Impaired performance on the rapid visual information processing task (RVIP) could be an endophenotype of schizophrenia

The aim of the present study was to investigate whether healthy first-degree relatives of schizophrenia patients show reduced sensitivity performance, higher intra-individual variability (IIV) in reaction time (RT), and a steeper decline in sensitivity over time in a sustained attention task. Healthy first-degree relatives of schizophrenia patients (n=23) and healthy control subjects (n=46) without a family history of schizophrenia performed a demanding version of the Rapid Visual Information Processing task (RVIP). RTs, hits, false alarms, and the sensitivity index A' were assessed. The relatives were significantly less sensitive, tended to have higher IIV in RT, but sustained the impaired level of sensitivity over time. Impaired performance on the RVIP is a possible endophenotype for schizophrenia. Higher IIV in RT, apparently caused by impaired context representations, might result in fluctuations in control and lead to more frequent attentional lapses.

Socio-Spatial Relationships in Dairy Cows

Farm animals may serve as models for evaluating social networks in a controlled environment. We used an automated system to track, at fine temporal and spatial resolution (once per minute, +/- 50 cm) every individual in six herds of dairy cows (Bos taurus). We then analysed the data using social network analyses. Relationships were based on non-random attachment and avoidance relationships in respect to synchronous use and distances observed in three different functional areas (activity, feeding and lying). We found that neither synchrony nor distance between cows was strongly predictable among the three functional areas. The emerging social networks were tightly knit for attachment relationships and less dense for avoidance relationships. These networks loosened up from the feeding and lying area to the activity area, and were less dense for relationships based on synchronicity than on median distance with respect to node degree, relative size of the largest cluster, density and diameter of the network. In addition, synchronicity was higher in dyads of dairy cows that had grown up together and shared their last dry period. This last effect disappeared with increasing herd size. Dairy herds can be characterized by one strongly clustered network including most of the herd members with many non-random attachment and avoidance relationships. Closely synchronous dyads were composed of cows with more intense previous contact. The automatic tracking of a large number of individuals proved promising in acquiring the data necessary for tackling social network analyses.

Novel ADAMTS13 mutations in an obstetric patient with upshaw-schulman syndrome

Upshaw-Schulman syndrome (USS) is a rarely reported congenital form of thrombotic thrombocytopenic purpura (TTP) that results from mutations in the ADAMTS13 gene. Many USS patients are diagnosed during the second or third trimester of their first pregnancy. We present a patient diagnosed with USS following retinal detachments and intrauterine fetal demise at 34 weeks of gestation. The patient's plasma was tested for ADAMTS13 activity, inhibitor, and antibody. Subsequently, she and her first-degree relatives had ADAMTS13 gene sequencing. Initially, the patient was found to have an ADAMTS13 activity of <5% in the absence of an ADAMTS13 inhibitor (FRETS assay) or antibody (immunoassay). Repeat studies in the months following hospital discharge showed persistent, undetectable ADAMTS13 activity and she was given a clinical diagnosis of USS. Molecular sequencing demonstrated two novel missense mutations in the ADAMTS13 gene: one in the maternal exon 17 (p.Ala690Thr due to nucleotide substitution c.2068 G>A) and another in the paternal exon 22 (p.Arg915Cys due to nucleotide substitution c.2746 C>T). In addition to being compound heterozygous for two ADAMTS13 mutations, the patient also had two maternally inherited single nucleotide polymorphisms: p.P618A (exon 16) and p.A732V (exon 18). Her parents and only sister had normal or near-normal ADAMTS13 activity. Each was heterozygous for one of the novel missense mutations. This case highlights the importance of molecular analysis of the ADAMTS13 gene in patients and family members when the severe ADAMTS13 deficiency does not appear to be autoimmune in nature. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

Social Cognition And Functional Brain Imaging: Extending The Broader Autism Phenotype

