Kidney disease in nail–patella syndrome

Nail–patella syndrome (NPS) is a pleiotropic autosomal-dominant disorder due to mutations in the gene LMX1B. It has traditionally been characterized by a tetrad of dermatologic and musculoskeletal abnormalities. However, one of the most serious manifestations of NPS is kidney disease, which may be present in up to 40% of affected individuals. Although LMX1B is a developmental LIM-homeodomain transcription factor, it is expressed in post-natal life in the glomerular podocyte, suggesting a regulatory role in that cell. Kidney disease in NPS seems to occur more often in some families with NPS, but it does not segregate with any particular mutation type or location. Two patterns of NPS nephropathy may be distinguished. Most affected individuals manifest only an accelerated age-related loss of filtration function in comparison with unaffected individuals. Development of symptomatic kidney failure is rare in this group, and proteinuria (present in approximately one-third) does not appear to be progressive. A small minority (5–10%) of individuals with NPS develop nephrotic-range proteinuria as early as childhood or young adulthood and progress to end-stage kidney failure over variable periods of time. It is proposed that this latter group reflects the effects of more global podocyte dysfunction, possibly due to the combination of a mutation in LMX1B along with an otherwise innocuous polymorphism or mutation involving any of several genes expressed in podocytes (e.g. NPHS2, CD2AP), the transription of which is regulated by LMX1B

How are podocytes affected in nail–patella syndrome?

Nail–patella syndrome is an autosomal-dominant hereditary disease named for dysplastic fingernails and toenails and hypoplastic or absent kneecaps evident in patients with the syndrome. Prognosis is determined by the nephropathy that develops in many such patients. Besides podocyte foot-process effacement, pathognomonic changes in the kidney comprise electron-lucent areas and fibrillar inclusions in the glomerular basement membrane. These characteristic symptoms are caused by mutations in the gene encoding the transcription factor LMX1B, a member of the LIM-homeodomain gene family. Comparable with the human syndrome, homozygous Lmx1b knockout mice lack patellae and suffer from severe podocyte damage. In contrast, however, podocin and the α3 and α4 chains of collagen IV are absent in the glomeruli of Lmx1b knockout mice. Further studies with podocyte-specific Lmx1b knockout mice have confirmed the importance of LMX1B in podocytes, as these mice apparently develop foot processes initially but lose them later on. We therefore conclude that LMX1B is essential for the development of metanephric precursor cells into podocytes and possibly also for maintaining the differentiation status of podocytes. LMX1B can serve as a model system to elucidate a genetic program in podocytes

Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora

Background The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora - South Africa's biodiversity hotspot - through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. Results Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. Conclusions Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record

One-step hydrothermal synthesis of graphene decorated V2O5 nanobelts for enhanced electrochemical energy storage

Graphene-decorated V2O5 nanobelts (GVNBs) were synthesized via a low-temperature hydrothermal method in a single step. V2O5 nanobelts (VNBs) were formed in the presence of graphene oxide, a mild oxidant, which also enhanced the conductivity of GVNBs. From the electron energy loss spectroscopy analysis, the reduced graphene oxide (rGO) are inserted into the layered crystal structure of V2O5 nanobelts, which further confirmed the enhanced conductivity of the nanobelts. The electrochemical energy-storage capacity of GVNBs was investigated for supercapacitor applications. The specific capacitance of GVNBs was evaluated using cyclic voltammetry (CV) and charge/discharge (CD) studies. The GVNBs having V2O5-rich composite, namely, V(3)G(1) (VO/GO = 3:1), showed superior specific capacitance in comparison to the other composites (V(1)G(1) and V(1)G(3)) and the pure materials. Moreover, the V(3)G(1) composite showed excellent cyclic stability and the capacitance retention of about 82% was observed even after 5000 cycles.open

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

The impact of mass drug administration and long-lasting insecticidal net distribution on Wuchereria bancrofti infection in humans and mosquitoes: an observational study in northern Uganda

