949 test. Such work is needed to provide the basis for accurate dose reconstruction in settlements since the predominance of short-lived radionuclides in the fallout and a high degree of heterogeneity in the distribution of fallout are problematic for the application of conventional dosimetry techniques. |
15545768 | corneal epithelial injury thresholds for exposures to 1.54 microm radiation-dependence on beam diameter. | Corneal epithelial injury thresholds have been determined for exposures to 1.54 mum infrared radiation from an Erbium fiber laser. Thresholds were determined for beam diameters from 0.05 to 0.7 cm for exposures having durations from approximately 1 to 100 s and for a fixed beam diameter of 0.1 cm for exposures with durations between 0.036 and 0.26 s. Near-threshold damage appeared within 30 min post-exposure. There was no evidence of latent damage from lesser exposures appearing up to 24-48 h post-exposure. The dependence of the threshold radiant exposures on laser beam diameter for exposures >1 s provides strong evidence supporting a critical temperature damage model. However, the shorter exposures are not in accord with a critical temperature damage model. Thresholds for exposures longer than 1 s are greater than 10 times the maximum permissible exposure (MPE) in ANSI Z-136.5-2000; however, the safety factor decreases to less than 10 for exposures less than 0.1 s with a 0.1-cm-diameter beam. |
15545767 | Projecting the time trend of thyroid cancers: its impact on assessment of radiation-induced cancer risks. | The incidence of thyroid cancer, which may be induced by ionizing radiation, has been rising in most Western countries for more than 20 years. In France, public worry about this increase and its possible connection with the fallout from Chernobyl led the government to ask for an evaluation of the health impact of this accident and an assessment of the feasibility of an epidemiological study. These requests raise two methodological questions: Which risk model should be used to relate exposure to risk? What is known about the spontaneous incidence rate of thyroid cancers? This article analyzes the impact of the time trend in the spontaneous incidence of thyroid cancers over the past 20 years in France when evaluating the risk of radiation-induced cancer. Age-period-cohort models were used to model the trend of spontaneous incidence from 1978 through 1997 and then to apply two scenarios for projections up to 2007: one with a constant incidence, the other using the trend observed over the past 20 years. Then the risk was assessed for a hypothetical population of 30,000 children aged 0 to 15 y, exposed to a hypothetical 0.1 Gy thyroid dose. The analysis shows that consideration of the trend instead of a constant spontaneous incidence can yield substantial differences in the risk estimates for thyroid cancer. |
15545766 | Characterization of plutonium aerosol collected during an accident. | This study determined the plutonium particle size distribution and dissolution rate of PuO2 aerosol collected during the 16 March 2000 release of an undetermined amount of PuO2 in a room within a plutonium facility at Los Alamos National Laboratory. The facility has been in operation since 1978 to support the development, fabrication, and testing of Pu heat sources for the U.S. Department of Energy. Several workers were in the room at the time of the release and in vivo study of five of the workers began the day after the exposure event. Four of the subjects subsequently received chelation therapy. Over 30 fixed air filter samplers (FASs) and four continuous air monitors (CAMs) were operating in the room during the radiological release. One 47-mm-diameter glass fiber FAS filter and one 25-cm-diameter mixed cellulose ester CAM filter containing Pu aerosol from the incident were examined in the study described here. Total alpha radioactivity on the filters was determined by gross alpha counting. Isotopic identification of the Pu was made by alpha spectrometry. Film autoradiography was used to characterize the spatial distribution of alpha-emitting particles on the filters. Track-etch autoradiography was used to estimate the distribution of alpha radioactivity in individual plutonium particles on the filters for particle size measurement. The glass fiber filter was then cut into six sections. Particles from two sections were resuspended in alcohol, dispersed as an aerosol using a Lovelace nebulizer, and characterized by aerodynamic diameter using a Lovelace Multi-jet cascade impactor. The measured activity median aerodynamic diameter from the cascade impactor was 4.8 mum with a geometric standard deviation of 1.5. That agreed with the size distribution obtained from the alpha track detection technique. The remaining four filter sections were used in an in vitro dissolution study with synthetic serum ultrafiltrate. The retention of undissolved Pu was consistent with a biphasic exponential function. The majority of the Pu dissolved with a half-time of 900 d. The information on particle size distribution and solubility from this study was useful in assigning a radiation dose to the exposed workers, supporting the decision to administer chelation therapy, and providing a model for characterizing accident-associated aerosols in the future. |
15545765 | Test of CAP88-PC's predicted concentrations of tritium in air at Lawrence Livermore National Laboratory. | Based on annual tritium release rates from the five sources of tritium at Lawrence Livermore National Laboratory and the Tritium Research Laboratory at Sandia National Laboratory, the regulatory dispersion and dose model, CAP88-PC, was used to predict tritium concentrations in air at perimeter and offsite air surveillance monitoring locations for 1986 through 2001. These predictions were compared with mean annual measured concentrations, based on biweekly sampling. Deterministic predictions were compared with deterministic observations using predicted-to-observed ratios. In addition, the uncertainty on observations and predictions was assessed: when the uncertainty bounds of the observations overlapped with the uncertainty bounds of the predictions, the predictions were assumed to agree with the observations with high probability. Deterministically, 54% of all predictions were higher than the observations, and 96% fell within a factor of three. Accounting for uncertainty, 75% of all predictions agreed with the observations; 87% of the predictions either matched or exceeded the observations. Predictions equaled or exceeded observations at those sampling locations towards which the wind blows most frequently, except those in the hills. Under-predictions were seen at locations towards which the wind blows infrequently when released tritium was from elevated sources. When a high fraction of tritium was from area (diffuse) sources, predictions matched observations. |
15545754 | Outline of a medical genetics curriculum for internal medicine residency training programs. | To keep pace with the rapid advances in medical genetics, internal medicine residency training programs need to train internists to develop new attitudes, knowledge bases, and skill sets. Currently, such programs have no medical genetics curriculum. Thus, to set a minimum standard for genetics education in the context of training in internal medicine, the Internal Medicine Residency Training Program Genetics Curriculum Committee was formed, with members representing professional organizations of medical geneticists, internists, genetic counselors, internal medicine and genetics residency program directors, and internal medicine residents. The committee's task was to develop a concise outline of a medical genetics curriculum for residents in internal medicine in accordance with requirements of the Residency Review Committee for Internal Medicine of the Accreditation Council for Graduate Medical Education. The curriculum outline was drafted and circulated for comment. Before publication, the final document was approved by those member organizations that had a policy of approving curricula. Key learning objectives of the curriculum include appreciation of the rapid advances in genetics, the need for lifelong learning, the need for referral, and the role of genetic counselors and medical geneticists, as well as developing the ability to construct and analyze a three-generation pedigree. A wide variety of teaching methods can be useful in these regards, including didactic lectures, multimedia CD- ROMs, and clinical experience. Teaching should be related to clinical experiences whenever possible. The curriculum developed by the committee and presented in this article will assist in teaching residents the attitudes, knowledge, and skills they will require. |
