Sex and pubertal variation in reward-related behavior and neural activation in early adolescents.

This study aimed to characterize the role of sex and pubertal markers in reward motivation behavior and neural processing in early adolescence. We used baseline and two-year follow-up data from the Adolescent Brain and Cognitive DevelopmentSM study (15844 observations; 52% from boys; age 9-13). Pubertal development was measured with parent-reported Pubertal Development Scale, and DHEA, testosterone, and estradiol levels. Reward motivation behavior and neural processing at anticipation and feedback stages were assessed with the Monetary Incentive Delay task. Boys had higher reward motivation than girls, demonstrating greater accuracy difference between reward and neutral trials and higher task earnings. Girls had lower neural activation during reward feedback than boys in the nucleus accumbens, caudate, rostral anterior cingulate, medial orbitofrontal cortex, superior frontal gyrus and posterior cingulate. Pubertal stage and testosterone levels were positively associated with reward motivation behavior, although these associations changed when controlling for age. There were no significant associations between pubertal development and neural activation during reward anticipation and feedback. Sex differences in reward-related processing exist in early adolescence, signaling the need to understand their impact on typical and atypical functioning as it unfolds into adulthood.

Sex and pubertal influences on the neurodevelopmental underpinnings of schizophrenia: A case for longitudinal research on adolescents.

Sex is a significant source of heterogeneity in schizophrenia, with more negative symptoms in males and more affective symptoms and internalizing comorbidity in females. In this narrative review, we argue that there are likely sex differences in the pathophysiological mechanisms of schizophrenia-spectrum disorders (SZ) that originate during puberty and relate to the sex-specific impacts of pubertal maturation on brain development. Pubertal maturation might also trigger underlying (genetic or other) vulnerabilities in at-risk individuals, influencing brain development trajectories that contribute to the emergence of SZ. This review is the first to integrate links between pubertal development and neural development with cognitive neuroscience research in SZ to form and evaluate these hypotheses, with a focus on the frontal-striatal and frontal-limbic networks and their hypothesized contribution to negative and mood symptoms respectively. To test these hypotheses, longitudinal research with human adolescents is needed that examines the role of sex and pubertal development using large cohorts or high risk samples. We provide recommendations for such studies, which will integrate the fields of psychiatry, developmental cognitive neuroscience, and developmental endocrinology towards a more nuanced understanding of the role of pubertal factors in the hypothesized sex-specific pathophysiological mechanisms of schizophrenia.

Engagement in HIV Care Among New York City Transgender Women of Color: Findings from the Peer-Led, TWEET Intervention, a SPNS Trans Women of Color Initiative.

Transgender women (TW) have higher HIV prevalence rates than cisgender (i.e., non-transgender) women. However, utilization of healthcare for transgender people in the U.S. is low. As part of a multisite initiative to facilitate entry and retention in HIV care for TW of color, we compared health outcomes between participants who became Peer Leaders and those who did not. From 2013 to 2016, 163 New York City, mostly Latina, TW enrolled in the Transgender Women Engagement and Entry to Care Project (TWEET). The TWEET intervention included peer-led, group-based educational sessions called Transgender Leader-Teach Back; 39% completed Peer Leadership requirements. Comparing pre-post change by Peer Leader status, Peer Leaders had a significant decrease in viral load and significant increase in CD4 at the last HIV care visit compared to the first. In multivariable logistic regression, predictors associated with Peer Leadership included having at least some college education, being in a relationship, stable housing, receiving legal assistance for political asylum, and having two or more HIV care visits during the intervention. Findings suggest that, for trans women who have completed at least secondary school education, participating in a peer-led intervention can lead to improved HIV care engagement. Understanding which program components lead to becoming a Peer Leader, and how to better engage non-Peer Leaders, are important next steps.

Implementation of a multilevel, multicomponent intervention for obesity control in Native American communities (OPREVENT2): challenges and lessons learned.

OPREVENT2 was a multilevel, multicomponent (MLMC) adult obesity prevention that sought to improve access and demand for healthier food and physical activity opportunities in six Native American communities in the Southwest and Midwest. OPREVENT2 worked with worksites, food stores, schools (grades 2-6), through social media and mailings, and with a local community action committee (CAC), in each of the three intervention communities, and was implemented in six phases. We conducted a process evaluation to assess implementation of each intervention component in terms of reach, dose delivered and fidelity. Implementation of each component was classified as high, medium or low according to set standards, and reported back at the end of each phase, allowing for improvements. The school and worksite components were implemented with high reach, dose delivered and fidelity, with improvement over time. The school program had only moderate reach and dose delivered, as did the social media component. The CAC achieved high reach and dose delivered. Overall, study reach and dose delivered reached a high implementation level, whereas fidelity was medium. Great challenges exist in the consistent implementation of MLMC interventions. The detailed process evaluation of the OPREVENT2 trial allowed us to carefully assess the relative strengths and limitations of each intervention component.

