Laparoscopic classification of the impalpable testis: an update

Purpose We present a classification for the nonpalpable testis (NPT) based on laparoscopic findings and suggest guidelines for the interpretation of these findings.Patients and methods From October 2002 to December 2010, 121 patients with NPT underwent laparoscopy at two tertiary centers of Pediatric surgery in Egypt. The lower abdomen and pelvis were inspected to identify the following structures and their inter-relationships: the internal inguinal ring (and its patency), spermatic vessels, vas deferens, and testis. The laparoscopic findings were documented by one of the authors who attended all procedures, and video recordings were available in some cases. Further management was dependent on laparoscopic findings, classification, and plan of treatment.Results The study included 117 patients with 142 nonpalpable testes. Their mean age was 4.9 years. Among patients with unilateral NPT, a contralateral palpable undescended testicle was always associated with a viable NPT (100%), whereas a contralateral scrotal testis had an equal chance (50%) of finding a viable NPT, without a significant difference whether it was right or left sided.Conclusion Failure of normal testicular descent leads to a spectrum of anatomical variations that can be precisely and safely defined by laparoscopy in about two-thirds of patients with nonpalpable testes. In the remaining one-third of patients, including inguinal exploration after laparoscopy can help us to exclude a missed viable inguinal testis.Keywords: cryptorchidism, laparoscopy, testi

Does severe dietary energy restriction increase binge eating in overweight or obese individuals? A systematic review

Severe dietary energy restriction is often used for overweight or obese individuals to achieve rapid weight loss and related health improvements. However, the extent of putative adverse effects on eating behaviour is unknown. We thus systematically searched seven databases for studies that assessed binge eating before and after severe dietary energy restriction (low or very low energy diets) in overweight or obese individuals. Fifteen clinically supervised interventions from 10 publications (nine of which involved only women) were included. Among individuals with clinically relevant pre-treatment binge eating disorder, severe dietary energy restriction significantly decreased binge eating in all four interventions involving this population, at least during the weight loss programme. In contrast, no consistent association between severe dietary energy restriction and the onset of bingeing was found in 11 interventions involving individuals without pre-treatment binge eating disorder, with four such interventions showing significant increases, two showing no change, and five showing significant decreases in binge eating. We conclude that clinically supervised severe dietary energy restriction appears safe and beneficial for overweight or obese individuals with pre-treatment binge eating disorder, and does not necessarily trigger binge eating in those without binge eating disorder

An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class

A new fireworm (Amphinomidae) from the Cretaceous of Lebanon identified from three-dimensionally preserved myoanatomy

© 2015 Parry et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The attached file is the published version of the article

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Glycogen Synthase Kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation

Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty

<p>Abstract</p> <p>Background</p> <p>The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty.</p> <p>Methods</p> <p>Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models.</p> <p>Results</p> <p>Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT) for malaria was estimated, and a policy of multiple first-line therapies (MFTs) was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases.</p> <p>Conclusions</p> <p>At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.</p

Water-Borne Cues of a Non-Indigenous Seaweed Mediate Grazer-Deterrent Responses in Native Seaweeds, but Not Vice Versa

Plants optimise their resistance to herbivores by regulating deterrent responses on demand. Induction of anti-herbivory defences can occur directly in grazed plants or from emission of risk cues to the environment, which modifies interactions of adjacent plants with, for instance, their consumers. This study confirmed the induction of anti-herbivory responses by water-borne risk cues between adjoining con-specific seaweeds and firstly examined whether plant-plant signalling also exists among adjacent hetero-specific seaweeds. Furthermore, differential abilities and geographic variation in plant-plant signalling by a non-indigenous seaweed as well as native seaweeds were assessed. Twelve-day induction experiments using the non-indigenous seaweed Sargassum muticum were conducted in the laboratory in Portugal and Germany with one local con-familiar (Portugal: Cystoseira humilis, Germany: Halidrys siliquosa) and hetero-familiar native species (Portugal: Fucus spiralis, Germany: F. vesiculosus). All seaweeds were grazed by a local isopod species (Portugal: Stenosoma nadejda, Germany: Idotea baltica) and were positioned upstream of con- and hetero-specific seaweeds. Grazing-induced modification in seaweed traits were tested in three-day feeding assays between cue-exposed and cue-free ( = control) pieces of both fresh and reconstituted seaweeds. Both Fucus species reduced their palatability when positioned downstream of isopod-grazed con-specifics. Yet, the palatability of non-indigenous S. muticum remained constant in the presence of upstream grazed con-specifics and native hetero-specifics. In contrast, both con-familiar (but neither hetero-familiar) native species reduced palatability when located downstream of grazed S. muticum. Similar patterns of grazer-deterrent responses to water-borne cues were observed on both European shores, and were almost identical between assays using fresh and reconstituted seaweeds. Hence, seaweeds may use plant-plant signalling to optimise chemical resistance to consumers, though this ability appeared to be species-specific. Furthermore, this study suggests that native species may benefit more than a non-indigenous species from water-borne cue mediated reduction in consumption as only natives responded to signals emitted by hetero-specifics

Converting simulated total dry matter to fresh marketable yield for field vegetables at a range of nitrogen supply levels

Simultaneous analysis of economic and environmental performance of horticultural crop production requires qualified assumptions on the effect of management options, and particularly of nitrogen (N) fertilisation, on the net returns of the farm. Dynamic soil-plant-environment simulation models for agro-ecosystems are frequently applied to predict crop yield, generally as dry matter per area, and the environmental impact of production. Economic analysis requires conversion of yields to fresh marketable weight, which is not easy to calculate for vegetables, since different species have different properties and special market requirements. Furthermore, the marketable part of many vegetables is dependent on N availability during growth, which may lead to complete crop failure under sub-optimal N supply in tightly calculated N fertiliser regimes or low-input systems. In this paper we present two methods for converting simulated total dry matter to marketable fresh matter yield for various vegetables and European growth conditions, taking into consideration the effect of N supply: (i) a regression based function for vegetables sold as bulk or bunching ware and (ii) a population approach for piecewise sold row crops. For both methods, to be used in the context of a dynamic simulation model, parameter values were compiled from a literature survey. Implemented in such a model, both algorithms were tested against experimental field data, yielding an Index of Agreement of 0.80 for the regression strategy and 0.90 for the population strategy. Furthermore, the population strategy was capable of reflecting rather well the effect of crop spacing on yield and the effect of N supply on product grading

Combined Spatial Prediction of Schistosomiasis and Soil-Transmitted Helminthiasis in Sierra Leone: A Tool for Integrated Disease Control

Two forms of schistosomiasis or bilharzia (intestinal and urogenital) exist in Sierra Leone. The main control strategy for this disease currently is through mass drug administration (MDA) according to the World Health Organization recommended anthelminthic chemotherapy guidelines, and others include snail control, behavior change, and safe water, sanitation and hygiene. Survey on distribution and prevalence of the disease is vital to the planning of MDA in each district. The distribution of intestinal schistosomiasis in the country has been reported previously. The current national survey showed that urogenital schistosomiasis has a specific focal distribution particularly in the central and eastern regions of the country, most prevalent in Bo (24.6%), Koinadugu (20.4%) and Kono (25.3%) districts. Using a simple probabilistic model, this map was combined with the previously reported maps on intestinal schistosomiasis and the combined schistosomiasis prevalence was estimated. The combined schistosomiasis map highlights the presence of high-risk communities in an extensive area in the northeastern half of the country, which provides a tool for planning the national MDA activities