Evidence suggests that the social cognition deficits prevalent in autism spectrum disorders (ASDs) are widely distributed in first degree and extended relatives. This ¿broader autism phenotype¿ (BAP) can be extended into non-clinical populations and show wide distributions of social behaviors such as empathy and social responsiveness ¿ with ASDs exhibiting these behaviors on the lower ends of the distributions. Little evidence has previously shown relationships between self-report measures of social cognition and more objective tasks such as face perception in functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs). In this study, three specific hypotheses were addressed: a) increased social ability, as measured by an increased Empathy Quotient, decreased Social Responsiveness Scale (SRS-A) score, and increased Social Attribution Task score, will predict increased activation of the fusiform gyrus in response to faces as compared to houses; b) these same measures will predict N170 amplitude and latency showing decreased latency and increased amplitude for faces as compared to houses with increased social ability; c) increased amygdala volume will predict increased fusiform gyrus activation when viewing faces as compared to houses. Findings supported all of the hypotheses. Empathy scores significantly predicted both right FFG activation [F(1,20) = 4.811, p = .041, ß = .450, R2 = 0.20] and left FFG activation [F(1,20) = 7.70, p = .012, ß = .537, R2 = 0.29]. Based on ERP results increased right lateralization face-related N170 was significantly predicted by the EQ [F(1,54) = 6.94, p = .011, ß = .338, R2 = 0.11]. Finally, total amygdala volume significantly predicted right [F(1,20) = 7.217, p = .014, ß = .515, R2 = 0.27] and left [F(1,20) = 36.77, p < .001, ß = .805, R2 = 0.65] FFG activation. Consistent with the a priori hypotheses, traits attributed to the BAP can significantly predict neural responses to faces in a non-clinical population. This is consistent with the face processing deficits seen in ASDs. The findings presented here contribute to the extension of the BAP from unaffected relatives of individuals with ASDs to the general population. These findings also give continued evidence in support of a continuous distribution of traits found in psychiatric illnesses in place of a traditional, dichotomous ¿all-or-nothing¿ diagnostic framework of neurodevelopmental and neuropsychiatric disorders.

[Pediatric cardiac disease: indications for family screening and risk stratification]

In some forms of cardiac disease in childhood, familial occurrence is frequent. This implies the question whether family members should undergo cardiologic screening examinations. For cardiomyopathies the familiarity is so frequent and morbidity so important that examination by echo of all first degree relatives is recommended. As these cardiomyopathies may develop its phenotype all along a lifetime, repetitive examinations usually are indicated. For the primary electrical diseases the so called channelopathies the same is true, as for the high rate of familial occurrence and the high morbidity. Thus ECG screening of first degree relatives is recommended. In a child with congenital heart disease there are no recommendations with regard to familial screening and cardiological examinations usually are indicated only in case of clinical suspicion for heart disease.

Effects of female genital mutilation on birth outcomes in Switzerland

OBJECTIVE: The primary aim of this study was to determine the desires and wishes of pregnant patients vis-à-vis their external genital anatomy after female genital mutilation (FGM) in the context of antenatal care and delivery in a teaching hospital setting in Switzerland. Our secondary aim was to determine whether women with FGM and non-mutilated women have different fetal and maternal outcomes. DESIGN: A retrospective case-control study. SETTING: A teaching hospital. POPULATION: One hundred and twenty-two patients after FGM who gave consent to participate in this study and who delivered in the Department of Obstetrics and Gynaecology in the University Hospital of Berne and 110 controls. METHODS: Data for patients' wishes concerning their FGM management, their satisfaction with the postpartum outcome and intrapartum and postpartum maternal and fetal data. As a control group, we used a group of pregnant women without FGM who delivered at the same time and who were matched for maternal age. MAIN OUTCOME MEASURES: Patients' satisfaction after delivery and defibulation after FGM, maternal and fetal delivery data and postpartum outcome measures. RESULTS: Six percent of patients wished to have their FGM defibulated antenatally, 43% requested a defibulation during labour, 34% desired a defibulation during labour only if considered necessary by the medical staff and 17% were unable to express their expectations. There were no differences for FGM patients and controls regarding fetal outcome, maternal blood loss or duration of delivery. FGM patients had significantly more often an emergency Caesarean section and third-degree vaginal tears, and significantly less first-degree and second-degree tears. CONCLUSION: An interdisciplinary approach may support optimal antenatal and intrapartum management and also the prevention of FGM in newborn daughters.

Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia.

INTRODUCTION Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. METHODS The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. RESULTS In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. CONCLUSION Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

Relationships between the alterations of tumor suppressor genes, risk factors and clinical outcomes of gliomas

The relationship between MMAC/PTEN, DMBT1 and the progression and prognosis of glioma, and the association between the alterations of MMAC/PTEN, p53, p16, and Rb and some cancer risk factors, such as smoking, exposure to radiation, family cancer history, and previous cancer history, were assessed in 4 studies. ^ By allelic deletion analysis, MMAC/PTEN locus was shown to be frequently lost in glioblastomas multiforme (GM) but maintained in most lower-grade astrocytic tumors. DMBT1 locus, however, was frequently lost in all grades of gliomas examined. The potential biological significance of these two regions was frontier assessed by examining microcell-hybrids that contained various fragments of 10q. Somatic cell hybrid clones that retained the MMAC/PTEN locus have less transformed phenotypes, exhibiting an inability to grow in soft agarose. On the other hand, the presence or absence of DAMT1 did not correlate with any in vitro phenotype assessed in our model system. Further, Cox proportional hazards regression analysis, adjusted for age at surgery and histologic grades (GM, and non-GM), showed that without LOH at the MMAC/PTEN locus had a significantly better prognosis than did patients with LOH at MMAC/ PTEN (hazard ratio = 0.5; 95% Cl = 0.28–0.89; P = 0.018). Furthermore, status of LOH at MMAC/PTEN was found to be significantly associated with age, while that for DMBT1 was not. These results suggest that the DMBT1 may be involved early in the oncogenesis of gliomas, while alterations in the MMAC /PTEN may be a late event in the oncogenesis related with progression of gliomas and provide a significant prognostic marker for patient survival. ^ The associations between 4 cancer risk factors and 4 tumor suppressor genes were assessed. The expression of p16 was observed to be associated with current smoking (adjusted OR = 1.9, 95% CI = 1.02–3.6) but not the former smoking (adjusted OR = 1.1, 95% Cl = 0.5–3.5). The expression of p53 was found to be associated with the family cancer history (OR = 3.5, 95% Cl = 1.07–11 for patients with first-degree family history of cancer). MMAC/ PTEN was associated with the histologic grade (OR = 2.8, 95% CI = 1.2–6.6) and age (P = 0.035). Also, the OR for LOH around MMAC/PTEN in patients with a family history of cancer was elevated (OR = 1.9, 95% CI = 0.8–4.6 for patients with first-degree family history of cancer). The associations between exposure and the alterations of tumor suppressor genes, between smoking and p16, between family history of cancer and p53 and MMAC/PTEN, provide suggestive evidences that those exposures are related to the development of gliomas. ^

Predictors of Permanent Pacemaker Implantation in Patients With Severe Aortic Stenosis Undergoing TAVR

Background Atrioventricular (AV) conduction disturbances requiring permanent pacemaker (PPM) implantation may complicate transcatheter aortic valve replacement (TAVR). Available evidence on predictors of PPM is sparse and derived from small studies. Objectives The objective of this study was to provide summary effect estimates for clinically useful predictors of PPM implantation after TAVR. Methods We performed a systematic search for studies that reported the incidence of PPM implantation after TAVR and that provided raw data for the predictors of interest. Data on study, patient, and procedural characteristics were abstracted. Crude risk ratios (RRs) and 95% confidence intervals for each predictor were calculated by use of random effects models. Stratified analyses by type of implanted valve were performed. Results We obtained data from 41 studies that included 11,210 TAVR patients, of whom 17% required PPM implantation after intervention. The rate of PPM ranged from 2% to 51% in individual studies (with a median of 28% for the Medtronic CoreValve Revalving System [MCRS] and 6% for the Edwards SAPIEN valve [ESV]). The summary estimates indicated increased risk of PPM after TAVR for men (RR: 1.23; p < 0.01); for patients with first-degree AV block (RR: 1.52; p < 0.01), left anterior hemiblock (RR: 1.62; p < 0.01), or right bundle branch block (RR: 2.89; p < 0.01) at baseline; and for patients with intraprocedural AV block (RR: 3.49; p < 0.01). These variables remained significant predictors when only patients treated with the MCRS bioprosthesis were considered. The data for ESV were limited. Unadjusted estimates indicated a 2.5-fold higher risk for PPM implantation for patients who received the MCRS than for those who received the ESV. Conclusions Male sex, baseline conduction disturbances, and intraprocedural AV block emerged as predictors of PPM implantation after TAVR. This study provides useful tools to identify high-risk patients and to guide clinical decision making before and after intervention.