Skeletal muscle mass is an imaging biomarker for decreased survival in patients with oropharyngeal squamous cell carcinoma.

OBJECTIVES: Low skeletal muscle mass (SMM) and sarcopenic obesity (co-presence of low SMM and obesity) are emerging prognosticators in oncology, but the prevalence and prognostic value in oropharyngeal squamous cell carcinoma (OPSCC) is not yet known. MATERIALS AND METHODS: Patients with OPSCC, curative treatment intention and pre-treatment diagnostic imaging of the head and neck area were included. Patients with unknown HPV-status, palliative treatment intention or unavailable imaging were excluded, Relevant demographic and clinical characteristics were collected between 2009 and 2016. Patients were stratified into a low-, intermediate-, and high-risk group according to HPV-status, amount of pack-years, tumor and nodal stage. SMM was radiologically measured and cutoff values were determined by optimal stratification. The prognostic value of low SMM and sarcopenic obesity for overall survival (OS) and disease-free survival (DFS) was determined by Cox regression analysis and Kaplan Meier survival curves. RESULTS: In 216 patients, low SMM and sarcopenic obesity were present in 140 (64.8%) and 13 (6.0%) patients, respectively. On multivariate analysis, stratification into a high-risk group (HPV-negative status with ≥10-pack-years or T4-stage) was a prognostic factor for OS and DFS (HR 2.93, p < 0.01) (HR 4.66, p < 0.01). Of specific interest, sarcopenic obesity was a strong negative prognostic factor for OS and DFS (HR 4.42, p < 0.01 and (HR 3.90, p < 0.05), independent from other well-known prognostic factors such as HPV-status. CONCLUSION: Low skeletal muscle mass is highly prevalent in OPSCC patients. Sarcopenic obesity is a novel pretreatment prognosticator for OS and DFS in OPSCC and should therefore be considered in clinical decision making.

Interobserver agreement of skeletal muscle mass measurement on head and neck CT imaging at the level of the third cervical vertebra.

OBJECTIVES: Skeletal muscle mass (SMM) is most often assessed in cancer patients on abdominal computed tomography (CT) imaging at the level of the third lumbar vertebra (L3). Abdominal CT imaging is not routinely performed in head and neck cancer (HNC) patients. Recently, a novel method to assess SMM on a single transversal CT slice at the level of the third cervical vertebra (C3) was published. The objective of this study was to assess the robustness of this novel C3 measurement method in terms of interobserver agreement. PATIENTS AND METHODS: Patients diagnosed with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) at our center between 2007 and 2011 were evaluated. Fifty-four patients with were randomly selected for analysis. Six observers independently measured the cross-sectional muscle area (CSMA) at the level of C3 using a predefined, written protocol as instruction. Interobserver agreement was assessed using intraclass correlation coefficients (ICCs), a Bland-Altman plot and Fleiss' kappa (κ). RESULTS: The agreement in vertebra selection between all observers was excellent (Fleiss' κ: 0.96). There was a substantial agreement between all observers in single slice selection (Fleiss' κ: 0.61). For all CSMA measurements, ICCs were excellent (0.763-0.969; all p < 0.001). The Bland-Altman plot showed good agreement between measurements, with narrow limits of agreement. CONCLUSION: Interobserver agreement for SMM measurement at the level of C3 was excellent. Assessment of SMM at the level of C3 is easy and robust and can performed on routinely available imaging in HNC patients.

First Accurate Normalization of the ß-delayed α Decay of

The ^{12}C(α,γ)^{16}O reaction plays a central role in astrophysics, but its cross section at energies relevant for astrophysical applications is only poorly constrained by laboratory data. The reduced α width, γ_{11}, of the bound 1^{-} level in ^{16}O is particularly important to determine the cross section. The magnitude of γ_{11} is determined via sub-Coulomb α-transfer reactions or the ß-delayed α decay of ^{16}N, but the latter approach is presently hampered by the lack of sufficiently precise data on the ß-decay branching ratios. Here we report improved branching ratios for the bound 1^{-} level [b_{ß,11}=(5.02±0.10)×10^{-2}] and for ß-delayed α emission [b_{ßα}=(1.59±0.06)×10^{-5}]. Our value for b_{ßα} is 33% larger than previously held, leading to a substantial increase in γ_{11}. Our revised value for γ_{11} is in good agreement with the value obtained in α-transfer studies and the weighted average of the two gives a robust and precise determination of γ_{11}, which provides significantly improved constraints on the ^{12}C(α,γ) cross section in the energy range relevant to hydrostatic He burning.

