A review of sex differences in the mechanisms and drivers of overeating.

Disordered eating is often associated with marked psychological and emotional distress, and severe adverse impact on quality of life. Several factors can influence eating behavior and drive food consumption in excess of energy requirements for homeostasis. It is well established that stress and negative affect contribute to the aetiology of eating disorders and weight gain, and there is substantial evidence suggesting sex differences in sub-clinical and clinical types of overeating. This review will examine how negative affect and stress shape eating behaviors, and how the relationship between the physiological, endocrine, and neural responses to stress and eating behaviors differs between men and women. We will examine several drivers of overeating and explore possible mechanisms underlying sex differences in eating behavior.

Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.

There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.

Multilocus phylogeny and Bayesian estimates of species boundaries reveal hidden evolutionary relationships and cryptic diversity in Southeast Asian monitor lizards.

Recent conceptual, technological and methodological advances in phylogenetics have enabled increasingly robust statistical species delimitation in studies of biodiversity. As the variety of evidence purporting species diversity has increased, so too have the kinds of tools and inferential power of methods for delimiting species. Here, we showcase an organismal system for a data-rich, comparative molecular approach to evaluating strategies of species delimitation among monitor lizards of the genus Varanus. The water monitors (Varanus salvator Complex), a widespread group distributed throughout Southeast Asia and southern India, have been the subject of numerous taxonomic treatments, which have drawn recent attention due to the possibility of undocumented species diversity. To date, studies of this group have relied on purportedly diagnostic morphological characters, with no attention given to the genetic underpinnings of species diversity. Using a 5-gene data set, we estimated phylogeny and used multilocus genetic networks, analysis of population structure and a Bayesian coalescent approach to infer species boundaries. Our results contradict previous systematic hypotheses, reveal surprising relationships between island and mainland lineages and uncover novel, cryptic evolutionary lineages (i.e. new putative species). Our study contributes to a growing body of literature suggesting that, used in concert with other sources of data (e.g. morphology, ecology, biogeography), multilocus genetic data can be highly informative to systematists and biodiversity specialists when attempting to estimate species diversity and identify conservation priorities. We recommend holding in abeyance taxonomic decisions until multiple, converging lines of evidence are available to best inform taxonomists, evolutionary biologists and conservationists.

Cutaneous mast cell tumor with epitheliotropism in 3 dogs.

Epitheliotropism is an important diagnostic feature of cutaneous epitheliotropic lymphoma and canine cutaneous histiocytoma; however, although noted in certain feline mastocytic diseases, it has not been considered a feature of canine cutaneous mast cell tumor. In this study, 3 canine cutaneous mast cell tumors had epitheliotropic invasion of neoplastic mast cells into the epidermis and follicular epithelium. This unusual histologic finding was characterized by infiltrates of individual and clusters of neoplastic mast cells in the stratum basale and stratum spinosum. The mast cell origin of these cells was documented by demonstration of metachromasia with Giemsa stain and positive immunoreactivity to KIT protein. On the basis of these findings, mast cell tumors should be included in the differential diagnosis for canine cutaneous round cell neoplasms that infiltrate the epidermis.

Search for charged Higgs bosons in e+e- collisions at [Formula: see text].

A search is made for charged Higgs bosons predicted by Two-Higgs-Doublet extensions of the Standard Model (2HDM) using electron-positron collision data collected by the OPAL experiment at [Formula: see text], corresponding to an integrated luminosity of approximately 600 pb-1. Charged Higgs bosons are assumed to be pair-produced and to decay into [Formula: see text], τντ or AW±. No signal is observed. Model-independent limits on the charged Higgs-boson production cross section are derived by combining these results with previous searches at lower energies. Under the assumption [Formula: see text], motivated by general 2HDM type II models, excluded areas on the [Formula: see text] plane are presented and charged Higgs bosons are excluded up to a mass of 76.3 GeV at 95 % confidence level, independent of the branching ratio BR(H±â†’τντ ). A scan of the 2HDM type I model parameter space is performed and limits on the Higgs-boson masses [Formula: see text] and mA are presented for different choices of tanß.

Chronic hepatitis C in children--review of natural history at a National Centre.

