COPD burden on sexual well-being.

BACKGROUND: Sexual function is often affected in patients suffering from chronic diseases especially chronic obstructive pulmonary disease (COPD). However, the effect of COPD on sexual satisfaction is underappreciated in clinical practice. The aim of this study is to evaluate the impact of COPD on patient's sexuality and the explanatory variables of sexual dissatisfaction. METHODS: Questionnaires were emailed to participants and they submitted their responses on the Santé Respiratoire France website. Data about sexual well-being (Arizona Sexual Experience Scale, ASEX), Quality of life (VQ11), anxiety, depression (Hospitalized anxiety and depression, HAD) and self-declared COPD grade were collected. RESULTS: Seven hundred and fifty one subjects were included and were characterized as follows: women-51%, mean age-61 years, in a couple-62% and 70%-retired. Every grade of COPD was represented. Out of 751 participants, 301 participants (40%) had no sexual activity and 450 (60%) had sexual activity. From the 450 participants, 60% needed to change their sexual life because of their disease (rhythm, frequency and position). Subjects often used medications to improve sexual performance (43% used short-acting bronchodilator and 13% -specific erectile dysfunction drugs). ASEX questionnaire confirmed patients' dissatisfaction (diminution of sexual appetite for 68% and sexual desire for 60%) because of breathlessness and fatigue. Eighty one percent of the responders had an altered quality of life (VQ11 mean score 35) and frequent suspected anxiety or depression (HAD mean score 10.8). Ninety percent declared that sexual dysfunction had never been discussed by their doctors, while 36% of patients would have preferred to undergo a specialized consultation. CONCLUSION: Sexual dysfunction is frequent among COPD patients and leads to an altered well-being, however being a cultural taboo, it remains frequently neglected. Sexual guidance should be a part of patient's consultations improve quality of sexual life.

Clustering of esophageal cancer among white men in the United States.

Studies of the geographic distribution of esophageal cancer in the United States have been limited. We aimed to examine geographic clustering of esophageal cancer in the United States and assess whether that clustering is explained by the distribution of known risk factors for esophageal cancer. We conducted cluster analyses derived from county mortality rates of esophageal cancer, using publicly available datasets. State incidence rates of esophageal adenocarcinoma were from the National Program of Cancer Registries, and county esophageal-cancer mortality rates were from the Vital Statistics Cooperative Program. County prevalences of cigarette use, alcohol use, obesity, education, and income were published estimates derived from the Behavioral Risk Factor Surveillance System and the American Community Survey. The primary outcomes were clusters of high and low esophageal-cancer mortality rates among non-Hispanic white men, both unadjusted and adjusted for risk factors. Age-standardized county rates of esophageal-cancer mortality among non-Hispanic white men ranged from 4.8 to 21.2 per 100,000/year. There was a cluster of high mortality in the Great Lakes states and New England and a cluster of low mortality in the Southeastern United States. State incidence rates of esophageal adenocarcinoma were consistent with this pattern. Adjusting for risk factors did little to change the pattern of observed rates or the clusters derived from them. Among non-Hispanic white men, there are clusters of high and low mortality rates with esophageal cancer within the United States, likely representing esophageal adenocarcinoma; but those clusters were not explained by several known risk factors. Focusing future efforts in the high-cluster areas might improve the efficiency of cancer screening and control.

Systematic review and meta-regressions: management of eosinophilic esophagitis requires histologic assessment.

