The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway.

Proliferation is one of the basic processes that control embryogenesis. To identify factors involved in the regulation of proliferation, we performed a zebrafish genetic screen in which we used proliferating cell nuclear antigen (PCNA) expression as a readout. Two mutants, hu418B and hu540A, show increased PCNA expression. Morphologically both mutants resembled the dre (dreumes), uki (ukkie), and lep (leprechaun) mutant class and both are shown to be additional uki alleles. Surprisingly, although an increased size is detected of multiple structures in these mutant embryos, adults become dwarfs. We show that these mutations disrupt repressors of the Hedgehog (Hh) signaling pathway. The dre, uki, and lep loci encode Su(fu) (suppressor of fused), Hip (Hedgehog interacting protein), and Ptc2 (Patched2) proteins, respectively. This class of mutants is therefore unique compared to previously described Hh mutants from zebrafish genetic screens, which mainly show loss of Hh signaling. Furthermore, su(fu) and ptc2 mutants have not been described in vertebrate model systems before. Inhibiting Hh activity by cyclopamine rescues uki and lep mutants and confirms the overactivation of the Hh signaling pathway in these mutants. Triple uki/dre/lep mutants show neither an additive increase in PCNA expression nor enhanced embryonic phenotypes, suggesting that other negative regulators, possibly Ptc1, prevent further activation of the Hh signaling pathway. The effects of increased Hh signaling resulting from the genetic alterations in the uki, dre, and lep mutants differ from phenotypes described as a result of Hh overexpression and therefore provide additional insight into the role of Hh signaling during vertebrate development

Endoscopic tri-modal imaging for surveillance in ulcerative colitis: randomised comparison of high-resolution endoscopy and autofluorescence imaging for neoplasia detection; and evaluation of narrow-band imaging for classification of lesions

Background: Endoscopic tri-modal imaging (ETMI) incorporates white light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging (NBI). Aims: To assess the value of ETMI for the detection and classification of neoplasia in patients with longstanding ulcerative colitis. Design: Randomised comparative trial of tandem colonoscopies. Setting: Academic Medical Centre Amsterdam, Netherlands. Patients and methods: Fifty patients with ulcerative colitis underwent surveillance colonoscopy with ETMI. Each colonic segment was inspected twice, once with AFI and once with WLE, in random order. All detected lesions were inspected by NBI for Kudo pit pattern analysis and additional random biopsies were taken. Main outcome measures: Neoplasia miss-rates of AFI and WLE, and accuracy of the Kudo classification by NBI. Results: Among patients assigned to inspection with AFI first (n = 25), 10 neoplastic lesions were primarily detected. Subsequent WLE detected no additional neoplasia. Among patients examined with WLE first (n = 25), three neoplastic lesions were detected; subsequent inspection with AFI added three neoplastic lesions. Neoplasia miss-rates for AFI and WLE were 0% and 50% (p = 0.036). The Kudo classification by NBI had a sensitivity and specificity of 75% and 81%; however, all neoplasia was coloured purple on AFI (sensitivity 100%). No additional patients with neoplasia were detected by random biopsies. Conclusion: Autofluorescence imaging improves the detection of neoplasia in patients with ulcerative colitis and decreases the yield of random biopsies. Pit pattern analysis by NBI has a moderate accuracy for the prediction of histology, whereas AFI colour appears valuable in excluding the presence of neoplasia. Trial registration number: ISRCTN0527274

The course of cytokine and chemokine gene expression in clinically suspect arthralgia patients during progression to inflammatory arthritis

Objectives: Autoantibody responses increase years before the onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels also increase years before IA onset. However, the course in the at-risk stage of CSA during progression to disease or non-progression is unknown. To increase the understanding of processes mediating disease development, we studied the course of cytokine, chemokine and related receptors gene expression in CSA patients during progression to IA and in CSA patients who ultimately did not develop IA. Methods: Whole-blood RNA expression of 37 inflammatory cytokines, chemokines and related receptors was determined by dual-colour reverse transcription multiplex ligation-dependent probe amplification in paired samples of CSA patients at CSA onset and either at IA development or after 24 months without IA development. ACPA-positive and ACPA-negative CSA patients developing IA were compared at CSA onset and during progression to IA. Generalised estimating equations tested changes over time. A false discovery rate approach was applied. Results: None of the cytokine/chemokine genes significantly changed in expression between CSA onset and IA development. In CSA patients without IA development, G-CSF expression decreased (P = 0.001), whereas CCR6 and TNIP1 expression increased (P Horizon 2020 (H2020)714312Pathophysiology and treatment of rheumatic disease

Prediagnostic sex steroid hormones in relation to male breast cancer risk

Purpose Although previous studies have implicated a variety of hormone-related risk factors in the etiology of male breast cancers, no previous studies have examined the effects of endogenous hormones. Patients and Methods Within the Male Breast Cancer Pooling Project, an international consortium comprising 21 case-control and cohort investigations, a subset of seven prospective cohort studies were able to contribute prediagnostic serum or plasma samples for hormone quantitation. Using a nested case-control design, multivariable unconditional logistic regression analyses estimated odds ratios and 95% CIs for associations between male breast cancer risk and 11 individual estrogens and androgens, as well as selected ratios of these analytes. Results Data from 101 cases and 217 matched controls were analyzed. After adjustment for age and date of blood draw, race, and body mass index, androgens were found to be largely unrelated to risk, but circulating estradiol levels showed a significant association. Men in the highest quartile had an odds ratio of 2.47 (95% CI, 1.10 to 5.58) compared with those in the lowest quartile (trend P = .06). Assessment of estradiol as a ratio to various individual androgens or sum of androgens showed no further enhancement of risk. These relations were not significantly modified by either age or body mass index, although estradiol was slightly more strongly related to breast cancers occurring among younger (age < 67 years) than older men. Conclusion Our results support the notion of an important role for estradiol in the etiology of male breast cancers, similar to female breast cancers