The natural history of hepatitis C virus (HCV) infection in adults has been established, but less is known about outcome in children. We conducted a retrospective review of patients referred to Birmingham Children's Hospital Liver Unit, from 1991 till 2008, with the diagnosis of HCV was undertaken. Only children with documented positive HCV RNA and a minimum duration of follow-up of 6 months were included. One hundred and thirty-three children were identified. The route of transmission was transfusion acquired in 47%, vertically acquired in 49% and transplantation in 2%. Since 2000, most children were infected vertically. The overall rate of spontaneous viral clearance was 17.5% with higher clearance (27%) in the transfusion group compared to the vertically acquired group (9%). Seventy-six had a liver biopsy at diagnosis. There was no evidence of fibrosis in 46%, mild fibrosis in 50% and moderate to severe fibrosis in 4%. None had cirrhosis. There was a statistically significant relationship between fibrosis score and older age at the time of biopsy (P = 0.02) and longer duration of infection (P = 0.05). Eighty children received treatment for HCV. Sustained viral response (SVR) was influenced by viral genotypes, with significantly increased response rates in genotypes (G) 2 and 3 compared to G 1 and 4. Vertical infection is now the major route of HCV infection in children in the UK. Histological changes were mild at diagnosis, but the severity of fibrosis progressed with age. Consideration should be given to improve detection and diagnosis to refer children to specialist centres for management and antiviral therapy before developing fibrosis.

Subcutaneous fat necrosis in a newborn associated with asymptomatic and uncomplicated hypercalcemia.

Subcutaneous fat necrosis in a newborn is a rare, benign and self-limiting panniculitis. Hypercalcemia may develop and has been implicated as the cause of serious complications including seizures, nephrocalcinosis, and death. We report a case of subcutaneous fat necrosis in a newborn associated with asymptomatic and uncomplicated hypercalcemia, which resolved spontaneously.

Lifetime reproductive success and longevity of queens in an annual social insect.

Although central to understanding life-history evolution, the relationship between lifetime reproductive success and longevity remains uncertain in many organisms. In social insects, no studies have reported estimates of queens' lifetime reproductive success and longevity within populations, despite the importance of understanding how sociality and associated within-group conflict affect life-history traits. To address this issue, we studied two samples of colonies of the annual bumblebee, Bombus terrestris audax, reared from wild-caught queens from a single population. In both samples, queens' lifetime reproductive success, measured as either queens' inclusive fitness or as total biomass of queen-produced sexuals (new queens and males), was significantly positively associated with queen longevity, measured from the day the first worker was produced. We suggest that a positive relationship between reproductive success and longevity was inherited from nonsocial ancestors showing parental care and maintained, at least in part, because the presence of workers buffers queens against extrinsic mortality.

The cytoplasmic domain of the cellulose-synthesizing complex in vascular plants.

The cytoplasmic domain of the rosette terminal complex has been imaged in situ in patches of plasma membrane isolated from tobacco BY-2 protoplasts. By partially extracting the plasma membrane lipids, cellulose microfibrils were observed through the plasma membrane. Rosette terminal complexes were identified on the basis of their association with the ends of these cellulose microfibrils. The cytoplasmic domain of the rosette terminal complex has been shown to be hexagonal in shape and has been measured to be 45-50 nm in diameter and 30-35 nm tall. These findings demonstrate that the terminal complex does indeed have a substantial cytoplasmic component, and that the hexagonal array observed in the lipid bilayer by freeze fracture is actually only a small part of the overall complex. These findings will allow better modeling of the terminal complex and may facilitate predictions of how many proteins are associated with the rosette terminal complex in vivo.

A putative exonic splicing enhancer in exon 7 of the PDHA1 gene affects splicing of adjacent exons.