15545748 | Familial 22q11.2 deletions in DiGeorge/velocardiofacial syndrome are predominantly smaller than the commonly observed 3Mb. | DiGeorge/velocardiofacial syndrome (DG/VCFS) is the most common cytogenetically characterized microdeletion of 22q11.2 region. In approximately 90% of patients, the deletion size is 3 Mb, whereas the remaining range from 1.5 to 2.5 Mb. The purpose of this study was to test the hypothesis that small deletions may be more easily tolerated in a familial fashion than larger deletions, especially for this syndrome. Sixteen FISH probes designed from bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PACs) mapped to 22q11.2 were used to determine the deletion sizes in 22 individuals from ten families with familial 22q11.2 deletion detected by standard FISH tests. Seven families had deletions of < 3 Mb ( approximately 1.5 Mb) in size and 3 families had the common 3-Mb deletion. The 70% frequency of smaller sized deletions among this group of patients with familial del(22)(q11.2) is significantly higher than that reported among unselected group of patients with del(22)(q11.2) (P < 0.0001, Fisher exact test). Familial del(22)(q11.2) are predominantly smaller than the common deletion size of 3 Mb, indicating that there may be some underlying mechanisms that favor parent-to-child transmission of smaller deletions in individuals with del(22)(q11.2), therefore, underscoring the need to exclude a familial basis in cases of del(22)(q11.2) smaller than 3 Mb. |
15545747 | Perceptions of genetic discrimination among at-risk relatives of colorectal cancer patients. | To explore the concerns of at-risk relatives of colorectal cancer patients about genetic discrimination and their awareness of current legislative protections. A questionnaire was sent to unaffected individuals with a family history of colorectal cancer who had enrolled in the Johns Hopkins Hereditary Colorectal Cancer Registry (N = 777). Of the 470 respondents, approximately half rated their level of concern about genetic discrimination as high. The majority of respondents, 79%, learned about genetic discrimination from at least one media source (television, newspapers, magazines, and radio). If they were to pursue genetic testing, respondents with a higher level of concern about genetic discrimination would be significantly more likely to pay out of pocket, use an alias, or ask for test results to be excluded from their medical record. Awareness and understanding of legislation regarding genetic discrimination was found to be minimal. Findings from this study demonstrate the negative effect of concerns about genetic discrimination on decisions about utilization of genetic services. Stronger legislative protections against genetic discrimination and increased public education through the scientific community and media sources are needed. |
15545746 | Family communication about positive BRCA1 and BRCA2 genetic test results. | The identification of a BRCA1 or BRCA2 genetic mutation can provide important health information to individuals who receive this result, but it can also provide crucial cancer risk information to family members. Most of the research on communication of genetic test results has focused on first degree relatives. The purpose of this retrospective study was to examine the process of communicating a positive BRCA1 or BRCA2 genetic test result to male and female first, second, and third degree relatives. Participants were 38 female mutation carriers who responded to a written survey assessing the number and relationship of relatives informed, methods used to inform relatives, topics discussed, and motivations and barriers for communication. Overall, 59% (470/803) of first, second, and third degree relatives were informed. The proportion of informed parents, siblings, and offspring was nearly twice that of more distant relatives including nieces, nephews, aunts, uncles, grandchildren, and cousins (88% versus 45%; P = 0.02). The method of communication differed by the gender of the relative, as did some of the topics discussed. The most important reasons for discussing the genetic test results were (1) to inform the relatives of their risk, (2) to suggest that they be tested, and (3) to fulfill a perceived duty to inform. The major barrier to communication was little contact and/or emotionally distant relationships. Female mutation carriers act on a perceived duty to inform close relatives of their positive test result; however, there is a need for genetic counseling strategies that address communication with more distant relatives. |
15545745 | Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. | Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal-dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, calcification of the falx cerebri, and spine and rib anomalies. NBCCS is due to mutations in PTCH1, the human homologue of the Drosophila segment polarity gene patched. Mutations are detected in approximately 60% to 85% of individuals tested by sequencing of PTCH1; therefore, clinical examination and x-rays remain important in diagnosis of NBCCS. We studied 82 NBCCS patients and 38 of their unaffected siblings at the NIH between 1985 and 1994. Chest, rib, spine, skull, hand and foot x-rays, brain MRI or CT, and pelvic ultrasound (in females) were obtained in the affected individuals and compared to their unaffected relatives. The following features were significantly more frequent in those with NBCCS: calcification of the falx cerebri, the most frequent radiological feature, was present in 79% of patients > 20 years and in 37% <20 years, calcification of the tentorium cerebellum was present in 20%, bridging of the sella in 68%, and abnormal frontal sinus aeration in 18% of affected individuals. Bifid ribs most often involving the third, fourth, and fifth ribs were seen in 26%; splayed, fused, and misshapen ribs in a further 16%, and widened ends of clavicles in 12%. Spine X-rays revealed calcification of the nuchal ligament in 18%, fusion of vertebrae in 10%, and hemivertebrae in 15%. Flame-shaped lucencies of the metacarpals and/or phalanges were present in 30%, modeling deformities of the phalanges in 14%, and polydactyly of the feet in 4%. The frequency of scoliosis, cervical ribs, absent or rudimentary ribs, spina bifida occulta, or short 4th metacarpal was not higher in the affected individuals as compared to their unaffected relatives. Except for falx calcification, the frequency of radiological manifestations was similar in different age groups. Cranial CT or MRI in 42 affected individuals revealed asymmetric or dilated ventricles in 24%, cerebral atrophy in 10%, cavum septum pellucidum in 19%, dysgenesis or agenesis of the corpus callosum in 10%, and meningioma in 5%. Ovarian fibromas were detected in 17% of females. This study reports the varied radiological manifestations of NBCCS. In the absence of major features such as basal cell carcinomas, jaw cysts, or falx calcification, which is often not evident until the teen years, other radiological manifestations of the disorder can permit early diagnosis of NBCCS in childhood. This will allow optimum surveillance for medulloblastoma and other neoplasms (cardiac fibromas and basal cell carcinomas) associated with NBCCS. |
15545744 | Maternal meiosis II nondisjunction in trisomy 21 is associated with maternal low socioeconomic status. | We evaluated whether the association of socioeconomic risk factors for trisomy 21 differed by type of maternal meiotic error. We determined meiotic errors by DNA analysis for 150 trisomy 21 cases, and maternal lifetime exposures to low socioeconomic factors by questionnaire. Mothers of meiosis II cases were significantly more likely to be exposed to four low socioeconomic factors than mothers of meiosis I cases (odds ratio = 9.50; 95% confidence interval = 1.8-49.8). Maternal lifetime exposure to poor socioeconomic environment is a risk factor for a trisomy 21, particularly if nondisjunction leads to a maternal meiosis II. |
15545743 | Lipoprotein lipase locus and progression of atherosclerosis in coronary-artery bypass grafts. | Our aim was to test whether polymorphisms in the lipoprotein lipase (LPL) gene were associated with the progression of atherosclerosis in grafts examined in the Post-Coronary Artery Bypass Graft Trial (Post-CABG Trial). 843 subjects in the post-CABG trial were genotyped for the LPL-D9N, N291S, PvuII, (TTTA)n, and HindIII polymorphisms. Associations between genotype and angiographically measured progression of atherosclerosis in grafts, medical history, and family history were examined. Greater progression of atherosclerosis was observed in subjects with LPL-HindIII 2/2 (56% versus 42% of those with other LPL HindIII genotypes, P = 0.025) and with LPL (TTTA)n 4/4 (63% versus 43% of those with other (TTTA)n genotypes, P = 0.020). Mantel-Haenszel analysis yielded an odds ratio of 1.84 for the effect of LPL HindIII 2/2 genotype on the progression of atherosclerosis in grafts (P = 0.015) and demonstrated that the effect of genotype on progression was of the same magnitude as, but independent of, the effect of drug treatment. The LPL-HindIII 2/2 genotype is a marker for genetic variation in the 3'-end of LPL that acts as an independent risk factor for the progression of atherosclerosis in grafts examined in the Post-CABG Trial. |
