Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Anal bulking agents for faecal incontinence.

The aim of this review was to assess and evaluate reports of studies on the efficacy of anal bulking agents used in the treatment of faecal incontinence. A systematic review of the literature was carried out to identify studies that have reported on the use of anal bulking agents. A variety of biomaterials have been employed for anal bulking. These include autologous fat, bovine glutaraldehyde cross-linked collagen, carbon-coated zirconium oxide beads, dextranomer microspheres in a gel, hydrogel cross-linked with polyacrylamide, polydimethylsiloxane elastomer in a gel, porcine dermal collagen and synthetic calcium hydroxylapatitie ceramic microspheres. Although the ideal site of injection (submucosal or intramuscular) and the mechanism of action remain the subject of debate, most published studies report a significant improvement in continence in at least 50% of subjects with mild to moderate symptoms with little or no associated morbidity.We concluded that anal bulking agents may be used to alleviate symptoms of faecal seepage and soilage.

T-cell responses in osteosarcoma patients vaccinated with an anti-idiotypic antibody, 105AD7, mimicking CD55.

We assessed T-cell responses in young osteosarcoma patients vaccinated with 105AD7, 1-6 months after having received chemotherapy. 105AD7 is a human anti-idiotypic antibody mimicking CD55, a glycoprotein that protects from attack by complement and which is overexpressed on osteosarcoma cells. Seven out of 21 investigated patients made a IFN-gamma T-cell response against the vaccine, 105AD7 as assessed by ELISPOT. Cytokine secretion was analysed using Luminex assays and revealed TNF-alpha and GM-CSF responses not only to the vaccine but also towards the native antigen, CD55, in 5 / 14 (36%) of investigated patients. Importantly, the Luminex assay was found to be more sensitive than the more established T-cell assays (ELISPOT and proliferation assay), since responses towards the native antigen were recorded in this assay. Clinical responses and induction of immune responses to both the anti-idiotype and the native CD55 antigen support the use of CD55 as a target in cancer treatment.

Transcriptional Signatures of Sleep Duration Discordance in Monozygotic Twins.

Introduction: Habitual short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (eg, genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of habitual short sleep duration on gene expression. Therefore, we investigated gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Methods: Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD = 18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with 2 weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Finally, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. Results: The mean 24-hour sleep duration of the total sample was 439.2 minutes (SD = 46.8 minutes; range 325.4-521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD = 21.2; range 45.9-114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such as interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Conclusions: Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of habitual short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular, and inflammatory outcomes.

Diffusion abnormalities in patients with Wernicke encephalopathy.

Diffusion-weighted imaging (DWI) can help to diagnose acute ischemic stroke. Other nonischemic disorders may show abnormal signals with DWI. The authors report two cases of Wernicke encephalopathy with DWI signal changes in characteristic midline locations, one with reduction in apparent diffusion constant and one without. DWI abnormalities may suggest early thiamine deficiency and are useful in diagnosing Wernicke encephalopathy.

When might hemispheric favouring of epileptiform discharges begin?

PURPOSE: EEG studies based on adult populations report interictal epileptiform discharges (EDS) favour the left hemisphere. It is not clear when favouring becomes apparent as similar paediatric studies have not been performed. METHODS: The authors reviewed 1,579 paediatric EEG interpretations for evidence of hemispheric favouring of focal epileptiform discharges. Analysis focused on first-time EEG results. RESULTS: Right hemispheric favouring of interictal epileptiform discharges occurs in childhood, it remits around 5 years of age whereupon left-sided favouring occurs more frequently (P=0.004, Fisher's Exact). CONCLUSION: Hemispheric vulnerabilities to interictal focal epileptiform activity may display discrete age-related favouring. These findings are discussed in context of normal hemispheric maturation.

CD24 shows early upregulation and nuclear expression but is not a prognostic marker in colorectal cancer.