A nonsense mutation (c.729C>A, Y243X) in exon 7 of the PDHA1 gene in a patient with pyruvate dehydrogenase deficiency results in aberrant splicing of the primary transcript with production of stable mRNAs which lack either both exons 6 and 7 or exon 7 alone. Transfection and expression of genomic constructs covering exons 5 to 8 of the mutant PDHA1 gene reproduced this aberrant splicing in vitro. The same pattern of abnormal splicing was found when a silent mutation was introduced at the same position. Both the nonsense and silent mutations alter a strong consensus site for the binding of SRp40, suggesting that they may interfere with an exonic splicing enhancer in exon 7 of the gene. However, this appears to affect splicing of not only exon 7, but also the adjacent upstream exon. The splice acceptor site of intron 5 has weak homology to the consensus sequence and this may contribute to the combined splicing defect.

Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials.

OBJECTIVE: To assess the use of n-of-1 trials for short-term choice of drugs for osteoarthritis, with particular reference to comparing the efficacy of sustained-release [SR] paracetamol with celecoxib in individual patients. METHODS: Evaluation of community-based patients undergoing n-of-1 trials which consisted of double-blind, crossover comparisons of celecoxib 200 or 400 mg/day with sustained-release paracetamol 1330 mg three times a day in three pairs of 2 week treatment periods per drug with random order of the drugs within pairs. Outcomes evaluated were pain and stiffness in sites nominated by the patient, functional limitation scores, preferred medication, side effects and changes in drug use after an n-of-1 trial. Participants were 59 patients with osteoarthritis in multiple sites (hip 6, knee 24, hand 6, shoulder/neck 8, back 14, foot 5), with pain for >or=1 month severe enough to warrant consideration of long-term use of celecoxib but for whom there was doubt about its efficacy. Forty-one n-of-1 trials were completed. RESULTS: Although on average, celecoxib showed better scores than SR paracetamol [0.2 (0.1) for pain, 0.3 (0.1) for stiffness and 0.3 (0.1) for functional limitation], 33 of the 41 individual patients (80%) failed to identify the differences between SR paracetamol and celecoxib in terms of overall symptom relief. Of the eight patients who were able to identify the differences, seven had better relief with celecoxib and one with SR paracetamol. In 25 out of 41 [61%] patients, subsequent management was consistent with their trial results. CONCLUSIONS: N-of-1 trials may provide a rational and effective method to best choose drugs for individuals with osteoarthritis. SR paracetamol is more useful than celecoxib for most patients of whom management is uncertain.

Pyruvate dehydrogenase E3 binding protein (protein X) deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a major cause of neurological dysfunction and lactic acidosis in infancy and early childhood. The great majority of cases (>80%) result from mutations in the X-linked gene for the E1alpha subunit of the complex (PDHA1). Mutations in the genes for the other subunits have all been described, but only dihydrolipoamide dehydrogenase (E3) and E3 binding protein (E3BP) defects contribute significantly to the total number of patients with PDH deficiency. Although previously considered rare, with only 13 reported cases, we have found that mutations in PDX1, the gene for the E3 binding protein, are in fact relatively common. Clinical, biochemical, and genetic features of six new patients (four males, two females; age range 15mo-6y) with mutations in this gene are compared with previously reported cases. All patients with E3BP deficiency identified to date have mutations which completely prevent synthesis of the protein product. However, they are generally less severely affected than patients with PDHA1 mutations, although there is considerable overlap in clinical and neuroradiological features.

Is serum gentamicin level a good predictor of graft injury in intestinal transplantation?

INTRODUCTION: Following intestinal transplant (SBT), the early diagnosis and treatment of rejection is a major management aim. The diagnosis of rejection is based on histology of stomal biopsies. Oral gentamycin (2.5 mg/kg) was used for selective decontamination of the digestive system. Our hypothesis was that gentamycin might be absorbed in the presence of graft dysfunction. AIM: Our goal was to assess the correlation between serum gentamycin level and the health of the intestinal graft. SUBJECTS AND METHODS: Among 33 SBT performed from 1993 to 2005, serum gentamycin levels were performed once weekly or more often when there was a suspicion of rejection. All data were analyzed retrospectively. RESULTS: Adequate trough levels were achieved for only 23 patients, six of whom had histologically proven rejection and only one did not have a raised gentamycin content. Five patients with raised levels but no rejection included two with severe intestinal ischemia and three with bowel obstruction/ileus. Four of the five patients required laparotomies. CONCLUSION: We concluded that in our study raised serum gentamycin levels were a good predictor of rejection or significant injury to the graft.

