Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

Background Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank.Methods A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure.Results After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death.Conclusion We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.Subject terms: Predictive markers, Prostate cancer, Risk factors     

Food deprivation and hypothalamic neuropeptide gene expression: effects of strain background and the diabetes mutation.

We have used a novel method to identify genes expressed in the hypothalamus which may be potentially involved in controlling food intake and energy metabolism. We assumed that food deprivation, a powerful stimulus of food intake, would stimulate the activity of neural pathways involved in feeding behavior which should be reflected in an increase in the synthesis of any relevant neuropeptide and its messenger RNA. A study of 5 neuropeptides in 5 strains of mice has identified neuropeptide Y (NPY) as a gene whose expression in the hypothalamus is controlled by nutritional status, suggesting that hypothalamic NPY neurons are a link in the neural network regulating feeding behavior and energy metabolism. In addition, we have studied the effect of the diabetes mutation on neuropeptide gene expression during fasting and refeeding. Our findings suggest that abnormal NPY and enkephalin gene expression in the hypothalamus may be two important determinants of the expression of the diabetes mutation.     

Short-term hyperglycemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobulin

Hyperglycemia accompanies a myriad of clinical conditions and causes an acceleration in the nonenzymatic glycosylation (NEG) of proteins. Since many proteins lose function when glycosylated, we assessed the effect of hyperglycemia on the function of immunoglobulin G. Twenty newborn Sprague-Dawley rats underwent splenectomy and 20, splenic mobilization alone. After 3 weeks, all animals received an intraperitoneal injection of Streptococcus pneumoniae. Twelve hours later, ten animals from each group received either control (CIG) or glycosylated (GIG) human immunoglobulin (0.3 gm/kg) intraperitoneally. Asplenic animals receiving GIG lived 28.5 hours vs. 49.6 hours for those receiving CIG (p less than 0.0001). Animals with spleens receiving GIG lived 48.2 hours vs. 51.7 hours for those receiving CIG (p = 0.03). Short-term glycosylation of immunoglobulin causes its inactivation. This may contribute to the increased risk of infection noted in hyperglycemic animals.     

Improved diagnostic effectiveness with a sequential diagnostic paradigm in idiopathic pediatric sensorineural hearing loss.

OBJECTIVES: To determine whether a stepwise diagnostic paradigm is more diagnostically efficient and cost-effective than a simultaneous testing approach in the evaluation of idiopathic pediatric sensorineural hearing loss (SNHL). DESIGN: Prospective prevalence study. SETTING: Tertiary referral children's hospital. PATIENTS: Consecutive children (n = 150) presenting with idiopathic SNHL in the last 2 years. INTERVENTIONS: All children were evaluated with full diagnostic evaluations including GJB2 screens, temporal bone computed tomography scans, and laboratory investigations. MAIN OUTCOME MEASURES: 1) Diagnostic yields of GJB2 screens, imaging, and laboratory results per SNHL category; 2) Cost analysis comparing a sequential versus a simultaneous testing approach. RESULTS: Overall, 12.0% of patients had biallelic mutations in the GJB2 gene, whereas 30% of patients had an abnormality on temporal bone scan. Laboratory testing did not reveal the SNHL etiology in any patient. While maintaining diagnostic accuracy, significant cost savings were inferred by using a sequential diagnostic algorithm. Our data show children with severe to profound SNHL should first be tested with a GJB2 screen, as opposed to those with milder SNHL, who should undergo imaging as the initial testing step. In patients with initially positive GJB2 or imaging screens, logistic regression analysis significantly predicted negative results on further testing. CONCLUSIONS: A stepwise diagnostic paradigm tailored to the level of the hearing loss in children with bilateral SNHL is more diagnostically efficient and cost effective than the more commonly used full, simultaneous testing approach. Laboratory investigation should not be routine but based on clinical history.     

Functional genomics and schizophrenia: endophenotypes and mutant models.