Treatment endpoints in eosinophilic esophagitis (EoE) are response of eosinophilic inflammation and of symptoms. Steroids and diet therapy are effective in inducing histologic response in EoE, but there may be poor correlation between histologic and symptomatic response. Despite this, we find that in clinical practice symptoms are commonly used to guide management without assessing histologic response. We hypothesized that symptom response alone is not reliable in assessing response to therapy and is confounded by endoscopic dilation. We conducted a systematic review and meta-regressions to estimate the association of histologic and symptomatic response, stratified by whether concurrent dilation was permitted. We performed a systematic search of PubMed, EMBASE, and Web of Science for studies describing both histologic and symptomatic responses to dilation, steroid, and diet therapies. We abstracted the proportion of histologic response and symptom response. Studies were stratified by whether dilation was permitted. We performed meta-regressions of the association between the proportions with histologic and symptomatic response, stratified by whether dilation was permitted. We identified 1359 articles, of which 62 articles were assessed for eligibility, and 23 were included providing data on 1202 patients with EoE. Unstratified meta-regression of histologic versus symptomatic response showed moderate association and large heterogeneity (inconsistency index [I2] = 89%). In adult studies in which dilation was allowed, there was weak association between symptomatic and histologic response (ß1 = 0.21), minimal symptomatic response of 67% and the heterogeneity persisted, I2 = 77%. In studies that prohibited dilation, maximal symptomatic response was 72% and was moderately associated with histologic response (ß1 = 0.39) with less heterogeneity, I2 = 59%. Studies of EoE that permit dilation obscure the relation between histologic and symptomatic response and have a high floor effect for symptomatic response. Studies that prohibit dilation demonstrate moderate association between histologic and symptomatic response, but have a ceiling effect for symptomatic response. Our results demonstrate that success of dietary or medical management for EoE cannot be judged by symptoms alone, and require histologic assessment, particularly if dilation has been performed.

Functional consequences of I56ii Dlx enhancer deletion in the developing mouse forebrain.

Dlx homeobox genes encode a group of transcription factors that play an essential role during developmental processes including maintaining the differentiation, proliferation and migration of GABAergic interneurons. The Dlx1/2 and Dlx5/6 genes are expressed in the forebrain and are arranged in convergently transcribed bigene clusters, with I12a/I12b and I56i/I56ii cis-regulatory elements (CREs) located in the intergenic region of each cluster respectively. We have characterized the phenotypic consequences of deleting I56ii on forebrain development and spatial patterning of corridor cells that are involved in guiding thalamocortical projections. Here we report that deletion of I56ii impairs expression of Dlx genes and that of potential targets including Gad2 as well as striatal markers Islet1, Meis2, and Ebf1. In addition, I56ii deletion reduces both the binding of DLX2 in the Dlx5/Dlx6 intergenic region and the presence of H3K9Ac at the Dlx5/Dlx6 locus, consistent with the reduced expression of these genes. Deletion of I56ii reduces the expression of the ISLET1 and CTIP2 in the striatum and disrupts the number of parvalbumin and calretinin expressing cells in the adult somatosensory cortex of the ΔI56ii mice. These data suggest an important regulatory role for I56ii in the developing forebrain by means of a potential regulatory mechanism which may regulate the expression of Dlx genes, notably Dlx6 as well as the spatial patterning of the ventral telencephalon, including possibly corridor cells.

Prevalence and risk factors for heterotopic gastric mucosa of the upper esophagus among men undergoing routine screening colonoscopy.

The prevalence of heterotopic gastric mucosa of the upper esophagus (inlet patch) has a wide range depending on the method and detail of examination. The inlet patch is believed to be a congenital malformation that rarely leads to symptoms. We aimed to quantify the prevalence of the inlet patch in a non-referred population and determine if there are any risk factors or associated symptoms. Men between ages 50 and 79 presenting for routine colonoscopy at two clinical sites were recruited to undergo an upper endoscopy. Endoscopists were prompted to examine for the presence of the inlet patch. Of the 822 enrolled patients, 795 had data regarding the presence of an inlet patch. Of these, 55 (6.9%) had an inlet patch identified. Education was inversely associated (odds ratio [OR] advanced degree vs. high school or less = 0.310; 95% confidence interval [CI] = 0.111, 0.869), and tobacco use was positively associated with the presence of an inlet patch (current vs. never smokers OR = 2.87; 95% CI = 1.23, 6.69; former vs. never smokers OR = 1.93; 95% CI = 0.922, 4.02). No association between the inlet patch and symptoms of heartburn, globus, or dysphagia was found. In a cross-sectional study of colon cancer screenees, inlet patches were common and were not associated with symptoms. Tobacco use appears to be associated with the presence of an inlet patch.

Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma.

BACKGROUND: While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease. PATIENTS AND METHODS: We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology. RESULTS: While PCNSL tumors usually express a BCL6+, MUM1+ 'activated, germinal center' immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses. CONCLUSIONS: There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease.

Comparing trends in esophageal adenocarcinoma incidence and lifestyle factors between the United States, Spain, and the Netherlands.

OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) in the western world has been rapidly increasing. The trends in obesity and other lifestyle-associated factors have been hypothesized to be important drivers of this increase. We tested this hypothesis by comparing changes in these factors with changes in EAC incidence over time between three western countries. METHODS: Data on EAC incidence trends were abstracted from the SEER-9 registry (1975-2009) for the United States, from multiple cancer registries (1980-2004) in Spain, and from Eindhoven Cancer Registry in the Netherlands (1974-2010). In addition, we collected trend data on obesity, smoking, and alcohol consumption. The trend data were analyzed using log-linear regression. RESULTS: In 1980, the EAC incidence was similar among the three countries ((0.46-0.63) per 100,000). EAC incidence increased in all, with the largest increase observed in the Netherlands, followed by the United States and Spain (estimated annual percentage of change=9.7%, 7.4%, 4.3%, respectively). However, this pattern was not observed in lifestyle factors associated with EAC. With regards to obesity, the United States clearly has had the highest prevalence rates both in the past and in the present. For alcohol, the highest consumption rates are seen in Spain. Smoking showed a reverse trend compared with EAC among all three countries in the last 20 years. CONCLUSIONS: International trends in EAC incidence do not match corresponding trends in lifestyle-associated factors including obesity. Our findings suggest that factors other than obesity must be the important drivers for the increase in EAC incidence.

The gene for pycnodysostosis maps to human chromosome 1cen-q21.

Pycnodysostosis (OMIM 265800) is an autosomal recessive skeletal disorder first described by Maroteaux and Lamy that is characterized by short stature, increased bone density, delayed closure of cranial sutures, loss of the mandibular angle, dysplastic clavicles, dissolution of the terminal phalanges of the hands and feet, dental abnormalities and increased bone fragility. Patients have a typical appearance secondary to prominence of the calvarium, smallness of the facial features, prominent nose and micrognathia. The French painter, Henri de Toulouse Lautrec (1864-1901), is believed to have had the disorder. Although more than 100 cases have been reported, we are aware of only two large consanguinous pedigrees in which the pycnodysostosis disorder segregates. We have studied the segregation of the pycnodysostosis phenotype in a large consanguinous Mexican pedigree, the clinical features of which are very similar to those described in the Arab pedigree studied by Edelson et al. Here, we report linkage for the pycnodysostosis phenotype in the 1cen-q21 region of human chromosome 1, and discuss candidate genes for this skeletal disorder.

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.

Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.

Association of adiponectin multimers with Barrett's oesophagus.

OBJECTIVE: Barrett's oesophagus is associated with abdominal obesity. Adiponectin is a peptide that is secreted from adipocytes and circulates in three multimeric forms: low molecular weight (LMW), middle molecular weight (MMW), and high molecular weight (HMW). The anti-inflammatory effects of adiponectin are specific to individual multimers, with LMW being most anti-inflammatory. We postulated that circulating levels of adiponectin and its multimers would be associated with the risk of Barrett's oesophagus. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in North Carolina, USA. PATIENTS: Cases of Barrett's oesophagus and controls undergoing upper endoscopy for gastro-oesophageal reflux disease (GORD). MAIN OUTCOME MEASURES: Adjusted odds ratios of plasma adiponectin levels and its multimers for Barrett's oesophagus. RESULTS: There were 112 cases of Barrett's oesophagus and 199 GORD controls. Total adiponectin was not associated with Barrett's oesophagus (3(rd) tertile vs 1(st) tertile adjusted odds ratio (aOR) = 0.88; 95% confidence interval (CI) = 0.44 to 1.78). High levels of LMW adiponectin were associated with a decreased risk of Barrett's oesophagus (3(rd) tertile vs 1(st) tertile aOR = 0.33; 95% CI, 0.16 to 0.69), and a high LMW/total ratio appeared particularly inversely associated with Barrett's oesophagus (3(rd) tertile vs 1(st) tertile aOR = 0.27; 95% CI, 0.13 to 0.58). CONCLUSIONS: High levels of LMW adiponectin are associated with a decreased risk of Barrett's oesophagus among patients with GORD. Further human studies are required to confirm these findings, and in vitro studies are needed to understand if there is a mechanism whereby adiponectin may affect Barrett's metaplasia.

Sex-specific neurotoxic effects of early-life exposure to fluoride: A review of the epidemiologic and animal literature.