Mice lacking the alpha4 nicotinic receptor subunit fail to modulate dopaminergic neuronal arbors and possess impaired dopamine transporter function.

Neuronal nicotinic acetylcholine receptors (nAChRs) at presynaptic sites can modulate dopaminergic synaptic transmission by regulating dopamine (DA) release and uptake. Dopaminergic transmission in nigrostriatal and mesolimbic pathways is vital for the coordination of movement and is associated with learning and behavioral reinforcement. We reported recently that the D2 DA receptor plays a central role in regulating the arbor size of substantia nigra dopaminergic neurons. Given the known effects of nAChRs on dopaminergic neurotransmission, we assessed the ability of the alpha4 nAChR subunit to regulate arbor size of dopaminergic neurons by comparing responses of wild-type and alpha4 nAChR subunit knockout [alpha4(-/-)] mice to long-term exposure to cocaine, amphetamine, nicotine, and haloperidol, and after substantia nigra neurotoxic lesioning. We found that dopaminergic neurons in adult drug-naive alpha4(-/-) mice had significantly larger terminal arbors, and despite normal short-term behavioral responses to drugs acting on pre- and postsynaptic D2 DA receptors, they were unable to modulate their terminal arbor in response to pharmacological manipulation or after lesioning. In addition, although synaptosome DA uptake studies showed that the interaction of the D2 DA receptor and the dopamine transporter (DAT) was preserved in alpha4(-/-) mice, DAT function was found to be impaired. These findings suggest that the alpha4 subunit of the nAChR is an independent regulator of terminal arbor size of nigrostriatal dopaminergic neurons and that reduced functionality of presynaptic DAT may contribute to this effect by impairing DA uptake.

Congenital nodular multiple glomangioma: a case report.

A 13 year old girl presented with recurrent painful "varicosities" on her right calf. These lesions were subsequently clinically diagnosed as "cavernous haemangiomas" after normal duplex scanning and were excised. Histological examination revealed multiple glomangiomas (glomus tumours). A literature review revealed only two reported cases of nodular multiple glomangioma, so that this is the third case to be reported in the literature.

Pyruvate dehydrogenase deficiency presenting as dystonia in childhood.

Two individuals with pyruvate dehydrogenase (PDH) deficiency due to missense mutations in the gene for the E1alpha subunit (PDHA1) presented during childhood with dystonia. The first patient, a male, presented at age 4 years with dystonia affecting the lower limbs, which responded to treatment with combined carbidopa and levodopa. The second patient, a female, was first investigated at age 6 years because of a dystonic gait disorder. In both patients, the main clue to the biochemical diagnosis was a raised concentration of lactate in the cerebrospinal fluid. PDH activity was significantly reduced in cultured fibroblasts in both cases. Dystonia is a previously unrecognized major manifestation of PDH deficiency and is of particular interest as the mutations in the PDHA1 gene in these patients have both been identified previously in individuals with typical presentations of the condition.

Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature.

BACKGROUND: Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by early infancy onset diabetes mellitus and multiple epiphyseal dysplasia. So far, 17 children have been described in the world literature. Recently, mutations in the gene encoding EIF2AK3 have been shown to segregate with the syndrome in three affected families. AIMS: We aimed to describe the clinical characterization and mutation analysis of a further child, and full clinical and follow-up details on our first family including the longest surviving child. METHODS: Retrospective case notes review of three children presenting to the diabetic unit at our institution; mutation analysis of the EIF2AK3 gene in our most recent patient; and review of the literature on Wolcott-Rallison syndrome. RESULTS: Previously unreported phenotypic features in our patients included developmental regression after episodes of hepatic failure, and pachygyria on brain imaging. We have identified a novel 4-base pair deletion (nt 3021-3024 del GAGA) in exon 13, which results in a frameshift and premature stop codon (R908 F/S +22X), causing premature truncation of the protein and abolition of the carboxy-segment of the catalytic domain. CONCLUSIONS: Wolcott-Rallison syndrome causes early-onset diabetes and acute hepatic failure, before epiphyseal dysplasia is manifest. We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families.