Genetic epidemiology of childhood brain tumors

A rare familial cancer syndrome involving childhood brain tumors (CBT), breast cancer, sarcomas and an array of other tumors has been described (Li and Fraumeni 1969, 1975, 1982, 1987). A survey of CBT identified through the Connnecticut Tumor Registry in 1984 revealed a high frequency of CBT, leukemia and other childhood cancer in siblings of CBT patients (Farwell and Flannery, 1984). Other syndromes such as neurofibromatosis and nevoid basal cell carcinoma syndrome have also been associated with CBT; however, no systematic family studies have been conducted to determine the extent to which cancer aggregates in family members of CBT patients. This family study was designed to determine the frequency of cancer aggregation overall or at specific sites, to determine the frequency of known or potentially hereditary syndromes in families of CBT patients, and to determine a genetic model to characterize familial cancer syndromes and to identify specific kindreds to which such a model(s) might apply. This study includes 244 confirmed CBT patients referred to the University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed under the age of 15 years and resident in the U.S. or Canada. Family histories were obtained on the proband's first (parents, siblings and offspring) and second degree (proband's aunts, uncles and grandparents) relatives following sequential sampling scheme rules. To determine if cancer aggregates in families, we compared the cancer experience in the population to that expected in the general population using Connecticut Tumor Registry calendar year, age, race and sex-specific rates. The standardized incidence ratio (SIR) for cancer overall was 0.91 (41 observed (O) and 44.94 expected (E); 95% Confidence Interval (CI) = 0.65-1.24). We observed a significant excess of colon cancer among the proband's first degree relatives (O/E = 5/1.64; 95% CI = 1.01-7.65), in particular those under age 45 year. Segregation analysis showed evidence for multifactorial inheritance in the small percentage (N = 5) of the families. ^

Colorectal cancer screening: Participation and determinants in West Texas

Early detection by screening is the key to colorectal cancer control. However, colorectal cancer screening and its determinants in rural areas have not been adequately studied. This goal of this study was to investigate the screening participation and determinants of colonoscopy, sigmoidoscopy, and/or fecal occult blood test (FOBT) in subjects of Project Frontier from the rural counties of Cochran, Bailey and Parmer, Texas. Subjects ( n=820 with 435 Hispanics, 355 Non-Hispanic Whites, 26 African Americans, and 4 unknown ethnicity; 255 males, 565 females, aged from 40 to 92 years) were from Project FRONTIER. Stepwise logistic regression analysis was performed. Explanatory variables included ethnicity (Hispanic, Non-Hispanic white and African American), gender, health insurance, smoking status, household income, education (years), physical activity, overweight, other health screenings, personal physicians, family history (first-degree relatives) of cancers, and preferred language (English vs. Spanish) for interview/testing. The screening percentage for ever having had a colonoscopy/sigmoidoscopy (51.8%) in this cohort aged 50 years or older is well below the percentage of the nation (65.2%) and Texas (64.6%) while the percentage for FOBT (29.2%) is higher than in the nation (17.2%) and Texas (14.9%). However, Hispanics had significantly lower participation than non-Hispanic whites for colonoscopy/sigmoidoscopy (37.0% vs. 66.0%) and FOBT (16.5% vs. 41.7%), respectively. Stepwise logistic regression showed that predictors for colonoscopy, sigmoidoscopy or FOBT included Hispanic race (p = 0.0045), age (p < 0.0001), other screening procedure (p < 0.0001), insurance status (p < 0.0001) and physician status (p = 0.0053). Screening percentage for colonoscopy/sigmoidoscopy in this rural cohort is well below the national and Texas level mainly due to the lower participation of Hispanics vs. Non-Hispanic whites. Health insurance, having had a personal physician, having had screenings for other cancers, race, and older age are among the main predictors.^

Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome

Our preliminary family studies have suggested that some female first-degree relatives of women with polycystic ovary syndrome (PCOS) have hyperandrogenemia per se. It was our hypothesis that this may be a genetic trait and thus could represent a phenotype suitable for linkage analysis. To investigate this hypothesis, we examined 115 sisters of 80 probands with PCOS from unrelated families. PCOS was diagnosed by the combination of elevated serum androgen levels and ≤6 menses per year with the exclusion of secondary causes. The sisters were compared with 70 healthy age- and weight-comparable control women with regular menses, no clinical evidence of hyperandrogenemia, and normal glucose tolerance. Twenty-two percent of the sisters fulfilled diagnostic criteria for PCOS. In addition, 24% of the sisters had hyperandrogenemia and regular menstrual cycles. Circulating testosterone (T) and nonsex hormone-binding globulin-bound testosterone (uT) levels in both of these groups of sisters were significantly increased compared with unaffected sisters and control women (P < 0.0001 for both T and uT). Probands, sisters with PCOS, and hyperandrogenemic sisters had elevated serum luteinizing hormone levels compared with control women. We conclude that there is familial aggregation of hyperandrogenemia (with or without oligomenorrhea) in PCOS kindreds. In affected sisters, only one-half have oligomenorrhea and hyperandrogenemia characteristic of PCOS, whereas the remaining one-half have hyperandrogenemia per se. This familial aggregation of hyperandrogenemia in PCOS kindreds suggests that it is a genetic trait. We propose that hyperandrogenemia be used to assign affected status in linkage studies designed to identify PCOS genes.

Peptide analogs to pathogenic epitopes of the human acetylcholine receptor alpha subunit as potential modulators of myasthenia gravis.

Myasthenia gravis is an autoimmune disease in which T cells specific to epitopes of the autoantigen, the human acetylcholine receptor, play a role. We identified two peptides, p195-212 and p259-271, from the alpha subunit of the receptor, which bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) from peripheral blood lymphocytes of myasthenia gravis patients and stimulated lymphocytes of >80% of the patients. We have prepared analogs of these myasthenogenic peptides and tested their ability to bind to MHC class II determinants and to interfere specifically with T-cell stimulation. We first determined relative binding efficiency of the myasthenogenic peptides and their analogs to APCs of patients. We found that single substituted analogs of p195-212 (Ala-207) and p259-271 (Lys-262) could bind to human MHC molecules on APCs as efficiently as the original peptides. Moreover, dual analogs containing the two single substituted analogs in one stretch (either sequentially, Ala-207/Lys-262, or reciprocally, Lys-262/Ala-207) could also bind to APCs of patients, including those that failed to bind one of the single substituted analogs. The single substituted analogs significantly inhibited T-cell stimulation induced by their respective myasthenogenic peptides in >95% of the patients. The dual analogs were capable of inhibiting stimulation induced by either of the peptides: They inhibited the response to p195-212 and p259-271 in >95% and >90% of the patients, respectively. Thus, the dual analogs are good candidates for inhibition of T-cell responses of myasthenia gravis patients and might have therapeutic potential.

A system of ethicks: Of morall phylosophy in generall & in speciall

This hardcover volume contains manuscript copies of Charles Morton's "A System of Ethicks," "Pneumatics. Or a treatise of the Rev'd Mr. Charles Morton about ye Nature of Spirit," "Appendix of the Souls of Brutes," "Some Theological Questions Answd," and a one-page list "Texts of Scripture to prove if ye head of Christ &c." copied by Harvard student Ebenezer Williams in February 1707/8.

Compendium physicæ ex authoribus extractum, 1714

Manuscript copy of Charles Morton’s Compendium Physicae prepared by copyist Robert Ward in 1714. The leather-bound volume includes text and drawings, and there is an index to the chapters of the book at the end of the volume. "Thomas Greaves's book Octob 1 Anno Salutis 1714" inscribed on flyleaf. Thomas Greaves may refer to the Charlestown physician and judge and member of the Harvard Class of 1703.