A Prospective Study to Establish a New-Onset Diabetes Cohort: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients

The merger of vertically offset quasi-geostrophic vortices

We examine the critical merging distance between two equal-volume, equal-potential-vorticity quasi-geostrophic vortices. We focus on how this distance depends on the vertical offset between the two vortices, each having a unit mean height-to-width aspect ratio. The vertical direction is special in the quasi-geostrophic model (used to capture the leading-order dynamical features of stably stratified and rapidly rotating geophysical flows) since vertical advection is absent. Nevertheless vortex merger may still occur by horizontal advection. In this paper, we first investigate the equilibrium states for the two vortices as a function of their vertical and horizontal separation. We examine their basic properties together with their linear stability. These findings are next compared to numerical simulations of the nonlinear evolution of two spheres of potential vorticity. Three different regimes of interaction are identified, depending on the vertical offset. For a small offset, the interaction differs little from the case when the two vortices are horizontally aligned. On the other hand, when the vertical offset is comparable to the mean vortex radius, strong interaction occurs for greater horizontal gaps than in the horizontally aligned case, and therefore at significantly greater full separation distances. This perhaps surprising result is consistent with the linear stability analysis and appears to be a consequence of the anisotropy of the quasi-geostrophic equations. Finally, for large vertical offsets, vortex merger results in the formation of a metastable tilted dumbbell vortex.Publisher PDFPeer reviewe

Application of new host biomarker profiles in quantitative point-of-care tests facilitates leprosy diagnosis in the field

Background: Transmission of Mycobacterium leprae, the pathogen causing leprosy, is still persistent. To facilitate timely (prophylactic) treatment and reduce transmission it is vital to both early diagnose leprosy, and identify infected individuals lacking clinical symptoms. However, leprosy-specific biomarkers are limited, particularly for paucibacillary disease. Therefore, our objective was to identify new biomarkers for leprosy and assess their applicability in point-of-care (POC) tests. Methods: Using multiplex-bead-arrays, 60 host-proteins were measured in a cross-sectional approach in 24-h whole blood assays (WBAs) collected in Bangladesh (79 patients; 54 contacts; 51 endemic controls (EC)). Next, 17 promising biomarkers were validated in WBAs of a separate cohort (55 patients; 27 EC). Finally, in a third cohort (36 patients; 20 EC), five candidate markers detectable in plasma were assessed for application in POC tests. Findings: This study identified three new biomarkers for leprosy (ApoA1, IL-1Ra, S100A12), and confirmed five previously described biomarkers (CCL4, CRP, IL-10, IP-10, αPGL-I IgM). Overnight stimulation in WBAs provided increased specificity for leprosy and was required for IL-10, IL-1Ra and CCL4. The remaining five biomarkers were directly detectable in plasma, hence suitable for rapid POC tests. Indeed, lateral flow assays (LFAs) utilizing this five-marker profile detected both multi- and paucibacillary leprosy patients with variable immune responses. Interpretation: Application of novel host-biomarker profiles to rapid, quantitative LFAs improves leprosy diagnosis and allows POC testing in low-resource settings. This platform can thus aid diagnosis and classification of leprosy and also provides a tool to detect M.leprae infection in large-scale contact screening in the field

California Men's Health Study (CMHS): a multiethnic cohort in a managed care setting

BACKGROUND: We established a male, multiethnic cohort primarily to study prostate cancer etiology and secondarily to study the etiologies of other cancer and non-cancer conditions. METHODS/DESIGN: Eligible participants were 45-to-69 year old males who were members of a large, prepaid health plan in California. Participants completed two surveys on-line or on paper in 2002 – 2003. Survey content included demographics; family, medical, and cancer screening history; sexuality and sexual development; lifestyle (diet, physical activity, and smoking); prescription and non-prescription drugs; and herbal supplements. We linked study data with clinical data, including laboratory, hospitalization, and cancer data, from electronic health plan files. We recruited 84,170 participants, approximately 40% from minority populations and over 5,000 who identified themselves as other than heterosexual. We observed a wide range of education (53% completed less than college) and income. PSA testing rates (75% overall) were highest among black participants. Body mass index (BMI) (median 27.2) was highest for blacks and Latinos and lowest for Asians, and showed 80.6% agreement with BMI from clinical data sources. The sensitivity and specificity can be assessed by comparing self-reported data, such as PSA testing, diabetes, and history of cancer, to health plan data. We anticipate that nearly 1,500 prostate cancer diagnoses will occur within five years of cohort inception. DISCUSSION: A wide variety of epidemiologic, health services, and outcomes research utilizing a rich array of electronic, biological, and clinical resources is possible within this multiethnic cohort. The California Men's Health Study and other cohorts nested within comprehensive health delivery systems can make important contributions in the area of men's health