15545741 | Genetic polymorphisms and heart failure. | Heart failure is a complex clinical syndrome. There is evidence for a genetic contribution to the pathophysiology of heart failure. Considering the fundamental role of neurohormonal factors in the pathophysiology and progression of cardiac dysfunction and hypertrophy, variants of genes involved in this system are logical candidate genes in heart failure. In this report, genetic polymorphisms of the major neurohormonal systems in heart failure will be discussed. Studies on polymorphisms of the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous polymorphisms that may be involved in the development or phenotypic expression of heart failure will be reviewed. Research on left ventricular hypertrophy is also included. The majority of genetic association studies focused on the ACE I/D polymorphism. Initial genetic associations have often been difficult to replicate, mainly due to problems in study design and lack of power. Promising results have been obtained with genetic polymorphisms of the RAAS and sympathetic system. Considering the evidence so far, a modifying role for these polymorphisms seems more likely than a role of these variants as susceptibility genes. Besides the need for larger studies to examine the effects of single nucleotide polymorphisms and haplotypes, future studies also need to focus on the complexity of these systems and study gene-gene interactions and gene-environment interactions. |
15545742 | Genetic tests and their evaluation: can we answer the key questions? | The rapid pace of research in the field of genetics has already yielded many benefits. The development of new genetic tests is one such example. Before there can be widespread uptake of these tests they need to be evaluated to confirm the benefits of their use. The authors review some of the key features of the evaluation of diagnostic tests focusing on analytical and clinical validity. Test properties such as sensitivity, specificity, likelihood ratios, positive and negative predictive values, and how they relate to molecular genetic testing are discussed. Associated issues such as the concepts of disease definition, imperfect reference standards, and false positives are also explored. The authors suggest possible approaches to addressing some of the problems identified. |
15545739 | Fine structure and meiotic behaviour of the male multiple sex chromosomes in the genus Alouatta. | The meiotic cytology and fine structure of the sex multiples in males from two species of the genus Alouatta are presented and compared with descriptions from other species of this genus. As shown in pachytene by synaptonemal complex analysis and in metaphase I by spreading, there is a quadrivalent in male meiosis in A. caraya, which is formed by an X(1)X(2)Y(1)Y(2) complex, while in A. palliata there is a trivalent formed by an X(1)X(2)Y(1) complex. Chromosome painting with human probes shows that A. caraya sex multiples share the same components as those of A. seniculus sara and A. seniculus arctoidea. However, as shown here for A. palliata and by others in A. fusca, there are differences among the multiples of some species. It is shown that in this genus there are several varieties of sex multiples that share some features, and that the origin of these multiples is most probably a primitive development in the genus Alouatta. |
15545738 | Inter- and intra-specific gene-density-correlated radial chromosome territory arrangements are conserved in Old World monkeys. | Recently it has been shown that the gene-density correlated radial distribution of human 18 and 19 homologous chromosome territories (CTs) is conserved in higher primates in spite of chromosomal rearrangements that occurred during evolution. However, these observations were limited to apes and New World monkey species. In order to provide further evidence for the evolutionary conservation of gene-density-correlated CT arrangements, we extended our previous study to Old World monkeys. They comprise the remaining species group to be analyzed in order to obtain a comprehensive overview of the nuclear topology of human 18 and 19 homologous CTs in higher primates. In the present study we investigated four lymphoblastoid cell lines from three species of Old World monkeys by three-dimensional fluorescence in situ hybridization (3D-FISH): two individuals of Japanese macaque (Macaca fuscata), crab-eating macaque (Macaca fascicularis), and an interspecies hybrid individual between African green monkey (Cercopithecus aethiops) and Patas monkey (Erythrocebus patas). Our data demonstrate that gene-poor human 18 homologous CTs are located preferentially close to the nuclear periphery, whereas gene-dense human 19 homologous CTs are oriented towards the nuclear center in all cell lines analyzed. The gene-density-correlated positioning of human 18 and 19 homologous CTs is evolutionarily conserved throughout all major higher primate lineages, despite chromosomal inversions, fusions, fissions or reciprocal translocations that occurred in the course of evolution in these species. This remarkable preservation of a gene-density-correlated chromatin arrangement gives further support for a functionally relevant higher-order chromatin architecture. |
15545737 | Chimpanzee chromosomes: retrotransposable compound repeat DNA organization (RCRO) and its influence on meiotic prophase and crossing-over. | The terminal C-bands that are a specific feature of chimpanzee chromosomes were dissected using a molecular cytogenetic technique, PRINS, with primers for telomeric sequences, subterminal satellite, and retrotransposable elements (HERV-K and -W). These DNA elements jointly formed a large block of retrotransposable compound repeat DNA organization (RCRO) at the terminal C-band regions of 30 chromosomes, and are also located at the centromeric regions of some chromosomes. Additionally, a block consisting of all members of the RCRO has transposed to the middle (q31.1) of the long arm of chromosome 6, and three members, the subterminal satellite and the two HERVs, have integrated into the proximal region (q14.4) of the long arm of chromosome 14. Terminal RCROs seem to induce and prolong the bouquet stage in meiotic prophase, and to affect chiasma formation, together with interstitial RCROs. It is also postulated that RCROs may cause a position effect to gene expression, resulting in gene silencing and/or late replication. |
15545736 | Evolutionary breakpoints are co-localized with fragile sites and intrachromosomal telomeric sequences in primates. | The concentration of evolutionary breakpoints in primate karyotypes in some particular regions or chromosome bands suggests that these chromosome regions are more prone to breakage. This is the first extensive comparative study which investigates a possible relationship of two genetic markers (intrachromosomal telomeric sequences [TTAGGG]n, [ITSs] and fragile sites [FSs]), which are implicated in the evolutionary process as well as in chromosome rearrangements. For this purpose, we have analyzed: (a) the cytogenetic expression of aphidicolin-induced FSs in Cebus apella and Cebus nigrivittatus (F. Cebidae, Platyrrhini) and Mandrillus sphinx (F. Cercopithecidae, Catarrhini), and (b) the intrachromosomal position of telomeric-like sequences by FISH with a synthetic (TTAGGG)n probe in C. apella chromosomes. The multinomial FSM statistical model allowed us to determinate 53 FSs in C. apella, 16 FSs in C. nigrivittatus and 50 FSs in M. sphinx. As expected, all telomeres hybridized with the probe, and 55 intrachromosomal loci were also detected in the Cebus apella karyotype. The chi(2) test indicates that the coincidence of the location of Cebus and Mandrillus FSs with the location of human FSs is significant (P < 0.005). Based on a comparative cytogenetic study among different primate species we have identified (or described) the chromosome bands in the karyotypes of Papionini and Cebus species implicated in evolutionary reorganizations. More than 80% of these evolutionary breakpoints are located in chromosome bands that express FSs and/or contain ITSs. |