Preliminary report: Surgical outcomes following genitoplasty in children with moderate to severe genital atypia.

INTRODUCTION: Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. OBJECTIVE: The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. STUDY DESIGN: This 11-site, prospective study included children aged ≤2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. RESULTS: Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. DISCUSSION: In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. CONCLUSION: In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management.

Variation in the clinical and genetic evaluation of undervirilized boys with bifid scrotum and hypospadias.

BACKGROUND: Bifid scrotum and hypospadias can be signs of undervirilization, yet boys presenting with these findings often do not undergo genetic evaluation. In some cases, identifying an underlying genetic diagnosis can help to optimize clinical care and improve guidance given to patients and families. OBJECTIVES: The aim of this study was to characterize current practice for genetic evaluation of patients with bifid scrotum, and to identify approaches with a good diagnostic yield. METHODS: A retrospective study of the Boston Children's Hospital electronic medical records (1993-2015) was conducted using the search term "bifid scrotum" and clinical data were extracted. Data were abstracted into a REDCap database for analysis. Statistical analysis was performed using SPSS, SAS, and Excel software. RESULTS: The search identified 110 subjects evaluated in the Urology and/or Endocrinology clinics for bifid scrotum. Genetic testing (including karyotype, microarray, or targeted testing) was performed on 64% of the subjects with bifid scrotum; of those tested, 23% (15% of the total cohort of 110 subjects) received a confirmed genetic diagnosis. Karyotype analysis, when performed, led to a diagnosis in 17% of patients. Of the ten instances when androgen receptor gene sequencing was performed, a pathogenic mutation was identified 20% of the time. CONCLUSION: This study demonstrated that the majority of individuals with moderate undervirilization resulting in bifid scrotum do not receive a genetic diagnosis. Over a third of the analyzed subjects did not have any genetic testing, even though karyotype analysis and androgen receptor (AR) sequencing were both relatively high yield for identifying a genetic etiology. Increased utilization of traditional genetic approaches could significantly improve the ability to find a genetic diagnosis.

Prospective assessment of cosmesis before and after genital surgery.

INTRODUCTION: Little data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center. OBJECTIVE: The present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery. STUDY DESIGN: This prospective, observational study included children aged <2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children's hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child's genitalia prior to and 6 months after genitoplasty. RESULTS: Of the 37 children meeting eligibility criteria, 20 (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child's genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P < 0.001) and fathers (P ≤ 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P < 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings. DISCUSSION: This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant pre-operatively, they were generally concordant postoperatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life. CONCLUSION: In this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.

The value of postoperative anticoagulants to improve flap survival in the free radial forearm flap: a systematic review and retrospective multicentre analysis.

BACKGROUND: Free radial forearm flap (FRFF) reconstruction is a valuable technique in head and neck surgery, which allows closure of large defects while striving to maintain functionality. Anticoagulative drugs are often administered to improve flap survival, although evidence regarding effectiveness is lacking. OBJECTIVE OF REVIEW: To investigate the effectiveness of postoperative anticoagulants to improve survival of the FRFF in head and neck reconstruction. TYPE OF REVIEW: Systematic review and multicentre, individual patient data meta-analysis. SEARCH STRATEGY: MEDLINE, EMBASE, Web of Science and CINAHL were searched for synonyms of 'anticoagulants' and 'free flap reconstruction'. EVALUATION METHOD: Studies were critically appraised for directness of evidence and risk of bias. Authors of the highest quality publications were invited to submit their original data for meta-analysis. RESULTS: Five studies were of adequate quality, and data from four studies (80%) were available for meta-analysis, describing 759 FRFF procedures. Anticoagulants used were as follows: aspirin (12%), low molecular weight dextran (18.3%), unfractioned heparin (28.1%), low molecular weight heparin (49%) and prostaglandin-E1 (2.1%). Thirty-one per cent did not receive anticoagulants. Flap failure occurred in 40 of 759 patients (5.3%) On univariate analysis, use of unfractioned heparin was associated with a higher rate of flap failure. However, these regimens were often administered to patients who had revision surgery of the anastomosis. In multivariate logistic regression analysis, anticoagulant use was not associated with improved flap survival or flap-related complications. CONCLUSIONS: The studied anticoagulative drugs did not improve FRFF survival or lower the rate of flap-related complications. In addition, some anticoagulants may cause systemic complications.

Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe.

BACKGROUND: The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice. METHODS: A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm. RESULTS: Efficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count <200 cells/mm³ (P < 0.001), GSS <3 (P = 0.002) and use of lamivudine (P < 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT). CONCLUSIONS: In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3.

Lifestyle factors and sensitization in children - the ALADDIN birth cohort.

BACKGROUND: Several cross-sectional studies indicate that an anthroposophic lifestyle reduces the risk of allergy in children. We initiated the Assessment of Lifestyle and Allergic Disease During Infancy (ALADDIN) birth cohort to elucidate the role of specific factors supposed to mediate this effect. The aims of this study are to describe the ALADDIN cohort and to report patterns of exposure and allergic sensitization during the first years of life. METHODS: The ALADDIN study is a prospective birth cohort study of 330 children from families with an anthroposophic, partly anthroposophic, or nonanthroposophic lifestyle. The children and their parents were following an extensive data collection scheme, including repeated questionnaires and biological samples. Blood samples were collected from the parents and from the child at birth as well as at 6, 12, and 24 months of age. RESULTS: Several lifestyle factors differed between the groups, such as diet, medication, and place of delivery. Children of families with an anthroposophic lifestyle had a markedly decreased risk of sensitization during the first 2 years of life compared with children of nonanthroposophic families with adjusted OR 0.25 (95% CI 0.10-0.64) and P-value 0.004. A similar situation held true for children from families with a partly anthroposophic lifestyle, adjusted OR 0.31 (95% CI 0.15-0.54), and P-value 0.002. CONCLUSIONS: The anthroposophic lifestyle comprises several factors of interest for allergy development and is here shown to be associated with reduced risk of IgE sensitization already in infancy. Identifying the factors responsible for this association would be of significant clinical importance.

Contribution of the medial orbital floor to endoscopic orbital decompression.

PROBLEM: This study explores contribution of the orbital floor to mechanical outcomes of orbital decompressions. METHOD OF STUDY: Endoscopic medial wall orbital decompressions with and without extensive medial orbital floor removal (OFR) were performed on opposite sides of ten thawed fresh-frozen cadaver heads Bone removal was compared on pre- and post-dissection CT scans and after orbital exenteration. RESULTS: Bony removal in the anterior orbital apex was significantly better after OFR (117 vs 66, p < 0.0001). An average of 10.3% (range 0 - 45.5%) of the orbital floor directly under the globe was removed with the OFR technique. The orbital floor preservation (OFP) technique resulted in average bone removal of 3.6 cm2, whereas OFR decompression resulted in average of 5.7 cm2 (p = 0.0003). Post-operative recession of the globe was significant in both arms of the study relative to the unoperated state (OFP averaged 2.99 mm decompression, p = 0.001 and OFR averaged 4.25 mm decompression, p = 0.02). CONCLUSIONS: Endoscopic removal of the medial orbital floor when performed in addition to medial wall decompression removes > 60% more orbital bone and an additional 51 of orbital apex bone. Extensive endoscopic removal of the mid-portion of the medial orbital floor results in bone loss beneath the globe itself.

Erythrocyte sedimentation rate as a marker of inflammation and ongoing coagulation in stroke and transient ischaemic attack.

OBJECTIVE: Systemic infection and inflammation have been implicated in the aetiology of thrombotic cerebral events, particularly in younger patients. We decided to determine whether those patients with raised D-dimer levels, indicating continuing thrombosis and fibrinolysis, had evidence of concurrent infection or inflammation as manifested by a raised erythrocyte sedimentation rate (ESR) measured after an ischaemic stroke/transient ischaemic attack (TIA). METHODS: One hundred and forty-eight patients who had suffered either single or recurrent cerebrovascular episodes were analysed. The patients were referred to the thrombosis and haemostasis unit at Johannesburg Hospital for evaluation of their thrombotic profiles, including D-dimer levels. Concurrent infection was assessed by measurement of white cell count (WCC) and ESR. The variable time interval between the date of the most recent cerebrovascular event and the date of venesection was determined. A history was taken, a physical and neurological examination was performed, and a cardiology assessment and neuroimaging studies were done. RESULTS: Raised D-dimer levels correlated significantly with ESR levels (p = 0.0094) in all patients. This was particularly evident when comparing the 70 younger patients (aged less than 45 years) with the 78 older patients (> 45 years) with raised D-dimers (p = 0.0070). When analysing other markers of inflammation/infection in association with raised D-dimer levels and ESR, mean fibrinogen levels were significantly raised at 6.56 g/l (p = 0.0122). An elevated WCC, as a categorical variable, was significantly associated with an elevated ESR (p = 0.0092). CONCLUSION: There is a significant correlation between elevated D-dimer levels (indicating abnormalities of coagulation and fibrinolysis) and markers of inflammatory and/or infective processes. This is particularly evident in black patients below the age of 45 years. These patients are believed to be at decreased risk for generalised atheromatous disease compared with older white patients. The ramifications of these findings are potentially important with regard to thrombotic cerebrovascular disease aetiology, investigation, management and prevention.