PURPOSE OF REVIEW: A growing body of evidence suggests adverse neurodevelopmental effects of early-life exposure to fluoride that may differ depending on timing of exposure and sex of the exposed. We conducted a literature search to identify the animal and human epidemiologic studies that examined sex-specific neurodevelopmental differences in response to prenatal and postnatal exposure to fluoride. RECENT FINDINGS: Six of 138 animal studies and 15 of 106 human epidemiologic studies tested for sex-specific effects. Prenatal exposure to fluoride was associated with a male susceptibility to adverse behavioural effects in four of six animal studies and lower IQ in one of three prospective cohort studies. The body of evidence examining sex-effects associated with postnatal fluoride exposure was scarce, and many animal and cross-sectional human studies were considered to have a high risk of bias. SUMMARY: Compared to females, male offspring appear to be more sensitive to prenatal, but not postnatal, exposure to fluoride. We discuss several sex-specific mechanisms and emphasize the need for future research.

Construction of a synthetic messenger RNA encoding a membrane protein.

We have synthesized microgram quantities of a functional eucaryotic mRNA by in vitro transcription. For this purpose, we constructed a plasmid in which the Escherichia coli lactose promoter was 5' to the vesicular stomatitis virus (VSV) G protein gene (Rose, J. K., and C. J. Gallione, 1981, J. Virol., 39:519-528). This DNA served as the template in an in vitro transcription reaction utilizing E. coli RNA polymerase. The RNA product was capped using the vaccinia guanylyltransferase. A typical preparation of the synthetic G mRNA was equivalent to the amount of G mRNA that can be isolated from approximately 10(8) VSV-infected cells. This synthetic mRNA was translated by a wheat germ extract in the presence of microsomes, producing a polypeptide that was indistinguishable from G protein in its size, antigenicity, degree of glycosylation, and its membrane insertion. This technique should aid in identifying features needed by proteins for insertion into membranes.

Purification of coated vesicles by agarose gel electrophoresis.

We have applied agarose gel electrophoresis as a novel step in the purification of clathrin-coated vesicles. Preparations of coated vesicles obtained by sedimentation velocity and isopycnic centrifugation are resolved into two distinct fractions upon electrophoresis. The slower migrating fraction contains smooth vesicles, whereas the faster contains only coated vesicles and empty clathrin coats. The faster mobility of the coated vesicles is primarily caused by the acidic nature of clathrin. Coated vesicles from three different cell types have different mobilities. In each case, however, all of the major polypeptides previously attributed to coated vesicles comigrate with the now homogeneous particles, even though a powerful ATPase activity is completely removed.

Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior.

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

Early neocortical regionalization in the absence of thalamic innervation.

There is a long-standing controversy regarding the mechanisms that generate the functional subdivisions of the cerebral neocortex. One model proposes that thalamic axonal input specifies these subdivisions; the competing model postulates that patterning mechanisms intrinsic to the dorsal telencephalon generate neocortical regions. Gbx-2 mutant mice, whose thalamic differentiation is disrupted, were investigated. Despite the lack of cortical innervation by thalamic axons, neocortical region-specific gene expression (Cadherin-6, EphA-7, Id-2, and RZR-beta) developed normally. This provides evidence that patterning mechanisms intrinsic to the neocortex specify the basic organization of its functional subdivisions.

Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions.

Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. Here, we show that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin 3A and semaphorin 3F. Migrating interneurons expressing neuropilins, receptors for semaphorins, are directed to the cortex; those lacking them go to the striatum. Loss of neuropilin function increases the number of interneurons that migrate into the striatum. These observations reveal a mechanism by which neuropilins mediate sorting of distinct neuronal populations into different brain structures, and provide evidence that, in addition to guiding axons, these receptors also control neuronal migration in the central nervous system.

Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes.

Although previous analyses indicate that neocortical neurons originate from the cortical proliferative zone, evidence suggests that a subpopulation of neocortical interneurons originates within the subcortical telencephalon. For example, gamma-aminobutyric acid (GABA)-expressing cells migrate in vitro from the subcortical telencephalon into the neocortex. The number of GABA-expressing cells in neocortical slices is reduced by separating the neocortex from the subcortical telencephalon. Finally, mice lacking the homeodomain proteins DLX-1 and DLX-2 show no detectable cell migration from the subcortical telencephalon to the neocortex and also have few GABA-expressing cells in the neocortex.