15545735 | Comparative mapping of human claudin-1 (CLDN1) in great apes. | The gene encoding claudin-1 (CLDN1) has been mapped to human chromosome 3 (HSA3; 3q28-->q29) using a radiation hybrid panel. Employing fluorescence in situ hybridization (FISH) we here show that a human P1-derived artificial chromosome (PAC) containing CLDN1 detects the orthologous sites in chromosomes of the great apes, chimpanzee, gorilla, and orangutan. Furthermore, the chromosomal position of CLDN1 was determined in mouse chromosomes by FISH. The position of fluorescent signals is confined to a single chromosomal site in both great apes and mouse and in each case maps to the chromosomal region that has conserved synteny with HSA3 (PTR2q28, GGO2q28, PPY2q38 and MMU16B1). Using a gene-specific probe our results are consistent with reports of the striking similarity of great ape and human genomes as illustrated previously by chromosome painting. |
15545734 | Panels of somatic cell hybrids specific for chimpanzee, gorilla, orangutan, and baboon. | The generation of panels of somatic cell hybrids specific for chimpanzee, gorilla, orangutan, and olive baboon is reported. The chromosome content of each hybrid clone was characterized using reverse painting on human normal metaphases and by the use of appropriate sequence tag sites (STSs), one for each chromosome arm. These resources can be advantageously exploited in the characterization of chromosome architecture of different primate species, with special reference to the discrimination of inter- and intra-chromosomal arrangement of segmental duplications. |
15545733 | New insights into the evolution of chromosome 1. | A complex low-repetitive human DNA probe (BAC RP11-35B4) together with two microdissection-derived region-specific probes of the multicolor banding (MCB) probe-set for chromosome 1 were used to re-analyze the evolution of human chromosome 1 in comparison to four ape species. BAC RP11-35B4 derives from 1q21 and contains 143 kb of non-repetitive DNA; however, it produces three specific FISH signals in 1q21, 1p12 and 1p36.1 of Homo sapiens (HSA). Human chromosome 1 was studied in comparison to its homologues in Hylobates lar (HLA), Pongo pygmaeus (PPY), Gorilla gorilla (GGO) and Pan troglodytes (PTR). A duplication of sequences homologous to human 1p36.1 could be detected in PPY plus an additional signal on PPY 16q. The region homologous to HSA 1p36.1 is also duplicated in HLA, and split onto chromosomes 7q and 9p; the region homologous to HSA 1q21/1p12 is present as one region on 5q. Additionally, the breakpoint of a small pericentric inversion in the evolution of human chromosome 1 compared to other great ape species could be refined. In summary, the results obtained here are in concordance with previous reports; however, there is evidence for a deletion of regions homologous to human 1p34.2-->p34.1 during evolution in the Pongidae branch after separation of PPY. |
15545732 | The evolution of the azoospermia factor region AZFa in higher primates. | Clones of a PAC contig encompassing the human AZFa region in Yq11.21 were comparatively FISH mapped to great ape Y chromosomes. While the orthologous AZFa locus in the chimpanzee, the bonobo and the gorilla maps to the long arm of their Y chromosomes in Yq12.1-->q12.2, Yq13.1-->q13.2 and Yq11.2, respectively, it is found on the short arm of the orang-utan subspecies of Borneo and Sumatra, in Yp12.3 and Yp13.2, respectively. Regarding the order of PAC clones and genes within the AZFa region, no differences could be detected between apes and man, indicating a strong evolutionary stability of this non-recombining region. |
15545731 | Evolutionary breakpoint analysis on Y chromosomes of higher primates provides insight into human Y evolution. | Comparative FISH mapping of PAC clones covering almost 3 Mb of the human AZFa region in Yq11.21 to metaphases of human and great apes unravels breakpoints that were involved in species-specific Y chromosome evolution. An astonishing clustering of evolutionary breakpoints was detected in the very proximal region on the long arm of the human Y chromosome in Yq11.21. These breakpoints were involved in deletions, one specific for the human and another for the orang-utan Y chromosome, in a duplicative translocation/transposition specific for bonobo and chimpanzee Y chromosomes and in a pericentric inversion specific for the gorilla Y chromosome. In addition, our comparative results allow the deduction of a model for the human Y chromosome evolution. |
15545730 | Application of molecular cytogenetics for chromosomal evolution of the Lemuriformes (Prosimians). | R-banding chromosomal studies of 21 species of Lemuriformes allowed us to reconstruct the presumed ancestral karyotype of all the Lemuriformes except for Daubentoniidae and permitted the construction of their phylogenetic tree. Chromosome painting with fluorescently labeled heterologous DNA probes permitted comparative chromosome maps to be established. The Zoo-FISH method was used to reassess the karyotypes of 22 species or subspecies. While our results largely confirm the previous reconstruction of the ancestral karyotype, they resulted in a modification of the previously established phylogenetic tree. The Daubentoniidae emerged first followed by the divergence of the families Cheirogaleidae, Indriidae, Lepilemuridae and Lemuridae. Eight chromosome rearrangements occurred in all Lemuriformes except for Daubentoniidae in the common trunk. The present findings do not allow us to propose the occurrence of any rearrangement common to Daubentoniidae and other Lemuriformes, and probably other Prosimii. Conserved syntenies previously described in various mammalian orders were also conserved, while others were specific to the Lemuriformes. |
15545729 | Investigation of marmoset hybrids (Cebuella pygmaea x Callithrix jacchus) and related Callitrichinae (Platyrrhini) by cross-species chromosome painting and comparative genomic hybridization. | We report on the cytogenetics of twin offspring from an interspecies cross in marmosets (Callitrichinae, Platyrrhini), resulting from a pairing between a female Common marmoset (Callithrix jacchus, 2n = 46) and a male Pygmy marmoset (Cebuella pygmaea, 2n = 44). We analyzed their karyotypes by multi-directional chromosome painting employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. Both hybrid individuals had a karyotype with a diploid chromosome number of 2n = 45. As a complementary tool, interspecies comparative genomic hybridization (iCGH) was performed in order to screen for genomic imbalances between the hybrids and their parental species, and between Callithrix argentata and S. oedipus, respectively. These genomic imbalances were confined to centromeric and telomeric heterochromatin, while euchromatic chromosome regions appeared balanced in all species investigated. When comparing marmosets and tamarins, sequence divergence of centromeric heterochromatin was already clearly noticeable. In the C. argentata and C. pygmaea genomes numerous subtelomeric regions were affected by amplification of different repetitive sequences. Cross-species FISH with a microdissection-derived C. pygmaea repetitive probe revealed species specificity of this repetitive sequence at the molecular cytogenetic level of resolution. |
15545728 | Phylogenetic inferences of Atelinae (Platyrrhini) based on multi-directional chromosome painting in Brachyteles arachnoides, Ateles paniscus paniscus and Ateles b. marginatus. | We performed multi-directional chromosome painting in a comparative cytogenetic study of the three Atelinae species Brachyteles arachnoides, Ateles paniscus paniscus and Ateles belzebuth marginatus, in order to reconstruct phylogenetic relationships within this Platyrrhini subfamily. Comparative chromosome maps between these species were established by multi-color fluorescence in situ hybridization (FISH) employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. The three species included in this study and four previously analyzed species from all four Atelinae genera were subjected to a phylogenetic analysis on the basis of a data matrix comprised of 82 discrete chromosome characters. The results confirmed that Atelinae represent a monophyletic clade with a putative ancestral karyotype of 2n = 62 chromosomes. Phylogenetic analysis revealed an evolutionary branching sequence [Alouatta [Brachyteles [Lagothrix and Ateles]]] in Atelinae and [Ateles belzebuth marginatus [Ateles paniscus paniscus [Ateles belzebuth hybridus and Ateles geoffroyi]]] in genus Ateles. The chromosomal data support a re-evaluation of the taxonomic status of Ateles b. hybridus. |
