Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes

Glucagon-like peptide 1 (GLP-1) is a promising candidate for the treatment of type II diabetes. However, the short in vivo half-life of GLP-1 has made peptide-based treatments challenging. Gene therapy aimed at achieving continuous GLP-1 expression presents one way to circumvent the rapid turnover of GLP-1. We have created a GLP-1 minigene that can direct the secretion of active GLP-1 (amino acids 7-37). Plasmid and adenoviral expression vectors encoding the 31-amino-acid peptide linked to leader sequences required for secretion of GLP-1 yielded sustained levels of active GLP-1 that were significantly greater than endogenous levels. Systemic administration of expression vectors to animals using two diabetic rodent models, db/db mice and Zucker Diabetic Fatty (ZDF) rats, yielded elevated GLP-1 levels that lowered both the fasting and random-fed hyperglycemia present in these animals. Because the insulinotropic actions of GLP-1 are glucose dependent, no evidence of hypoglycemia was observed. Improved glucose homeostasis was demonstrated by improvements in %HbA1c (glycated hemoglobin) and in glucose tolerance tests. GLP-1-treated animals had higher circulating insulin levels and increased insulin immunostaining of pancreatic sections. GLP-1-treated ZDF rats showed diminished food intake and, in the first few weeks following vector administration, a diminished weight gain. These results demonstrate the feasibility of gene therapy for type II diabetes using GLP-1 expression vectors.     

Renal adaptation and gut hormone release during sodium restriction in ileostomized man

The renal excretion of water, electrolytes, aldosterone and kallikrein was monitored in 12 ileostomized patients before and during sodium deprivation. Changes in plasma renin activity (PRA), plasma aldosterone and plasma arginine vasopressin (AVP) concentrations were measured, together with aldosterone in ileal fluid. The pattern of gut peptide release in response to a test meal was also examined to assess whether a circulating gut peptide might be involved in the renal adaptation to sodium restriction, and compared with healthy normal subjects who were under no dietary constraint. In each patient renal sodium excretion fell within 8-12 h of sodium deprivation and was associated with a prompt and significant rise in PRA; much later increases in plasma aldosterone concentration and renal aldosterone excretion occurred, and were established by day 2 of sodium restriction. No consistent change in renal kallikrein excretion was found. Ileal sodium loss was little changed by sodium deprivation, but ileal potassium concentration rose steadily and became significantly correlated with PRA, and to a lesser extent with renal aldosterone excretion. Of the gut peptides measured in plasma, only the insulin profile was altered by sodium deprivation, with an increase in the test meal response; insulin has previously been shown to have a significant antinatriuretic action at physiological concentrations. Plasma levels of pancreatic polypeptide and motilin were increased in ileostomized patients when compared with normal subjects, but were unaffected by the change to a low sodium diet. An early increase in urine flow and water diuresis occurred during sodium deprivation, following a cyclical pattern with peaks each evening.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Impact of Deployment on Parental,Family and Child Adjustment in Military Families

Since 9/11, military service in the United States has been characterized by wartime deployments and reintegration challenges that contribute to a context of stress for military families. Research indicates the negative impact of wartime deployment on the well being of service members, military spouses, and children. Yet, few studies have considered how parental deployments may affect adjustment in young children and their families. Using deployment records and parent-reported measures from primary caregiving (N = 680) and military (n = 310) parents, we examined the influence of deployment on adjustment in military families with children ages 0–10 years. Greater deployment exposure was related to impaired family functioning and marital instability. Parental depressive and posttraumatic stress symptoms were associated with impairments in social emotional adjustment in young children, increased anxiety in early childhood, and adjustment problems in school-age children. Conversely, parental sensitivity was associated with improved social and emotional outcomes across childhood. These findings provide guidance to developing preventive approaches for military families with young children.     

In vitro displacement of bilirubin by antibiotics and 2-hydroxybenzoylglycine in newborns

Hyperbilirubinemia is frequently observed in neonates, and serious neurological complications such as kernicterus can be precipitated when the concentration of unconjugated bilirubin is abnormally increased. The administration of drugs which bind to albumin and compete with bilirubin can increase the possibility of such a complication. To test the bilirubin-displacing activity of pharmacological agents that are used with newborns, 52 antimicrobial agents were investigated in vitro. A glycine conjugate of salicylate, 2-hydroxybenzoylglycine, which is known to be present at elevated levels in newborns and has a potent bilirubin-displacing property, was used as a positive control agent. Pooled cord serum was used as a source of hyperbilirubinemic serum. A centrifugal ultrafiltration method with semipermeable cones was employed to determine the effects of potential bilirubin-displacing agents on the levels of total bilirubin. 2-Hydroxybenzoylglycine was demonstrated to be the most potent bilirubin-displacing agent. Antibiotics could be classified into four groups: high-level displacers (sulfisoxazole, sulfamethoxazole, dicloxacillin, cefoperazone, and ceftriaxone), intermediate-level displacers (moxalactam, nafcillin, and 14 others), low-level displacers (aztreonam, carbenicillin, and 11 others), and nondisplacers (mezlocillin, cefuroxime, kanamycin, and 15 others). It is concluded that the ultrafiltration method is a rapid and readily reproducible for the determination of bilirubin displacement and that antibiotics with a tendency to displace bilirubin should be avoided in jaundiced newborns whenever appropriate alternatives are available.     

