A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis

Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre/loxP technology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Müllerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox gene Pem, which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatid development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.     

MELD score as a predictor of pretransplant and posttransplant survival in OPTN/UNOS status 1 patients

The Model for End-Stage Liver Disease (MELD) score is predictive of survival and is used to prioritize patients with chronic liver disease patients for orthotopic liver transplantation (OLT). The aims of this study are (1) to assess the ability of MELD score at listing to predict pretransplant and posttransplant survival for nonchronic liver disease patients listed with the Organ Procurement and Transplantation Network/ United Network for Organ Sharing (OPTN/UNOS) as Status 1; and (2) to compare survival associated with 4 diagnostic groups within the Status 1 designation. The study population consisted of adult patients listed for OLT at Status 1 in the UNOS national database between November 1, 1999 and March 14, 2002 (N = 720). Events within 30 days of listing were analyzed using Kaplan-Meier and Cox regression methodology. Patients meeting criteria for fulminant hepatic failure without acetaminophen toxicity (FHF-NA, n = 312) had the poorest survival probability while awaiting OLT; this was negatively correlated with MELD score (P =.0001). These patients experienced the greatest survival benefit associated with OLT, with an estimated improvement of survival from about 58% to 91% (P <.0001). Patients listed for primary nonfunction within 7 days of OLT (n = 268) did not show mortality to be related to MELD score (P =.41) and did not show a significant association between survival and OLT (P =.68). In conclusion, liver allocation within the Status 1 designation may need to be further stratified by diagnosis, and MELD score may be useful for prioritizing FHF-NA candidates.     

The use of computerized birthday greeting reminders in the management of diabetes

BACKGROUND: Although mailed reminders have been used for prevention among general populations, few studies have evaluated their effectiveness among chronically ill populations. OBJECTIVE: We evaluated the effectiveness of mailed reminders for improving diabetes management. The reminder included a letter from the individual's primary care physician (PCP), a self-care handbook, a preventive care checklist, and specific recommendations regarding receipt of routine monitoring and screening. METHODS: Of 195 PCPs practicing with a large group practice, 111 agreed to have their adult patients with diabetes randomized to receive the reminder (n = 1,641) or usual care (n = 1,668). Using data from automated databases, we fit generalized estimating equations to evaluate the effect of reminder receipt on fasting lipid profile and glycated hemoglobin testing, dilated retinal exam receipt, and visit frequency during the 6 and 12 months following randomization, and glycated hemoglobin and cholesterol levels in the year following randomization. RESULTS: Reminder and usual care recipients did not differ in sociodemographic, clinical, or prior testing characteristics. In the 6 months following randomization, reminder recipients were more likely to receive a retinal exam (odds ratio [OR], 1.29; 95% confidence interval [95% CI], 1.12 to 1.49) and diabetes visit (OR, 1.28; 95% CI, 1.12 to 1.47). In the 12 months following randomization, reminder recipients were more likely to receive a glycated hemoglobin test (OR, 1.21; 95% CI, 1.03 to 1.43), retinal exam (OR, 1.23; 95% CI, 1.07 to 1.41), and diabetes visit (OR, 1.25; 95% CI, 1.09 to 1.29). In the follow-up year, reminder recipients also tended to have a glycated hemoglobin test that did not reflect poor control (<9.5%). CONCLUSIONS: We found small but significant improvements in the management of patients with diabetes receiving a computerized mailed reminder.     

Predictors of changes in disease activity among children with juvenile dermatomyositis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry

Determinants of changes in disease activity among patients with juvenile dermatomyositis (JDM) are unknown. Our objective was to develop predictive models to predict changes in disease activity using the CARRA Legacy Registry. The CARRA Legacy Registry included 658 subjects with definite or probably JDM with 297 subjects with a one follow-up visit after baseline, and we studied the 65 subjects with active disease at baseline. Linear regression models were used to build risk scores for changes in disease activity adjusted for baseline disease activity, age, sex, and disease duration. Disease activity improved from baseline to 6-month follow-up as measured by patient/parent global health score (median 4; p = 0.008), patient pain score (median 2; p = 0.014), physician global (median 4; p < 0.001), and Childhood Myositis Assessment Scale (CMAS) (median 41, p < 0.001). Anti-nuclear antibodies (p = 0.013) and hydroxychloroquine use (p = 0.045) were significant predictors of less improvement in patient/parent global and baseline patient/parent global. Anti-nuclear antibodies (p = 0.001) and V/shawl sign (p = 0.005) were significant predictors of less improvement in patient pain (R-square improved from 0.29 for adjustors alone to 0.46 for the full model). Small joint arthritis (p < 0.01) predicted less improvement and dysphagia/dysphonia (p = 0.033) predicted greater improvement in CMAS and baseline CMAS (R-square improved from 0.73 for adjustors alone to 0.86 for the full model). Disease characteristics can help identify patients who are less likely to improve over time. Risk scores to predict future changes in disease activity could be used to trigger more aggressive treatment earlier in the disease course.     