BACKGROUND AND AIMS: The putative stem cell marker CD24 is a small, heavily glycosylated, cell surface molecule which was originally associated with tumour metastasis. Recently it has been reported to be upregulated and of prognostic importance in colorectal tumours. The study aims to study the prognostic value of CD24 in a large series of colorectal cancer (CRC). METHODS: CD24 protein expression was examined by immunohistochemistry. A total of 10 whole tissue sections (WTS) of adenoma and 345 CRCs arranged as tissue microarrays (TMAs) were evaluated. For comparison with non-neoplastic tissue, 10 WTS containing tumour with associated non-neoplastic tissue were also studied. RESULTS: None of the samples of normal tissue (adjacent to tumour) showed CD24 expression. In the tumours, CD24 expression was seen on the luminal surface of the cells, within the cytoplasm and, unexpectedly, also within the nucleus. Positive immunostaining was seen in 9/10 (90%) adenomas and 313/345 (91%) of CRCs. Weak statistical associations were found between CD24 expression and some clinicopathological features. In contrast to other published studies, however, the analysis did not show any association between CD24 expression and poor prognosis-if anything it was found that loss of CD24 expression appeared to be more related to poor outcome. CONCLUSION: Upregulation of CD24 is an early and common event during the development of CRC and it may be expressed in any cellular compartment, including the nucleus. CD24 is not, however, a good prognostic marker in CRC.

A prospective audit of early pain and patient satisfaction following out-patient band ligation of haemorrhoids.

INTRODUCTION: Information regarding early morbidity, pain and patient satisfaction following band ligation of haemorrhoids is limited. This is the first report to address these issues specifically. PATIENTS AND METHODS: A total of 183 patients underwent the procedure over a 10-month period. Prospective data were collected using a detailed structured questionnaire regarding symptoms, analgesia requirements and patient satisfaction in the following week. RESULTS: The response rate was 74% (135/183). Pain scores were highest 4 h following the procedure. At 1 week, 75% of patients were pain-free, with 9 (7%) still experiencing moderate-to-severe pain. About 65% required oral analgesia, most frequently on the day of procedure. Rectal bleeding occurred in 86 patients (65%) on the day after banding, persisting in 32 (24%) at 1 week. Vaso-vagal symptoms occurred in 41 patients (30%) and were commonest at the time of banding. Eighty patients (59%) were satisfied with their experience and would undergo the procedure again. Patients requiring oral analgesia and those experiencing bleeding or vaso-vagal symptoms were significantly less likely to be satisfied with the procedure. Only 57% of the patients surveyed would recommend the procedure to a friend. CONCLUSIONS: Data from this large cohort of patients suggest that discomfort and bleeding may persist for a week or more following banding of haemorrhoids. Patients should be aware of this in order to make an informed decision as to whether to undergo the procedure, and surgeons should investigate ways of reducing it. Patient satisfaction may be further improved by more accurate counselling regarding the incidence of specific complications.

Malignant transformation of high-grade anal intraepithelial neoplasia.

BACKGROUND: The natural history of anal intraepithelial neoplasia (AIN) is uncertain. This makes management problematic as treatment options to eradicate the condition carry morbidity. The authors report their 10-year experience with conservative management of this condition, highlighting the lessons learnt. METHODS: All patients were diagnosed with high-grade AIN (AIN III) between 1994 and 2003. Diagnosis was by full-thickness biopsy and histopathological examination. Excision of localized lesions was undertaken, and all patients underwent follow-up every 6 months. Prospective data were collected regarding recurrence, postoperative complications and progression to invasive carcinoma. RESULTS: Thirty-five patients were followed for a median of 63 (range 14-120) months. Excision of localized high-grade AIN was carried out in 28 patients with minimal morbidity. Six patients were systemically immunosuppressed at diagnosis, all of whom had multifocal perianal lesions. Three immunosuppressed patients developed invasive anal squamous carcinoma during follow-up. By contrast, no invasive carcinomas were identified among immunocompetent patients with either localized or multifocal perianal disease. CONCLUSION: AIN III appears to have a relatively low potential for malignant transformation in the immunocompetent patient. However, immunosuppressed patients are more likely to have extensive AIN III and a greater risk of malignant change.