15545727 | Reciprocal painting between humans, De Brazza's and patas monkeys reveals a major bifurcation in the Cercopithecini phylogenetic tree. | We report on reciprocal painting between humans and two Cercopithecini species, Erythrocebus patas (patas monkey) and Cercopithecus neglectus (De Brazza's monkey). Both human and monkeys chromosome-specific probes were made by degenerate oligonucleotide primed PCR (DOP-PCR) from flow sorted chromosomes. Metaphases of both monkey species were first hybridized with human chromosome-specific probes and then human metaphases were hybridized with chromosome paints from each monkey species. The human paint probes detected 34 homologous segments on the C. neglectus karyotype, while the C. neglectus probes, including the Y, revealed 41 homologous segments on the human karyotype. The probes specific for human chromosomes detected 29 homologous segments in the E. patas karyotype, while the patas monkey probes painted 34 segments on the human karyotype. We tested various hypotheses of Cercopithecini phylogeny and taxonomy developed by morphologists, molecular biologists and cytogeneticists. Our hybridization data confirm that fissions (both Robertsonian and non-Robertsonian) are the main mechanism driving the evolutionary trend in Cercopithecini toward higher diploid numbers and strongly suggest an early phylogenetic bifurcation in Cercopithecini. One branch leads to Cercopithecus neglectus/Cercopithecus wolfi while the other line leads to Erythrocebus patas/Chlorocebus aethiops. Allenopithecus nigroviridis may have diverged prior to this major phylogenetic node. |
15545726 | Evolutionary conserved chromosomal segments in the human karyotype are bounded by unstable chromosome bands. | In this paper an ancestral karyotype for primates, defining for the first time the ancestral chromosome morphology and the banding patterns, is proposed, and the ancestral syntenic chromosomal segments are identified in the human karyotype. The chromosomal bands that are boundaries of ancestral segments are identified. We have analyzed from data published in the literature 35 different primate species from 19 genera, using the order Scandentia, as well as other published mammalian species as out-groups, and propose an ancestral chromosome number of 2n = 54 for primates, which includes the following chromosomal forms: 1(a+c(1)), 1(b+c(2)), 2a, 2b, 3/21, 4, 5, 6, 7a, 7b, 8, 9, 10a, 10b, 11, 12a/22a, 12b/22b, 13, 14/15, 16a, 16b, 17, 18, 19a, 19b, 20 and X and Y. From this analysis, we have been able to point out the human chromosome bands more "prone" to breakage during the evolutionary pathways and/or pathology processes. We have observed that 89.09% of the human chromosome bands, which are boundaries for ancestral chromosome segments, contain common fragile sites and/or intrachromosomal telomeric-like sequences. A more in depth analysis of twelve different human chromosomes has allowed us to determine that 62.16% of the chromosomal bands implicated in inversions and 100% involved in fusions/fissions correspond to fragile sites, intrachromosomal telomeric-like sequences and/or bands significantly affected by X irradiation. In addition, 73% of the bands affected in pathological processes are co-localized in bands where fragile sites, intrachromosomal telomeric-like sequences, bands significantly affected by X irradiation and/or evolutionary chromosomal bands have been described. Our data also support the hypothesis that chromosomal breakages detected in pathological processes are not randomly distributed along the chromosomes, but rather concentrate in those important evolutionary chromosome bands which correspond to fragile sites and/or intrachromosomal telomeric-like sequences. |
15545725 | Fluorescence in situ hybridization to chromosomes as a tool to understand human and primate genome evolution. | For the last 15 years molecular cytogenetic techniques have been extensively used to study primate evolution. Molecular probes were helpful to distinguish mammalian chromosomes and chromosome segments on the basis of their DNA content rather than solely on morphological features such as banding patterns. Various landmark rearrangements have been identified for most of the nodes in primate phylogeny while chromosome banding still provides helpful reference maps. Fluorescence in situ hybridization (FISH) techniques were used with probes of different complexity including chromosome painting probes, probes derived from chromosome sub-regions and in the size of a single gene. Since more recently, in silico techniques have been applied to trace down evolutionarily derived chromosome rearrangements by searching the human and mouse genome sequence databases. More detailed breakpoint analyses of chromosome rearrangements that occurred during higher primate evolution also gave some insights into the molecular changes in chromosome rearrangements that occurred in evolution. Hardly any "fusion genes" as known from chromosome rearrangements in cancer cells or dramatic "position effects" of genes transferred to new sites in primate genomes have been reported yet. Most breakpoint regions have been identified within gene poor areas rich in repetitive elements and/or low copy repeats (segmental duplications). The progress in various molecular and molecular-cytogenetic approaches including the recently launched chimpanzee genome project suggests that these new tools will have a significant impact on the further understanding of human genome evolution. |
15545724 | Origins of primate chromosomes - as delineated by Zoo-FISH and alignments of human and mouse draft genome sequences. | This review examines recent advances in comparative eutherian cytogenetics, including Zoo-FISH data from 30 non-primate species. These data provide insights into the nature of karyotype evolution and enable the confident reconstruction of ancestral primate and boreo-eutherian karyotypes with diploid chromosome numbers of 48 and 46 chromosomes, respectively. Nine human autosomes (1, 5, 6, 9, 11, 13, 17, 18, and 20) represent the syntenies of ancestral boreo-eutherian chromosomes and have been conserved for about 95 million years. The average rate of chromosomal exchanges in eutherian evolution is estimated to about 1.9 rearrangements per 10 million years (involving 3.4 chromosome breaks). The integrated analysis of Zoo-FISH data and alignments of human and mouse draft genome sequences allow the identification of breakpoints involved in primate evolution. Thus, the boundaries of ancestral eutherian conserved segments can be delineated precisely. The mapping of rearrangements onto the phylogenetic tree visualizes landmark chromosome rearrangements, which might have been involved in cladogenesis in eutherian evolution. |
15545723 | The impact of chromosome sorting and painting on the comparative analysis of primate genomes. | Chromosome sorting by flow cytometry is the main source of chromosome-specific DNA for the production of painting probes. These probes have been used for cross-species in situ hybridization in the construction of comparative maps, in the study of karyotype evolution and phylogenetics, in delineating territories in interphase nuclei, and in the analysis of chromosome breakpoints. We review here the contributions that this technology has made to the analysis of primate genomes. |
15545722 | Cytochrome b polymorphisms and population structure of two species of Alouatta (Primates). | We carried out a phylogenetic and population study in Alouatta caraya and Alouatta belzebul based on cytochrome b DNA sequence data. Maximum Parsimony and Median-Joining analyses grouped A. caraya from different localities showing a population structure in accordance with geographic distribution. The relation between A. caraya haplotypes could be explained with respect to the species range in the Cerrado, one of the most ancient morphoclimatic domains of South America, and the Chaco. Conversely, A. belzebul from the Amazonas and Atlantic forests grouped in a paraphyletic arrangement without an evident geographic pattern. Recent geologic events resulting in the separation of A. belzebul might explain why these geographically distant groups shared similar haplotypes and why ancestral polymorphisms might have been maintained in this species. Time of divergence estimates indicated that the splitting of the Alouatta lineage leading to A. caraya occurred some 4.58 MYA while the lineage leading to A. belzebul emerged 4.14 MYA. |