The continuing benefits of education: adult education and midlife cognitive ability in the British 1946 birth cohort

OBJECTIVE: Evidence shows education positively impacts cognitive ability. However, researchers have given little attention to the potential impact of adult education on cognitive ability, still malleable in midlife. The primary study aim was to examine whether there were continuing effects of education over the life course on midlife cognitive ability. METHODS: This study used data from the Medical Research Council National Survey of Health and Development, also known as the British 1946 birth cohort, and multivariate regression to estimate the continuing effects of adult education on multiple measures of midlife cognitive ability. RESULT: Educational attainment completed by early adulthood was associated with all measures of cognitive ability in late midlife. The continued effect of education was apparent in the associations between adult education and higher verbal ability, verbal memory, and verbal fluency in late midlife. We found no association between adult education and mental speed and concentration. Discussion: Associations between adult education and midlife cognitive ability indicate wider benefits of education to health that may be important for social integration, well-being, and the delay of cognitive decline in later life.     

Characterization of three novel β-defensin antimicrobial peptides in rainbow trout (Oncorhynchus mykiss)

An initial bioinformatics investigation followed by cloning and sequencing analysis, has led to the identification of three novel members (omDB-2, omDB-3, omBD-4) of the β-defensin family in rainbow trout (Oncorhynchus mykiss). The contiguous sequences could be translated to give predicted peptides of 62 (omDB-2), 63 (omDB-3) and 68 (omDB-4) amino acids (aa) in length, with mature peptides of 43 (omDB-2), 39 (omDB-3) and 42 (omDB-4) aa, with no obvious proregion present. Analysis of the gene organization found that all three new genes contained three exons divided by two introns, as seen in defensin genes of other fish species. Constitutive expression of all the trout defensins was detected by RT-PCR in a wide range of mucosal and systemic tissues from healthy fish, with omDB-3 and omDB-4 showing the highest expression levels. Following bacterial challenge in vivo, the defensin genes were induced at the three mucosal sites examined (skin, gill, gut), with levels of omDB-2 and omDB-3 increased some 16-fold in gut and gill respectively. Using polyinosinic polycytosinic RNA (polyI:C) as a viral mimic, all of the four trout β-defensin genes were induced in head kidney primary leucocyte cultures at 4 h post-stimulation, with omDB-1 and omDB-3 particularly highly expressed. These data suggest that β-defensins are likely an important component of the innate defences of fish, and reveal an added level of antimicrobial peptide complexity in fish to that known previously.     

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data

Aims/hypothesis

We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes.

Methods

Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies.

Results

Data were available for 29 predominantly European studies (five cohort, 24 case–control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01–1.11]; p?=?0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04–1.19]; p?=?0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00–1.06]; p?=?0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings.

Conclusions/interpretation

Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.     

Spontaneous generation of mammalian prions

Prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. Prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. While investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mouse brain homogenate. This phenomenon proved to be reproducible in rigorous and exhaustive control experiments designed to exclude prion contamination. The infectivity generated in cell culture could be readily transferred to mice and had strain characteristics distinct from the mouse-adapted prion strains used in the laboratory. The apparent ”spontaneous generation” of prions from normal brain tissue could result if the metal surface, possibly with bound cofactors, catalyzed de novo formation of prions from normal cellular prion protein. Alternatively, if prions were naturally present in the brain at levels not detectable by conventional methods, metal surfaces might concentrate them to the extent that they become quantifiable by the scrapie cell assay.     

Genetic Characterization of Foot-and-Mouth Disease Viruses, Ethiopia, 1981�C2007

Foot-and-mouth disease (FMD) is endemic to sub-Saharan Africa. To further understand its complex epidemiology, which involves multiple virus serotypes and host species, we characterized the viruses recovered from FMD outbreaks in Ethiopia during 1981–2007. We detected 5 of the 7 FMDV serotypes (O, A, C, Southern African Territories [SAT] 1, and SAT 2). Serotype O predominated, followed by serotype A; type C was not recognized after 1983. Phylogenetic analysis of virus protein 1 sequences indicated emergence of a new topotype within serotype O, East Africa 4. In 2007, serotype SAT 1 was detected in Ethiopia and formed a new distinct topotype (IX), and serotype SAT 2 reappeared after an apparent gap of 16 years. The diversity of viruses highlights the role of this region as a reservoir for FMD virus, and their continuing emergence in Ethiopia will greatly affect spread and consequent control strategy of the disease on this continent.     

First report of Creutzfeldt-Jakob disease occurring in 2 siblings unexplained by PRNP mutation

Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.