BACKGROUND: Lymphatic filariasis (LF) in Uganda is caused by Wuchereria bancrofti and transmitted by anopheline mosquitoes. The mainstay of elimination has been annual mass drug administration (MDA) with ivermectin and albendazole, targeted to endemic districts, but has been sporadic and incomplete in coverage. Vector control could potentially contribute to reducing W. bancrofti transmission, speeding up progress towards elimination. To establish whether the use of long-lasting insecticidal nets (LLINs) can contribute towards reducing transmission of W. bancrofti in a setting with ongoing MDA, a study was conducted in an area of Uganda highly endemic for both LF and malaria. Baseline parasitological and entomological assessments were conducted in 2007, followed by high-coverage LLIN distribution. Net use and entomological surveys were carried out after one year, and final parasitological and entomological evaluations were conducted in 2010. Three rounds of MDA had taken place before the study commenced, with a further three rounds completed during the course of the study. RESULTS: In 2007, rapid mapping indicated 22.3% of schoolchildren were W. bancrofti antigen positive, and a baseline survey during the same year found age-adjusted microfilaraemia prevalence was 3.7% (95% confidence interval (CI): 2.6-5.3%). In 2010, age-adjusted microfilaraemia prevalence had fallen to 0.4%, while antigenaemia rates were 0.2% in children < 5 years and 6.0% in ≥ 5 years. In 2010, universal coverage of mosquito nets in a household was found to be protective against W. bancrofti antigen (odds ratio = 0.44, 95% CI: 0.22-0.89). Prevalence of W. bancrofti larvae in anopheline mosquitoes had decreased significantly between the 2007 and 2010 surveys, but there was an apparent increase in vector densities. CONCLUSION: A marked reduction in W. bancrofti infection and infectivity in humans was observed in the study area, where both MDA and LLINs were used to reduce transmission. The extent to which LLINs contributed to this decline is equivocal, however. Further work investigating the impact of vector control on anopheline-transmitted LF in an endemic area not benefitting from MDA would be valuable to determine the effect of such interventions on their own

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Rationale and design of The Delphi Trial – I(RCT)(2): international randomized clinical trial of rheumatoid craniocervical treatment, an intervention-prognostic trial comparing 'early' surgery with conservative treatment [ISRCTN65076841]

BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease, which affects 1% of the population. Hands and feet are most commonly involved followed by the cervical spine. The spinal column consists of vertebrae stabilized by an intricate network of ligaments. Especially in the upper cervical spine, rheumatoid arthritis can cause degeneration of these ligaments, causing laxity, instability and subluxation of the vertebral bodies. Subsequent compression of the spinal cord and medulla oblongata can cause severe neurological deficits and even sudden death. Once neurological deficits occur, progression is inevitable although the rapidity of progression is highly variable. The first signs and symptoms are pain at the back of the head caused by compression of the major occipital nerve, followed by loss of strength of arms and legs. The severity of the subluxation can be observed with radiological investigations (MRI, CT) with a high sensitivity. The authors have sent a Delphi Questionnaire about the current treatment strategies of craniocervical involvement by rheumatoid arthritis to an international forum of expert rheumatologists and surgeons. The timing of surgery in patients with radiographic instability without evidence of neurological deficit is an area of considerable controversy. If signs and symptoms of myelopathy are present there is little chance of recovery to normal levels after surgery. DESIGN: In this international multicenter randomized clinical trial, early surgical atlantoaxial fixation in patients with rheumatoid arthritis and radiological abnormalities without neurological deficits will be compared with prolonged conservative treatment. The main research question is whether early surgery can prevent radiological and neurological progression. A cost-effectivity analysis will be performed. 250 patients are needed to answer the research question. DISCUSSION: Early surgery could prevent serious neurological deficits, but may have peri-operative morbidity and loss of rotation of the head and neck. The objective of this study is to identify the best timing of surgery for patients at risk for the development of neurological signs and symptoms