Context: Kisspeptin, encoded by the KISS1 gene, is a key stimulatory factor of GnRH secretion and puberty onset. Inactivating mutations of its receptor (KISS1R) cause isolated hypogonadotropic ...hypogonadism (IHH). A unique KISS1R-activating mutation was described in central precocious puberty (CPP).
Objective: Our objective was to investigate KISS1 mutations in patients with idiopathic CPP and normosmic IHH.
Patients: Eighty-three children with CPP (77 girls) and 61 patients with IHH (40 men) were studied. The control group consisted of 200 individuals with normal pubertal development.
Methods: The promoter region and the three exons of KISS1 were amplified and sequenced. Cells expressing KISS1R were stimulated with synthetic human wild-type or mutant kisspeptin-54 (kp54), and inositol phosphate accumulation was measured. In a second set of experiments, kp54 was preincubated in human serum before stimulation of the cells.
Results: Two novel KISS1 missense mutations, p.P74S and p.H90D, were identified in three unrelated children with idiopathic CPP. Both mutations were absent in 400 control alleles. The p.P74S mutation was identified in the heterozygous state in a boy who developed CPP at 1 yr of age. The p.H90D mutation was identified in the homozygous state in two unrelated girls with CPP. In vitro studies revealed that the capacity of the P74S and H90D mutants to stimulate IP production was similar to the wild type. After preincubation of wild-type and mutant kp54 in human serum, the capacity to stimulate signal transduction was significantly greater for P74S compared with the wild type, suggesting that the p.P74S variant is more stable. Only polymorphisms were found in the IHH group.
Conclusion: Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggesting a role for this mutation in the precocious puberty phenotype.
A mutation in the KISS1 gene (P74S), identified in a boy with central precocious puberty, results in higher kisspeptin resistance to degradation in vitro.
We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an ...international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term “endocapillary proliferation” is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.
The interiors of giant planets remain poorly understood. Even for the planets in the Solar System, difficulties in observation lead to large uncertainties in the properties of planetary cores. ...Exoplanets that have undergone rare evolutionary processes provide a route to understanding planetary interiors. Planets found in and near the typically barren hot-Neptune ‘desert’ (a region in mass–radius space that contains few planets) have proved to be particularly valuable in this regard. These planets include HD149026b, which is thought to have an unusually massive core, and recent discoveries such as LTT9779b and NGTS-4b, on which photoevaporation has removed a substantial part of their outer atmospheres. Here we report observations of the planet TOI-849b, which has a radius smaller than Neptune’s but an anomalously large mass of 39.1(+2.7−2.6) Earth masses and a density of 5.2(+0.7−0.8) grams per cubic centimetre, similar to Earth’s. Interior-structure models suggest that any gaseous envelope of pure hydrogen and helium consists of no more than 3.9(+0.8−0.9) per cent of the total planetary mass. The planet could have been a gas giant before undergoing extreme mass loss via thermal self-disruption or giant planet collisions, or it could have avoided substantial gas accretion, perhaps through gap opening or late formation. Although photoevaporation rates cannot account for the mass loss required to reduce a Jupiter-like gas giant, they can remove a small (a few Earth masses) hydrogen and helium envelope on timescales of several billion years, implying that any remaining atmosphere on TOI-849b is likely to be enriched by water or other volatiles from the planetary interior. We conclude that TOI-849b is the remnant core of a giant planet.
Background Albuminuria is a risk factor for chronic kidney disease progression, end-stage renal disease, cardiovascular events, and mortality. Animal studies suggested that vitamin D insufficiency ...may contribute to the pathogenesis of albuminuria. Study Design Cross-sectional study. Setting & Participants 15,068 adults participating in the Third National Health and Nutrition Examination Survey. Predictor Serum 25-hydroxyvitamin D concentration, examined in quartiles. Outcomes & Measurements Albuminuria, defined using established sex-specific cutoff values for urine albumin-creatinine ratio (25 to 2,999 mg/g for women, 17 to 2,999 mg/g for men). Results A stepwise increase in the prevalence of albuminuria was observed with decreasing quartiles of vitamin D concentration: 8.9%, 11.5%, 13.7%, and 15.8% ( P < 0.001). Adjusting for age, sex, race/ethnicity, region and season of measurement, smoking status, body mass index, and estimated glomerular filtration rate, relative risks for albuminuria by decreasing quartile of vitamin D concentration were 1.00 (reference group), 1.14 (95% confidence interval, 0.95 to 1.37), 1.22 (95% confidence interval, 1.03 to 1.45), and 1.37 (95% confidence interval, 1.10 to 1.71; P = 0.006). Additionally adjusting for blood pressure and diabetes mellitus, these risks were somewhat attenuated and retained statistical significance. Limitations The cross-sectional design of this study does not allow demonstration of temporal or causal relationships between vitamin D and albuminuria. Conclusions Additional studies are needed to clarify the relationship of vitamin D with albuminuria and determine whether vitamin D therapy prevents or improves markers of kidney and cardiovascular disease.
