Gone but not forgotten: lesional memory in psoriatic skin

One of the most frustrating aspects of treating psoriasis is the tendency of psoriatic skin lesions to recur after therapy has been discontinued. Not only do lesions recur, but they often recur in the same anatomical locations, expanding to the size they were before therapy. This engenders feelings of frustration and futility in both patients and the dermatologists who care for them. In this issue, Suárez-Fari?as and colleagues identified a gene set-the residual disease genomic profile-of psoriasis, suggesting the presence of both immunologic and structural abnormalities within healed psoriatic lesions. By understanding this "invisible lesion," we may be one step closer to curing psoriasis.     

Effect of caffeine on leg-muscle pain during intense cycling exercise: possible role of anxiety sensitivity

This experiment examined the effect of a moderate dose of caffeine on perceptions of leg-muscle pain during a bout of high-intensity cycling exercise and the role of anxiety sensitivity in the hypoalgesic effect of caffeine on muscle pain during exercise. Sixteen college-age women ingested caffeine (5 mg/kg body weight) or a placebo and 1 hr later completed 30 min of cycling on an ergometer at 80% of peak aerobic capacity. The conditions were completed in a counterbalanced order, and perceptions of leg-muscle pain were recorded during the bouts of exercise. Caffeine resulted in a large reduction in leg-muscle pain-intensity ratings compared with placebo (d = -0.95), and the reduction in leg-muscle pain-intensity ratings was larger in those with lower anxiety-sensitivity scores than those with higher anxiety-sensitivity scores (d = -1.28 based on a difference in difference scores). The results support that caffeine ingestion has a large effect on reducing leg-muscle pain during high-intensity exercise, and the effect is moderated by anxiety sensitivity.     

Diet and obesity among Chamorro and Filipino adults on Guam

The purpose of this study was to compare the body mass index (BMI) and dietary intakes of Chamorro (n=66) and Filipino (n=61) adults, ages 25-65 years, living in Guam. Participants were recruited via community-based sampling; however, recruitment was targeted to ensure approximately equal numbers from each ethnic group, equal numbers of men and women within each ethnic group, and proportional representation of the main geographic areas of the island. In addition, subjects were recruited and stratified based on the 2000 Guam Census Data to assure proportional distribution by age. Dietary energy density (ED) was calculated as kcal/g and compared by gender, ethnicity, and obesity status. Mean BMI for Chamorros was significantly higher than for Filipinos, and a significantly higher proportion of Chamorros (49%) were obese compared to Filipinos (20%). Chamorros reported higher ED than Filipinos (1.9 kcal/g versus 1.6 kcal/g), although the difference was significant among males only. Non-obese subjects had a lower ED than obese subjects (1.9 versus 2.3 kcal/g). Overweight and obese subjects both reported a significantly higher % energy consumed as sugar-sweetened beverages than healthy weight subjects (8% and 9% versus 3%). Differences in ED may contribute to differences in obesity rates between Chamorros and Filipinos in Guam, particularly among men, and lowering ED may be an appropriate goal for nutrition interventions.     

Prediagnostic adiponectin concentrations and pancreatic cancer risk in male smokers

Adiponectin, a hormone secreted by adipocytes, has insulin-sensitizing, antidiabetic, antiinflammatory, and antiangiogenic properties. The authors conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort, a cohort of male Finnish smokers aged 50-69 years at baseline, to test whether prediagnostic adiponectin concentrations are associated with pancreatic cancer. Between January 1985 and October 2004, 311 incident exocrine pancreatic cancer cases were diagnosed among cohort participants with serum samples. Controls (n = 510) were alive and free of cancer at the time the case was diagnosed and were matched to the cases by age and date of blood drawing. The authors used conditional logistic regression adjusted for smoking, blood pressure, and C-peptide level to calculate odds ratios and 95% confidence intervals for pancreatic cancer. Higher adiponectin concentrations were inversely associated with pancreatic cancer (for highest quintile (> 9.8 microg/mL) vs. lowest (< or =4.6 microg/mL), odds ratio = 0.65, 95% confidence interval: 0.39, 1.07; P-trend = 0.04). The inverse association was significant among cases diagnosed 5 or more years after blood collection (n = 238) (for highest quintile vs. lowest, odds ratio = 0.55, 95% confidence interval: 0.31, 0.98; P-trend = 0.03). These results support the hypothesis that higher adiponectin concentrations may be inversely associated with the development of pancreatic cancer.     

Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects

Endocytic dysfunction is an early pathological change in Alzheimer's disease (AD) and Down's syndrome (DS). Using primary fibroblasts from DS individuals, we explored the interactions among endocytic compartments that are altered in AD and assessed their functional consequences in AD pathogenesis. We found that, like neurons in both AD and DS brains, DS fibroblasts exhibit increased endocytic uptake, fusion, and recycling, and trafficking of lysosomal hydrolases to rab5-positive early endosomes. Moreover, late endosomes identified using antibodies to rab7 and lysobisphosphatidic acid increased in number and appeared as enlarged, perinuclear vacuoles, resembling those in neurons of both AD and DS brains. In control fibroblasts, similar enlargement of rab5-, rab7-, and lysobisphosphatidic acid-positive endosomes was induced when endocytosis and endosomal fusion were increased by expression of either a rab5 or an active rab5 mutant, suggesting that persistent endocytic activation results in late endocytic dysfunction. Conversely, expression of a rab5 mutant that inhibits endocytic uptake reversed early and late endosomal abnormalities in DS fibroblasts. Our results indicate that DS fibroblasts recapitulate the neuronal endocytic dysfunction of AD and DS, suggesting that increased trafficking from early endosomes can account, in part, for downstream endocytic perturbations that occur in neurons in both AD and DS brains.     

Psychosocial assessment following self-harm: results from the multi-centre monitoring of self-harm project

BACKGROUND: Psychosocial assessment is central to the management of self-harm, but not all individuals receive an assessment following presentation to hospital. Research exploring the factors associated with assessment and non-assessment is sparse. It is unclear how assessment relates to subsequent outcome. METHODS: We identified episodes of self-harm presenting to six hospitals in the UK cities of Oxford, Leeds, and Manchester over an 18-month period (1st March 2000 to 31st August 2001). We used established monitoring systems to investigate: the proportion of episodes resulting in a specialist assessment in each hospital; the factors associated with assessment and non-assessment; the relationship between assessment and repetition of self-harm. RESULTS: A total of 7344 individuals presented with 10,498 episodes of self-harm during the study period. Overall, 60% of episodes resulted in a specialist psychosocial assessment. Factors associated with an increased likelihood of assessment included age over 55 years, current psychiatric treatment, admission to a medical ward, and ingestion of antidepressants. Factors associated with a decreased likelihood of assessment included unemployment, self-cutting, attending outside normal working hours, and self-discharge. We found no overall association between assessment and self-harm repetition, but there were differences between hospitals--assessments were protective in one hospital but associated with an increased risk of repetition in another. LIMITATIONS: Some data may have been more likely to be recorded if episodes resulted in a specialist assessment. This was a non-experimental study and so the findings relating specialist assessment to repetition should be interpreted cautiously. CONCLUSION: Many people who harm themselves, including potentially vulnerable individuals, do not receive an adequate assessment while at hospital. Staff should be aware of the organizational and clinical factors associated with non-assessment. Identifying the active components of psychosocial assessment may help to inform future interventions for self-harm.     

From feeding one to feeding many: hormone-induced changes in bodyweight homeostasis during pregnancy

Pregnancy is associated with hyperphagia, increased fat mass, hyperleptinaemia and hyperprolactinaemia. The neuroendocrine control of bodyweight involves appetite-regulating centres in the hypothalamus, containing both orexigenic and anorexigenic neurons that express leptin receptors (LepR). In the rat, central leptin resistance develops during mid pregnancy, well after hyperphagia becomes apparent, to negate the appetite suppressing effects of leptin. We have investigated the hypothalamic response to leptin during pregnancy and examined the role of pregnancy hormones in inducing these changes. We have shown that there are multiple levels of leptin resistance during pregnancy. Despite elevated serum leptin, neuropeptide Y and agouti related peptide mRNA in the arcuate nucleus are not suppressed and may even be increased during pregnancy. LepR mRNA and leptin-induced pSTAT3 expression, however, are relatively normal in the arcuate nucleus. In contrast, both LepR and leptin-induced pSTAT3 are reduced in the ventromedial hypothalamic nucleus. Injecting alpha-melanocyte-stimulating hormone (alpha-MSH) into the brain, to bypass the first-order leptin-responsive neurons in the arcuate nucleus, also fails to suppress food intake during pregnancy, suggesting that pregnancy is also a melanocortin-resistant state. Using a pseudopregnant rat model, we have demonstrated that in addition to the changes in maternal ovarian steroid secretion, placental lactogen production is essential for the induction of leptin resistance in pregnancy. Thus, hormonal changes associated with pregnancy induce adaptive changes in the maternal hypothalamus, stimulating food intake and then allowing elevated food intake to be maintained in the face of elevated leptin levels, resulting in fat deposition to provide energy stores in preparation for the high metabolic demands of late pregnancy and lactation.     

Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines

HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.