Endosonographic Imaging of Anal Sphincter Injury

PURPOSE: This study was designed to test the hypothesis that the extent of anal sphincter muscle injury as graded at endosonography correlates with the degree of functional impairment. METHODS: Three hundred and thirty adults presenting for evaluation of fecal incontinence were recruited. Ultrasound was performed with a 7.5-MHz radial rotating axial endoprobe in the left lateral position. Anal sphincter muscle tears were graded on the basis of the degree of circumferential involvement (< or >25 percent) and by an assessment of the superoinferior longitudinal extent of an external anal sphincter tear. Muscles that demonstrated multiple tears, poor visualization, or fragmentation were classed as fragmented. Sphincter injuries were correlated with basal and squeeze pressures at manometry, pudendal nerve terminal latencies, and the severity of symptoms using the Parks-Browning clinical score. RESULTS: Patients with an intact external anal sphincter had a higher squeeze pressure (mean, 162.6 cm H(2)O) than those with a partial- (mean, 125.7 cm H(2)O) or full-length tear (mean, 124.9 cm H(2)O; P < 0.0001). There was no significant difference in squeeze pressure between those with partial- vs. full-length external anal sphincter tears nor between circumference tears < or >25 percent. Basal pressure was significantly lower in those with a full-length external anal sphincter tear (47.8 cm H(2)O) vs. an intact external anal sphincter (65.7 cm H(2)O; P < 0.001). The basal pressure in those with an intact internal anal sphincter was not significantly different from those with clearly defined internal anal sphincter tears, and the degree of circumferential involvement was also not important in this regard. However, those with a fragmented internal anal sphincter had a significantly lower basal pressure than other subgroups of internal anal sphincter injuries (P < 0.001). There was no association between external or internal anal sphincter status and the mean pudendal nerve terminal motor latency, suggesting the patient groups were neurologically similar. There was no significant association between external or internal anal sphincter status and the severity of reported symptoms. CONCLUSION: Correlations between the presence or absence of muscle tears and reduced manometric function have been identified. Further grading of tears was of less importance. No relationship between muscle injuries and the severity of clinical symptoms could be elicited.     

Predicting the growth response to growth hormone in patients with intrauterine growth retardation

OBJECTIVE Human GH treatment of short children who had intrauterine growth retardation (IUGR) results in a highly variable growth response. The object of this study was to test the hypothesis that differences in responsiveness to exogenously administered GH might reflect differences in endogenous GH secretion or sensitivity. DESIGN Prospective study evaluating the growth response to GH therapy in short individuals with prior IUGR. PATIENTS Ten short, prepubertal children with prior IUGR were studied. Mean age was 6 years (3.39–8.61). Mean bone age was 4.6 years (2.3–8.3). Mean body mass index was 13.2 kg/m² (9.9–14.0; normal 13.5–19.0). MEASUREMENTS Overnight spontaneous GH release was measured using a constant withdrawal pump and stimulated GH release was measured following clonidine (0.15 mg/m²) administration. IGF-I concentrations were measured at baseline and 12, 24, 36 and 48 hours after sequential doses of GH (0.05 and 0.2 mg/kg/dose) given 48 hour apart. Patients were treated with GH (0.125 mg/kg three times a week) and growth response was assessed. In the second and third year, attempts were made to improve the growth rate by nutritional supplementation and increasing the dose of GH to 0.25 mg/kg three times a week. RESULTS All patients had normal integrated nocturnal GH secretion (>3 μg/l, 6mU/l) and normal peak GH secretion in response to clonidine (>7 μg/l). In the first year of the trial, mean growth velocity (GV) increased from 5.39 cm/year ± 0.29 to 7.32 cm/year ± 0.39 (P = 0.004). Changes in GV correlated inversely with integrated GH (r = ? 0.69; P = 0038), baseline IGF-I concentration (r = ? 0.88; P = 0.002) and baseline GV-SDS (r = ? 0.68; P = 0.043). There was no correlation between change in GV and GH binding protein, baseline height SDS or age. The effect of GH waned in the second year, but tended to remain greater than the pretreatment growth rate (6.54 ± 0.49 vs 5.53 cm/year ± 0.29; P = 0.09). No significant advancement of bone age over chronological age was observed over the first 2 years. Increasing nutritional intake by 17% did not result in significant weight gain nor increase in height velocity. Doubling the dose of GH in the second or third year did not result in a significant increase in GV. CONCLUSION The variable response to GH therapy in short children with a history of intrauterine growth retardation may partly reflect relative sufficiency or insufficiency of GH. Baseline IGF-I levels and baseline growth velocity appear to be useful and practical predictors of response to GH.     