15545721 | Genomic structure and paralogous regions of the inversion breakpoint occurring between human chromosome 3p12.3 and orangutan chromosome 2. | Intrachromosomal duplications play a significant role in human genome pathology and evolution. To better understand the molecular basis of evolutionary chromosome rearrangements, we performed molecular cytogenetic and sequence analyses of the breakpoint region that distinguishes human chromosome 3p12.3 and orangutan chromosome 2. FISH with region-specific BAC clones demonstrated that the breakpoint-flanking sequences are duplicated intrachromosomally on orangutan 2 and human 3q21 as well as at many pericentromeric and subtelomeric sites throughout the genomes. Breakage and rearrangement of the human 3p12.3-homologous region in the orangutan lineage were associated with a partial loss of duplicated sequences in the breakpoint region. Consistent with our FISH mapping results, computational analysis of the human chromosome 3 genomic sequence revealed three 3p12.3-paralogous sequence blocks on human chromosome 3q21 and smaller blocks on the short arm end 3p26-->p25. This is consistent with the view that sequences from an ancestral site at 3q21 were duplicated at 3p12.3 in a common ancestor of orangutan and humans. Our results show that evolutionary chromosome rearrangements are associated with microduplications and microdeletions, contributing to the DNA differences between closely related species. |
15545720 | Breakpoint analysis of the pericentric inversion between chimpanzee chromosome 10 and the homologous chromosome 12 in humans. | During this study, we analysed the pericentric inversion that distinguishes human chromosome 12 (HSA12) from the homologous chimpanzee chromosome (PTR10). Two large chimpanzee-specific duplications of 86 and 23 kb were observed in the breakpoint regions, which most probably occurred associated with the inversion. The inversion break in PTR10p caused the disruption of the SLCO1B3 gene in exon 11. However, the 86-kb duplication includes the functional SLCO1B3 locus, which is thus retained in the chimpanzee, although inverted to PTR10q. The second duplication spans 23 kb and does not contain expressed sequences. Eleven genes map to a region of about 1 Mb around the breakpoints. Six of these eleven genes are not among the differentially expressed genes as determined previously by comparing the human and chimpanzee transcriptome of fibroblast cell lines, blood leukocytes, liver and brain samples. These findings imply that the inversion did not cause major expression differences of these genes. Comparative FISH analysis with BACs spanning the inversion breakpoints in PTR on metaphase chromosomes of gorilla (GGO) confirmed that the pericentric inversion of the chromosome 12 homologs in GGO and PTR have distinct breakpoints and that humans retain the ancestral arrangement. These findings coincide with the trend observed in hominoid karyotype evolution that humans have a karyotype close to an ancestral one, while African great apes present with more derived chromosome arrangements. |
15545719 | Nucleotide sequence comparison of a chromosome rearrangement on human chromosome 12 and the corresponding ape chromosomes. | Chromosome rearrangement has been considered to be important in the evolutionary process. Here, we demonstrate the evolutionary relationship of the rearranged human chromosome 12 and the corresponding chromosome XII in apes (chimpanzee, bonobo, gorilla, orangutan, and gibbon) by examining PCR products derived from the breakpoints of inversions and by conducting shotgun sequencing of a gorilla fosmid clone containing the breakpoint and a "duplicated segment" (duplicon). We confirmed that a pair of 23-kb duplicons flank the breakpoints of inversions on the long and short arms of chimpanzee chromosome XII. Although only the 23-kb duplicon on the long arm of chimpanzee chromosome XII and its telomeric flanking sequence are found to be conserved among the hominoids (human, great apes, and gibbons), the duplicon on the short arm of chimpanzee chromosome XII is suggested to be the result of a duplication from that on the long arm. Furthermore, the shotgun sequencing of a gorilla fosmid indicated that the breakpoint on the long arm of the gorilla is located at a different position 1.9 kb from that of chimpanzee. The region is flanked by a sequence homologous to that of human chromosome 6q22. Our findings and sequence analysis suggest a close relationship between segmental duplication and chromosome rearrangement (or breakpoint of inversion) in Hominoidea. The role of the chromosome rearrangement in speciation is also discussed based on our new results. |
15545718 | Molecular evolution of the human chromosome 15 pericentromeric region. | We present a detailed molecular evolutionary analysis of 1.2 Mb from the pericentromeric region of human 15q11. Sequence analysis indicates the region has been subject to extensive interchromosomal and intrachromosomal duplications during primate evolution. Comparative FISH analyses among non-human primates show remarkable quantitative and qualitative differences in the organization and duplication history of this region - including lineage-specific deletions and duplication expansions. Phylogenetic and comparative analyses reveal that the region is composed of at least 24 distinct segmental duplications or duplicons that have populated the pericentromeric regions of the human genome over the last 40 million years of human evolution. The value of combining both cytogenetic and experimental data in understanding the complex forces which have shaped these regions is discussed. |
15545717 | Identity by descent and DNA sequence variation of human SINE and LINE elements. | To test the hypothesis that Alu and L1 elements are genetic characters that are essentially homoplasy-free, we sequenced a total of five human L1 elements and eleven recently integrated Alu elements from 160 chromosomes (80 individuals representing four diverse human populations). Analysis of worldwide samples at L1 loci revealed 292 segregating sites and a nucleotide diversity of 0.0050. For Ya5 Alu loci, there were 129 segregating sites and nucleotide diversity was estimated at 0.0045. The Alu and L1 sequence diversity varied element to element. No completely or partially deleted Alu or L1 alleles were identified during the analysis. These data suggest that mobile element insertions are identical by descent characters for the study of human population genetics. |
15545716 | Tandem insertions of Alu elements. | Alu elements are non-autonomous, non-LTR retroposons that represent the most abundant mobile elements in the human genome (1.1 x 10(6) copies/genome). They preferentially insert adjacent to existing Alu elements. It has been proposed that Alu elements utilize LINE-1 machinery for their retroposition. The LINE-1 endonuclease cleaves at a loose consensus sequence. We have utilized a bioinformatics approach to show the order of insertion of pairs of young (Y) and old (S or J) Alu subfamily members. Our data suggest that the consensus LINE-1 endonuclease cleavage site used for insertion of the old Alu elements can be reused for integration of the younger ones inserting adjacent to them. However, there is also a preference at the 3' end of Alu into a non-ideal cleavage site that may represent unique properties of the A-tail for integration. Alu elements inserting adjacent to one another may suggest the saturation of the optimal integration sites with existing Alu elements, rather than any innate preference for Alu elements to integrate adjacent to other Alus. |
15545715 | Evolutionary implications of pericentromeric gene expression in humans. | Human pericentromeric sequences are enriched for recent sequence duplications. The continual creation and shuffling of these duplications can create novel intron-exon structures and it has been suggested that these regions have a function as gene nurseries. However, these sequences are also rich in satellite repeats which can repress transcription, and analyses of chromosomes 10 and 21 have suggested that they are transcript poor. Here, we investigate the relationship between pericentromeric duplication and transcription by analyzing the in silico transcriptional profiles within the proximal 1.5 Mb of genomic sequence on all human chromosome arms in relation to duplication status. We identify an approximately 5x excess of transcripts specific to cancer and/or testis in pericentromeric duplications compared to surrounding single copy sequence, with the expression of >50% of all transcripts in duplications being restricted to these tissues. We also identify an approximately 5x excess of transcripts in duplications which contain large quantities of interspersed repeats. These results indicate that the transcriptional profiles of duplicated and single copy sequences within pericentromeric DNA are distinct, suggesting that pericentromeric instability is unlikely to represent a common route for gene creation but may have a disproportionate effect upon genes whose function is restricted to the germ line. |
15545714 | The primates of the Neotropics: genomes and chromosomes. | The classification of neotropical primates has been controversial. Different arrangements have been proposed, depending on taxonomic criteria and on the traits selected for phylogenetic reconstructions. These include gross morphologic characters, karyotypic attributes and DNA sequence data of nuclear and mitochondrial genes and of repetitive genomic components. These approaches have substantially clarified the main intergeneric relationships although several intrageneric arrangements still remain to be elucidated. In this review, we compare karyologic and molecular data of this speciose group. |
