Multiple endocrine neoplasia type 4: a new member of the MEN family.

OBJECTIVE Multiple endocrine neoplasia type 4 (MEN4) is caused by a CDKN1B germline mutation first described in 2006. Its estimated prevalence is less than 1/million. The aim of this study was to define the disease characteristics. METHODS Systematic review according to the PRISMA 2020 criteria. MEDLINE® and Web of ScienceTM search from January 2006 to August 2022. RESULTS Forty-eight symptomatic patients fulfilled the pre-defined eligibility criteria. Twenty-eight different CDKN1B variants, mostly missense (21/48, 44%) and frameshift mutations (17/48, 35%), were reported. The majority of patients were women (36/48, 75%). Men became symptomatic at a median age of 32.5 years (range 10-68, mean 33.7 ± 23), whereas the same event was recorded for women at a median age of 49.5 years (range 5-76, mean 44.8 ± 19.9) (p = 0.25). The most frequently affected endocrine organ was the parathyroid gland (36/48, 75%; uniglandular disease 31/36, 86%), followed by the pituitary gland (21/48, 44%; hormone-secreting 16/21, 76%), the endocrine pancreas (7/48, 15%) and the thyroid gland (4/48, 8%). Tumours of the adrenal glands and thymus were found in three and two patients, respectively. The presenting first endocrine pathology concerned the parathyroid (27/48, 56%) and the pituitary gland (11/48, 23%). There were one (27/48, 56%), two (13/48, 27%), three (3/48, 6%), or four (5/48, 10%) syn- or metachronously affected endocrine organs in a single patient, respectively. CONCLUSION MEN4 is an extremely rare disease, which most frequently affects women around 50 years of age. Primary hyperparathyroidism as a uniglandular disease is the leading pathology

Calculating Quenching Weights

We calculate the probability (``quenching weight'') that a hard parton radiates an additional energy fraction due to scattering in spatially extended QCD matter. This study is based on an exact treatment of finite in-medium path length, it includes the case of a dynamically expanding medium, and it extends to the angular dependence of the medium-induced gluon radiation pattern. All calculations are done in the multiple soft scattering approximation (Baier-Dokshitzer-Mueller-Peign\'e-Schiff--Zakharov ``BDMPS-Z''-formalism) and in the single hard scattering approximation (N=1 opacity approximation). By comparison, we establish a simple relation between transport coefficient, Debye screening mass and opacity, for which both approximations lead to comparable results. Together with this paper, a CPU-inexpensive numerical subroutine for calculating quenching weights is provided electronically. To illustrate its applications, we discuss the suppression of hadronic transverse momentum spectra in nucleus-nucleus collisions. Remarkably, the kinematic constraint resulting from finite in-medium path length reduces significantly the transverse momentum dependence of the nuclear modification factor, thus leading to consistency with the data measured at the Relativistic Heavy Ion Collider (RHIC).Comment: 45 pages LaTeX, 20 eps-figure

Statistical Modeling of SAR Images: A Survey

Statistical modeling is essential to SAR (Synthetic Aperture Radar) image interpretation. It aims to describe SAR images through statistical methods and reveal the characteristics of these images. Moreover, statistical modeling can provide a technical support for a comprehensive understanding of terrain scattering mechanism, which helps to develop algorithms for effective image interpretation and creditable image simulation. Numerous statistical models have been developed to describe SAR image data, and the purpose of this paper is to categorize and evaluate these models. We first summarize the development history and the current researching state of statistical modeling, then different SAR image models developed from the product model are mainly discussed in detail. Relevant issues are also discussed. Several promising directions for future research are concluded at last

Enigmatic presence of mitochondrial complex I in Trypanosoma brucei bloodstream forms

The presence of mitochondrial respiratory complex I in the pathogenic bloodstream stages of Trypanosoma brucei has been vigorously debated: increased expression of mitochondrially encoded functional complex I mRNAs is countered by low levels of enzymatic activity that show marginal inhibition by the specific inhibitor rotenone. We now show that epitope-tagged versions of multiple complex I subunits assemble into α and β subcomplexes in the bloodstream stage and that these subcomplexes require the mitochondrial genome for their assembly. Despite the presence of these large (740- and 855-kDa) multisubunit complexes, the electron transport activity of complex I is not essential under experimental conditions since null mutants of two core genes (NUBM and NUKM) showed no growth defect in vitro or in mouse infection. Furthermore, the null mutants showed no decrease in NADH:ubiquinone oxidoreductase activity, suggesting that the observed activity is not contributed by complex I. This work conclusively shows that despite the synthesis and assembly of subunit proteins, the enzymatic function of the largest respiratory complex is neither significant nor important in the bloodstream stage. This situation appears to be in striking contrast to that for the other respiratory complexes in this parasite, where physical presence in a life-cycle stage always indicates functional significance

Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice

Background RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders. Methods RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction and a candidate lncRNA, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncRNA was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding RNA-directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays. Results RNA sequencing analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncRNAs. In particular, we detected a significant downregulation of Gomafu lncRNA. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior. Conclusions Experience-dependent expression of lncRNAs plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders

Differences across health care systems in outcome and cost-utility of surgical and conservative treatment of chronic low back pain: a study protocol

<p>Abstract</p> <p>Background</p> <p>There is little evidence on differences across health care systems in choice and outcome of the treatment of chronic low back pain (CLBP) with spinal surgery and conservative treatment as the main options. At least six randomised controlled trials comparing these two options have been performed; they show conflicting results without clear-cut evidence for superior effectiveness of any of the evaluated interventions and could not address whether treatment effect varied across patient subgroups. Cost-utility analyses display inconsistent results when comparing surgical and conservative treatment of CLBP. Due to its higher feasibility, we chose to conduct a prospective observational cohort study.</p> <p>Methods</p> <p>This study aims to examine if</p> <p>1. Differences across health care systems result in different treatment outcomes of surgical and conservative treatment of CLBP</p> <p>2. Patient characteristics (work-related, psychological factors, etc.) and co-interventions (physiotherapy, cognitive behavioural therapy, return-to-work programs, etc.) modify the outcome of treatment for CLBP</p> <p>3. Cost-utility in terms of quality-adjusted life years differs between surgical and conservative treatment of CLBP.</p> <p>This study will recruit 1000 patients from orthopaedic spine units, rehabilitation centres, and pain clinics in Switzerland and New Zealand. Effectiveness will be measured by the Oswestry Disability Index (ODI) at baseline and after six months. The change in ODI will be the primary endpoint of this study.</p> <p>Multiple linear regression models will be used, with the change in ODI from baseline to six months as the dependent variable and the type of health care system, type of treatment, patient characteristics, and co-interventions as independent variables. Interactions will be incorporated between type of treatment and different co-interventions and patient characteristics. Cost-utility will be measured with an index based on EQol-5D in combination with cost data.</p> <p>Conclusion</p> <p>This study will provide evidence if differences across health care systems in the outcome of treatment of CLBP exist. It will classify patients with CLBP into different clinical subgroups and help to identify specific target groups who might benefit from specific surgical or conservative interventions. Furthermore, cost-utility differences will be identified for different groups of patients with CLBP. Main results of this study should be replicated in future studies on CLBP.</p

Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview

As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular factors which are also involved in the replication of HIV and hence their role as potential candidates will be discussed. HIV/AIDS being an exceptional epidemic, demands an exceptional approach and that forms very much focus for the current review

High aboveground carbon stock of African tropical montane forests

Tropical forests store 40-50 per cent of terrestrial vegetation carbon(1). However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests(2). Owing to climatic and soil changes with increasing elevation(3), AGC stocks are lower in tropical montane forests compared with lowland forests(2). Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4 megagrams of carbon per hectare (95% confidence interval 137.1-164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network(4) and about 70 per cent and 32 per cent higher than averages from plot networks in montane(2,5,6) and lowland(7) forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa(8). We find that the low stem density and high abundance of large trees of African lowland forests(4) is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to help to guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse(9,10) and carbon-rich ecosystems. The aboveground carbon stock of a montane African forest network is comparable to that of a lowland African forest network and two-thirds higher than default values for these montane forests.Peer reviewe

The CMS Phase-1 pixel detector upgrade

The CMS detector at the CERN LHC features a silicon pixel detector as its innermost subdetector. The original CMS pixel detector has been replaced with an upgraded pixel system (CMS Phase-1 pixel detector) in the extended year-end technical stop of the LHC in 2016/2017. The upgraded CMS pixel detector is designed to cope with the higher instantaneous luminosities that have been achieved by the LHC after the upgrades to the accelerator during the first long shutdown in 2013–2014. Compared to the original pixel detector, the upgraded detector has a better tracking performance and lower mass with four barrel layers and three endcap disks on each side to provide hit coverage up to an absolute value of pseudorapidity of 2.5. This paper describes the design and construction of the CMS Phase-1 pixel detector as well as its performance from commissioning to early operation in collision data-taking.Peer reviewe

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701