This article summarizes the rationale, methods, and results of gene discovery programs in schizophrenia research and describes functional methods of investigating potential candidate genes. It focuses next on the most prominent current candidate genes and describes (1) evidence for their association with schizophrenia and research into the function of each gene; (2) investigation of the clinical phenotypes and endophenotypes associated with each gene, at the levels of psychopathologic, neurocognitive, electrophysiologic, neuroimaging, and neuropathologic findings; and (3) research into the ethologic, cognitive, social, and psychopharmacologic phenotype of mutants with targeted deletion of each gene. It examines gene-gene and gene-environment interactions. Finally, it looks at future directions for research.     

Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives

Structural brain abnormalities are consistently reported in schizophrenic subjects but the etiology of these abnormalities remains unclear. We tested the contribution of genetic predisposition and obstetric complications to the structural brain abnormalities found in schizophrenic probands and their relatives. MRI scans were carried out on 35 schizophrenic probands from families multiply affected with the disorder, and 63 of their unaffected relatives, including 10 parents who appeared to transmit genetic risk to their children; as well as 31 schizophrenic probands from families with no other affected members, 33 of their unaffected relatives; and finally 68 controls. Volumetric measurements of whole brain, lateral ventricles, third ventricle, cerebellum, and temporal lobes were completed for each subject. The impact of obstetric complications on brain structure was assessed across the gradient of presumed genetic predisposition. Both groups of schizophrenic probands displayed enlargement of the lateral and third ventricles, and there was a gradient of ventricular enlargement amongst the unaffected relatives in proportion to their likelihood of carrying schizophrenic genes. Ventricular enlargement was largely confined to males in both probands and unaffected relatives. Obstetric complications were associated with ventricular enlargement only in the familial probands. Non-familial probands displayed reduced volume of the temporal lobes bilaterally. In families with several schizophrenic members, ventricular enlargement is a marker for genetic liability, particularly in males. Individuals inheriting the susceptibility to schizophrenia appear particularly prone to develop ventricular enlargement in response to obstetric complications.     

Evaluation of the purity of a purified, inactivated hepatitis A vaccine (VAQTA).

Manufacture of VAQTA, an inactivated hepatitis A virus vaccine, includes extensive purification of the intact virus particle to remove endogenous components from the host cell culture lysate as well as compounds introduced in the upstream purification process. Analysis of the final purified hepatitis A virus product by SDS-PAGE prior to inactivation shows that greater than 95% of the protein in the preparation is found in four protein bands, which have been confirmed to be hepatitis A virus capsid proteins VP0, VP1, VP2 and VP3 based on Western blot and mass spectrometry analyses. Validation of the manufacturing process and direct analysis of the final product were used to demonstrate that no other specific host cell-derived components are detected and that process residuals are all below the limits of detection of the assays used. Establishment of a rigorous standard of high purity for this product was pursued to minimize the impact of impurities during clinical development of this product and will facilitate the incorporation of this product into combination vaccines.     

The effect of regular antenatal perineal massage on postnatal pain and anal sphincter injury: a prospective observational study.

OBJECTIVE: Antenatal perineal massage has been shown to reduce the incidence of perineal tears in primiparous women. The aim of this study was to determine whether perineal massage impacts on primary prevention of symptomatic disruption of the fecal continence mechanism. METHODS: An observational study recruited two cohorts of women. The first, massage group (MG) chose to perform daily perineal massage from 34 weeks gestation, and the second, control group (CG) was asked to avoid massage. Perineal injury and postnatal pain were documented and all women were invited to attend at three months postpartum for continence assessment, anal manometry, and endoanal ultrasound. RESULTS: Of 179 women recruited, 100 were in the MG while 79 women were controls. Mode of delivery was not influenced by perineal massage. Although the impact did not reach statistical significance, women aged over 30 years in the MG were more likely to be delivered with an intact perineum than controls. Postnatal perineal pain was much reduced in the MG compared with the CG (p = 0.029). Of the women recruited, 136 (75.9%) returned for a postnatal continence assessment. Manometry pressures, continence scores, and endoanal ultrasound findings were similar in both groups. CONCLUSION: Antenatal perineal massage was found to significantly affect postnatal perineal pain scores although it did not impact on the incidence of intact perineum at delivery, postnatal continence scores, anal manometry pressures, or endoanal ultrasound findings.