15545713 | Primate phylogeny: molecular evidence from retroposons. | In these postgenomic times where aspects of functional genetics and character evolution form a focal point of human-mouse comparative research, primate phylogenetic research gained a widespread interest in evolutionary biology. Nevertheless, it also remains a controversial subject. Despite the surge in available primate sequences and corresponding phylogenetic interpretations, primate origins as well as several branching events in primate divergence are far from settled. The analysis of SINEs - short interspersed elements - as molecular cladistic markers represents a particularly interesting complement to sequence data. The following summarizes and discusses potential applications of this new approach in molecular phylogeny and outlines main results obtained with SINEs in the context of primate evolutionary research. Another molecular cladistic marker linking the tarsier with the anthropoid primates is also presented. This eliminates any possibility of confounding phylogenetic interpretations through lineage sorting phenomena and makes use of a new point of view in settling the phylogenetic relationships of the primate infraorders. |
15545712 | The dynamic nature and evolutionary history of subtelomeric and pericentromeric regions. | The organization and evolution of the subtelomeric and pericentromeric regions of human chromosomes exhibit unique characteristics compared to other regions of the genome. As shown in Fig. 1 the functional elements of the centromere and telomere are comprised of highly repetitive DNA sequences, which are responsible for carrying out the main mechanistic duties of these two regions: chromosome segregation and end replication, respectively. The nature of the repeats in these two regions and their function have been reviewed separately and, therefore, will not be discussed in more detail here (Sullivan et al., 1996, 2001; McEachern et al., 2000; Henikoff et al., 2001). Adjacent to these functional element regions, the centromere and telomere regions share an interesting architecture as depicted in Fig. 1. For both pericentromeric and subtelomeric regions, blocks of recent genomic duplications form a zone of shared sequence homologies between certain subsets of human chromosomes. The dynamic nature and evolutionary history of these regions and the unique DNA sequence adjacent to them will be the focus of this review. |
15545711 | Evolution of hominoids and the search for a genetic basis for creating humanness. | The phylogenetic relationship of human and apes are reviewed. The history of molecular phylogenetic studies in this field is then discussed, as is the role of natural selection at the molecular level. It is argued that approximately 10,000 genetic changes are responsible for creating human specific phenotypes. A genome-wide comparison is necessary to decipher those changes. |
15545710 | Conservation genomics: applying whole genome studies to species conservation efforts. | Studies of complete genomes are leading to a new understanding of the biology of mammals and providing ongoing insights into the fundamental aspects of the organization and evolution of biological systems. Comparison of primate genomes can identify aspects of their organization, regulation and function that appeared during the primate radiation, but without comparison to more evolutionarily distant mammals and other vertebrates, highly conserved aspects of genome architecture will not be accurately identified nor will the lineage-specific changes be identified as such. Many species of primates face risks of extinction; yet the knowledge of their genomes will provide a deeper understanding of primate adaptations, human origins, and provide the framework for discoveries anticipated to improve human medicine. The great apes, the closest relatives of the human species, are among the most vulnerable and most important for human medical studies. However, apes are not the only species whose genomic information will enrich humankind. Comparative genomic studies of endangered species can benefit conservation efforts on their behalf. Increased knowledge of genome makeup and variation in endangered species finds conservation application in population evaluation monitoring and management, understanding phylozoogeography, can enhance wildlife health management, identify risk factors for genetic disorders, and provide insights into demographic management of small populations in the wild and in captivity. |
15545708 | Comparison of metabolic oscillations from mouse pancreatic beta cells and islets. | Rhythmic insulin secretion from pancreatic islets is the culmination of many processes both intrinsic and extrinsic to the beta cell. We wished to examine and compare endogenous metabolic oscillations in islets and isolated single beta cells that underlie secretion. Fluorescence patterns of rhodamine 123, an indicator of mitochondrial membrane potential (DeltaPsim), were analyzed for period and amplitude of oscillations using two methods: CLUSTER7 and fast Fourier transform (FFT). The period of DeltaPsim oscillations was greater in islets (271 +/- 21 s, n = 34) compared to dispersed beta cells (180 +/- 10 s, n = 54) by FFT analysis (p < 0.0005). CLUSTER7 confirmed differences in period and also detected oscillatory amplitude differences between beta cells (12.0 +/- 0.8) and islets (7.1 +/- 2.3% of baseline fluorescence, p < 0.0001). Depolarizing responses to the mitochondrial poison NaN3 were reduced in beta cells (35 +/- 4%) vs islets (58 +/- 9%), and hyperpolarizing responses to the calcium channel blocker nifedipine were enhanced in beta cells (15 +/- 4%) vs islets (8 +/- 1%), suggesting that mitochondria in dispersed beta cells were less energized than those in intact islets (p < 0.005), possibly due to elevated intracellular calcium. These findings suggest that individual beta cells possess the proper machinery to generate metabolic oscillations. Differences in oscillatory period, DeltaPsim, and nifedipine response suggest that incorporation into islets provides beta cells with additional modulatory influences. |
15545707 | Radioiodine treatment of hyperthyroidism: prognostic factors affecting outcome. | To assess the effectiveness of radioactive iodine (RAI) treatment in patients with hyperthyroidism and to evaluate prognostic factors affecting outcome. Our cohort comprised 115 consecutive patients with hyperthyroidism treated with RAI at the Endocrinology Clinic at the Farabi Hospital, Trabzon, between 1994 and 2002. Data were retrieved from the endocrinology clinic database. Patients were categorized into three diagnostic groups: Graves' disease (GD), toxic multinodular (TMN) hyperthyroidism, and toxic adenoma. Our policy, over the period of the study, was to offer a single fixed first dose (10 mCi) 131I to all patients with toxic nodular goiter (TNG) for the first time and to all patients with relapsed GD. There was no significant difference in the cure rate between GD and TNG, but Graves' patients had a significantly higher incidence of hypothyroidism (p < 0.001). In contrast, incidence of euthyroidism was significantly increased in TNG than those of the patients with GD (p < 0.05). The incidences of hyperthyroidism, euthyroidism, cure rate, and persistent hyperthyroidism did not vary significantly between females and males. Age at onset of hyperthyroidism at diagnosis was not associated with outcome of RAI therapy. The incidence of hypothyroidism in patients who had nonpalpable goiter was higher than those in patients who had medium or large goiter (p < 0.05). The means of serum FT3 and TT4 at presentation were correlated with the development of hypothyroidism after RAI therapy. Logistic regression analysis showed serum FT3 concentration at presentation to be significant contributing factor to failure to respond to a single dose of RAI. Patients who had higher FT3 concentrations at diagnosis were more likely to fail to respond to RAI therapy. The results of the present study of a cohort of patients with hyperthyroidism demonstrate that a single fixed dose of 10 mCi of RAI is highly effective in curing GD as well as toxic nodular hyperthyroidism. Therefore, treatment protocols for these groups should be identical. The most important factors that determine efficacy of RAI treatment are serum FT3 concentrations at diagnosis before the initiation of treatment and goiter size. Therefore, these factors should be taken into consideration when planning treatment. If such factors are present, the initial dose of RAI should be increased. |