The Arctic has undergone substantial changes over the last few decades in various cryospheric and derivative systems and processes. Of these, the Arctic sea ice regime has seen some of the most rapid ...change and is one of the most visible markers of Arctic change outside the scientific community. This has drawn considerable attention not only from the natural sciences, but increasingly, from the political and commercial sectors as they begin to grapple with the problems and opportunities that are being presented. The possible impacts of past and projected changes in Arctic sea ice, especially as it relates to climatic response, are of particular interest and have been the subject of increasing research activity. A review of the current knowledge of the role of sea ice in the climate system is therefore timely. We present a review that examines both the current state of understanding, as regards the impacts of sea-ice loss observed to date, and climate model projections, to highlight hypothesised future changes and impacts on storm tracks and the North Atlantic Oscillation. Within the broad climate-system perspective, the topics of storminess and large-scale variability will be specifically considered. We then consider larger-scale impacts on the climatic system by reviewing studies that have focused on the interaction between sea-ice extent and the North Atlantic Oscillation. Finally, an overview of the representation of these topics in the literature in the context of IPCC climate projections is presented. While most agree on the direction of Arctic sea-ice change, the rates amongst the various projections vary greatly. Similarly, the response of storm tracks and climate variability are uncertain, exacerbated possibly by the influence of other factors. A variety of scientific papers on the relationship between sea-ice changes and atmospheric variability have brought to light important aspects of this complex topic. Examples are an overall reduction in the number of Arctic winter storms, a northward shift of mid-latitude winter storms in the Pacific and a delayed negative NAO-like response in autumn/winter to a reduced Arctic sea-ice cover (at least in some months). This review paper discusses this research and the disagreements, bringing about a fresh perspective on this issue.
► Observed decrease in sea-ice extent is faster than predicted. ► September sea ice reaching record low in recent years. ► Reduction in the number of Arctic winter storms. ► Northward shift of midlatitude storms and uncertainty over changes in intensity. ► Most models simulate a negative NAO response when forced with less Arctic sea-ice.
Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).
To investigate KISS1R defects in ...patients with absent or delayed puberty.
We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP).
The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification.
One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position -2 to -4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3' splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP.
Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.
ABSTRACT
We present the bright (Vmag = 9.12), multiplanet system TOI-431, characterized with photometry and radial velocities (RVs). We estimate the stellar rotation period to be 30.5 ± 0.7 d using ...archival photometry and RVs. Transiting Exoplanet Survey Satellite (TESS) objects of Interest (TOI)-431 b is a super-Earth with a period of 0.49 d, a radius of 1.28 ± 0.04 R⊕, a mass of 3.07 ± 0.35 M⊕, and a density of 8.0 ± 1.0 g cm−3; TOI-431 d is a sub-Neptune with a period of 12.46 d, a radius of 3.29 ± 0.09 R⊕, a mass of $9.90^{+1.53}_{-1.49}$ M⊕, and a density of 1.36 ± 0.25 g cm−3. We find a third planet, TOI-431 c, in the High Accuracy Radial velocity Planet Searcher RV data, but it is not seen to transit in the TESS light curves. It has an Msin i of $2.83^{+0.41}_{-0.34}$ M⊕, and a period of 4.85 d. TOI-431 d likely has an extended atmosphere and is one of the most well-suited TESS discoveries for atmospheric characterization, while the super-Earth TOI-431 b may be a stripped core. These planets straddle the radius gap, presenting an interesting case-study for atmospheric evolution, and TOI-431 b is a prime TESS discovery for the study of rocky planet phase curves.
Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard ...treatment of acute venous thromboembolism.
To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.
Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism THRIVE Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.
Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.
Recurrent venous thromboembolism, bleeding, and mortality.
Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval CI, -1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, -1.0%; 95% CI, -2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, -1.1%; 95% CI, -2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).
Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.
Previously, we have shown that 17β‐oestradiol (E2) induces an increase in firing activity and modifies the pattern of intracellular calcium (Ca2+i) oscillations with a latency < 1 min in primate ...luteinising hormone‐releasing hormone (LHRH) neurones. A recent study also indicates that E2, the nuclear membrane impermeable oestrogen, oestrogen‐dendrimer conjugate, and the plasma membrane impermeable oestrogen, E2‐BSA conjugate, all similarly stimulated LHRH release within 10 min of exposure in primate LHRH neurones, indicating that the rapid action of E2 is caused by membrane signalling. The results from a series of studies further suggest that the rapid action of E2 in primate LHRH neurones appears to be mediated by GPR30. Although the oestrogen receptor antagonist, ICI 182, 780, neither blocked the E2‐induced LHRH release nor the E2‐induced changes in Ca2+i oscillations, E2 application to cells treated with pertussis toxin failed to result in these changes in primate LHRH neurones. Moreover, knockdown of GPR30 in primate LHRH neurones by transfection with human small interference RNA for GPR30 completely abrogated the E2‐induced changes in Ca2+i oscillations, whereas transfection with control siRNA did not. Finally, the GPR30 agonist, G1, resulted in changes in Ca2+i oscillations similar to those observed with E2. In this review, we discuss the possible role of G‐protein coupled receptors in the rapid action of oestrogen in neuronal cells.
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