Clinical Characteristics and Outpatient Mental Health Service Use of Transition-Age Youth in the USA

This study examines diagnostic and service utilization patterns of transition-age youth in outpatient care derived from the 2007 nationally representative Client/Patient Sample Survey. Comparisons between 16–17, 18–21, and 22–25 year olds are highlighted. Among transition-age outpatients, the oldest youth had the highest rates of depression and bipolar disorder and co-occurring medical and substance use problems. Controlling for sociodemographic and clinical characteristics, 18–21 year olds were less likely to receive individual therapy than 16–17 year olds, but there were no age group differences in receipt of specialized therapy or psychotropic medication. Female gender and Hispanic ethnicity were positively associated with the number of services received and specialized service use, respectively; youth with private insurance were more likely than those with public insurance to receive psychotropic medication. Implications are discussed regarding access to and adequacy of services provided for young people in the critical transition to adulthood, especially with the implementation of the 2010 Affordable Care Act.     

Understanding Perinatal Death: A Systematic Analysis of New York City Fetal and Neonatal Death Vital Record Data and Implications for Improvement, 2007–2011

We aimed to compare demographic, medical, and cause-of-death information reported for third-trimester fetal and neonatal death vital records collected in New York City (NYC) before and after implementation of the revised fetal death certificate to identify: (1) the limitations of combining fetal and neonatal death records for the purpose of perinatal death prevention; and (2) improvement opportunities for fetal death vital records registration. Using Chi squared tests, we compared data completeness and cause-of-death information between third-trimester NYC fetal (n = 1,930) and neonatal deaths (n = 735) from 2007 to 2011. We also compared fetal death data before and after the 2011 implementation of the 2003 United States (US) Standard Report of Fetal Death and an electronic reporting system. Compared with neonatal deaths, fetal death data were generally less complete (P < 0.0001). Fetal death data much more frequently reported an ill-defined cause of death (67 vs. 5 %). Most ill-defined reported causes of fetal death (73 %) were attributed to stillbirth synonyms (e.g., “fetal demise”). Ill-defined causes of fetal death decreased from 68 to 61 % (P < 0.01) after 2011. Both data completeness and ill-defined causes of death varied widely by hospital. In NYC, fetal deaths lack demographic, medical, and cause-of-death information compared with neonatal deaths, with implications for research that uses combined perinatal mortality data sets. Electronic implementation of the US Standard Report of Fetal Death minimally improved cause-of-death information. Substantial variability by hospital suggests opportunities for improvement exist.     

Prospective Associations between Bilingualism and Executive Function in Latino Children: Sustained Effects While Controlling for Biculturalism

The study purpose was to test 1-year prospective associations between English–Spanish bilingualism and executive function in 5th to 6th grade students while controlling for biculturalism. Participants included 182 US Latino students (50 % female). Self-report surveys assessed biculturalism, bilingualism, and executive function (i.e., working memory, organizational skills, inhibitory control, and emotional control, as well as a summary executive function score). General linear model regressions demonstrated that bilingualism significantly predicted the summary executive function score as well as working memory such that bilingual proficiency was positively related to executive function. Results are the first to demonstrate (a) prospective associations between bilingualism to executive function while controlling for the potential third variable of biculturalism, and (b) a principal role for working memory in this relationship. Since executive function is associated with a host of health outcomes, one implication of study findings is that bilingualism may have an indirect protective influence on youth development.