Validation of questions on asthma and wheeze in farming and anthroposophic children.

BACKGROUND: In most epidemiological surveys the estimated prevalence of asthma is based on questionnaire responses, which may depend on the individual's perception as well as medical consulting habits in a given population. Therefore, measurement of bronchial hyper-responsiveness as a key feature of asthma has been suggested as an objective parameter for asthma. OBJECTIVE: The aim of the present study was to validate questionnaire responses on asthma and wheeze against bronchial response to hypertonic saline (HS) (4.5%) in populations previously shown to have a lower prevalence of asthma and allergies: farmers' children and children from anthroposophic families. METHODS: Children whose parents had completed a written questionnaire in the cross-sectional PARSIFAL-study were drawn from the following four subgroups: 'farm children' (n=183), 'farm reference children' (n=173), 'Steiner schoolchildren' (n=243) and 'Steiner reference children' (n=179). Overall, 319 children with wheeze in the last 12 months and 459 children without wheeze in the last 12 months performed an HS challenge. RESULTS: Odds ratios, sensitivity, specificity, likelihood ratios and measures of association did not differ significantly between the four subgroups. The correlation between the bronchial response to HS and wheeze and asthma questions was moderate and similar for farm children, farm reference children, Steiner schoolchildren and Steiner reference children (kappa for 'wheeze': 0.25, 0.33, 0.31, 0.35, respectively, P=0.754, kappa for 'doctor's diagnosis of asthma': 0.33, 0.19, 0.33, 032, respectively, P=0.499). CONCLUSION: The findings from this study suggest that the reliabilitiy of questionnaire responses on asthma and wheeze is comparable between farmers' children, children raised in families with anthroposophic lifestyle and their respective peers.

Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease.

Huntington's disease (HD) is one of 10 known diseases caused by a (CAG)(n) trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. We have developed stable inducible neuronal (PC12) cell lines that express huntingtin exon 1 with varying CAG repeat lengths under doxycycline (dox) control. The expression of expanded repeats is associated with aggregate formation, caspase-dependent cell death and decreased neurite outgrowth. Post-mitotic cells expressing mutant alleles were more prone to cell death compared with identical cycling cells. To determine early metabolic changes induced by this mutation in cell models, we studied changes in gene expression after 18 h dox induction, using Affymetrix arrays, cDNA filters and adapter-tagged competitive PCR (ATAC-PCR). At this time point there were low rates of inclusion formation, no evidence of mitochondrial compromise and no excess cell death in the lines expressing expanded compared with wild-type repeats. The expression profiles suggest novel targets for the HD mutation and were compatible with impaired cAMP response element (CRE)-mediated transcription, which we confirmed using CRE-luciferase reporter assays. Reduced CRE-mediated transcription may contribute to the loss of neurite outgrowth and cell death in polyglutamine diseases, as these phenotypes were partially rescued by treating cells with cAMP or forskolin.

Metabolic oscillations in an E. coli fermentation.

Recombinant E. coli fermentations were observed to undergo regular, reproducible oscillations in oxygen uptake for several hours during a controlled fermentation process. Culture growth slowed during the period of oscillations, delaying induction of recombinant protein production. The oscillations were similar in 10-L and 1,000-L fermentors and also occurred with different feed control algorithms. Both observations support the hypothesis that the oscillations are metabolic in nature. Analysis of amino acid, ATP, and GTP pools suggests that the oscillations result from aberrant regulation of isoleucine biosynthesis leading to repeated starvation events in which protein synthesis and growth are impaired. Both a nutritional solution, isoleucine feeding, and a genetic solution, repair of an ilvG frameshift mutation in E. coli K-12 strains, were found to eliminate the oscillations, further supporting the proposed mechanism for the behavior. These results illustrate the interesting and complicated physiological behavior which can be displayed in metabolic networks and provide another example of surprising problems that can arise in growing recombinant organisms in fermentors.

Temporal bone trauma.

Temporal bone trauma has numerous manifestations, many of which are detectable by current imaging techniques. Our discussion of temporal bone trauma is subdivided into fractures and pseudofractures, fistulous communication, hearing loss, and facial nerve involvement.