15545706 | Regulation of follicle-stimulating and luteinizing hormone receptor signaling by. | Follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) belong to the super-family of G protein-coupled receptors (GPCR); GPCRs are negatively regulated by RGS ("regulators of G protein signaling") proteins. In this study we evaluated the effects of RGS3 and RGS10 on FSHR and LHR ligand binding and effector coupling. FSHR and LHR ligand binding were unchanged in the presence of RGS3 or RGS10. However, signaling by FSHR and LHR was diminished by RGS3 but not by RGS10. This constitutes the first demonstration of an interaction between RGS proteins and LH and FSH signaling pathways and identifies a mechanism for negative regulation of RGS3 on FSHR and LHR signaling. |
15545705 | 24-hour pattern of circulating prolactin and growth hormone levels and submaxillary lymph node immune responses in growing male rats subjected to social isolation. | To assess the effect of social isolation of growing rats on 24-h rhythmicity of circulating prolactin and growth hormone (GH) levels and submaxillary lymph node immune responses, male Wistar rats were either individually caged or kept in groups (4-5 animals per cage) for 30 d starting on d 35 of life. Plasma prolactin and GH levels, and submaxillary lymph node lymphocyte subset populations, interferon (IFN)-gamma release and mitogenic responses to concanavalin A (Con A) and lipopolysaccharide (LPS) were determined at six time intervals during the 24 h span. Social isolation brought about changes in mean values and 24-h pattern of plasma prolactin and GH levels and lymph node immune responses. After isolation, prolactin and GH mean values decreased, and lymph node T, B, non T-non B, CD8+, and CD4+-CD8+ cells augmented, whereas lymph node CD4+/CD8+ ratio, IFN-gamma release and mitogenic responses decreased. Social isolation resulted in disruption of 24 h rhythmicity of every immune parameter tested. CD4+/CD8+ ratio, IFN-gamma release and Concanavalin A (Con A) and lipopolysaccharide (LPS) responses correlated significantly with plasma prolactin or GH levels while T/B ratio correlated with plasma prolactin levels only. B, non T-non B, and CD4+-CD8+ cells correlated negatively with plasma prolactin. Modifications in mean value and 24-h rhythmicity of plasma prolactin and GH levels are presumably involved in the effect of social isolation on immune responsiveness. |
15545704 | Effect of recombinant human growth hormone on age-related hepatocyte changes in old male and female Wistar rats. | Aging induces changes in several organs, such as the liver, and this process might be due to damage caused by free radicals and inflammatory mediators. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis shows a reduction with age, and this fact could be associated with some age-related changes. The aim of this study was to investigate the effect of GH administration on age-induced alterations in hepatocytes. Two and twenty two month-old male and female Wistar rats were used. Old rats were treated with human recombinant GH for 10 wk. At the end of the treatment, hepatocytes were isolated from the liver and cultured, and different parameters were measured in cells and medium. Plasma IGF-1 was also measured. Aging significantly decreased plasma IGF-1 in males. In females, plasma IGF-1 was also reduced, but not significantly. GH treatment restored plasma IGF-1 levels to values similar to young males. Aging was associated with a significant increase in lipid peroxidation (LPO), nitric oxide (NO), carbon monoxide (CO) and cyclic guanosyl-monophosphate (cGMP), as well as a reduction in adenosyl triphosphate (ATP) and phosphatidylcholine (PC) synthesis. GH administration partially prevented all these changes in males. In females, some of the parameters were significantly improved by GH (ATP, CO, cGMP), while others showed a tendency to improvement, although differences did not reach significance. In conclusion, GH administration could exert beneficial effects against age-related changes in hepatocytes, mainly in males. |
15545703 | Androgen receptor regulates expression of skeletal muscle-specific proteins and muscle cell types. | C2C12 myoblasts expressing the androgen receptor (AR) were used to analyze the role of androgen-AR signaling pathway in skeletal muscle development. Marked up-regulation of AR expression was observed in differentiated myotubes. A nuclear run-on transcription assay demonstrated that transcription of the AR gene is increased during skeletal muscle cell differentiation. Regulation of skeletal muscle-specific protein expression by the androgen-AR signaling pathway was further analyzed using quadriceps skeletal muscle from wild-type (WT) and AR knock-out (ARKO) male mice. A histological analysis of quadriceps skeletal muscle indicates no morphological differences between ARKO and WT mice. However, the androgen-AR signaling pathway increases expression of slow-twitch-specific skeletal muscle proteins and downregulates fast-twitch-specific skeletal muscle proteins, resulting in an increase of slow-twitch muscle fiber type cells in quadriceps muscle. |
15545702 | Stimulation by D-glucose of 36Cl- efflux from prelabeled rat pancreatic islets. | D-glucose was previously reported to cause a concentration-related decrease in the 36Cl- content of prelabeled islets prepared from ob/ob mice, a current animal model of inherited obesity. From these findings, it was inferred that the hexose stimulates Cl- efflux from islet cells and that such an increase in Cl- permeability may partly mediate glucose-induced depolarization of insulin-producing cells. The aim of the present study was to investigate the possible extension of these findings to islets prepared from normal rats by measuring the changes evoked by increasing concentrations of D-glucose in 36Cl- outflow itself from prelabeled isolated islets. After 60 min preincubation at 37 degrees C in the presence of 3 mM D-glucose and 36Cl- (75 microCi/mL), the islets were incubated for 8-10 min at 37 degrees C in the presence of increasing concentrations of the hexose (3-20 mM). The changes in 36Cl- outflow during incubation indicated that D-glucose, in excess of a threshold concentration close to 5 mM, indeed increases effluent radioactivity from the prelabeled islets. It is proposed, therefore, that a gating of volume-sensitive anion channels in glucose-stimulated insulin-producing islet cells participates in the depolarization of the plasma membrane recorded in the range of insulinotropic concentrations of the hexose. |
15545701 | Age-related decreases in gonadal hormones in Long-Evans rats: relationship to rise in arterial pressure. | Sex steroids modify sexual behavior and autonomic function. The gradual decline in circulating levels is correlated with several diseases in humans and animals. However, little is known about age-related changes that occur in the availability of these steroids. In the current studies, we characterized age-related changes in (1) circulating levels of estradiol (females) or testosterone (males), (2) reproductive function (estrous cyclicity in females; erectile reflexes in males), and (3) blood pressure in a longitudinal study. In a separate study, we characterized the estrous cyclicity of sex steroids in female, and diurnal periodicity in male, Long-Evans rats. Young females exhibit regular estrous cycles, transition to irregular cycles at about 10 mo of age, then to cycles characterized by extended periods of estrous, and to persistent estrous. Despite the loss of cyclicity, circulating 17beta-estradiol in middle-aged females was maintained at levels similar to those in young females during diestrous. Males display an age-related decline in testosterone, circulating levels decrease by about 25% during the period from 8 to 16 mo of age. Also, during any 24 h period testosterone levels in young males vary from a peak of about 3.5 ng/mL (late light period) to a trough of 0.7 ng/mL (early dark period). In middle-aged males the rhythm amplitude is greatly blunted (1.4 to 0.7 ng/mL). Males exhibit age-related decrements in erectile reflexes. In females and males systolic blood pressure is relatively stable until 8 mo of age, but significantly increases during the next 5 mo of age. In males, the increase in arterial pressure is gradual from about 8 mo of age. Young females have lower blood pressures than age-matched males, but by 14 mo of age this sex-related advantage is lost. Thus, by middle age, male and female rats are exposed to less gonadal hormone/altered patterns of availability, exhibit decrements in reproductive function, and display an increase in systolic blood pressure. |
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