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Predictive factors of polycystic ovary syndrome in girls with precocious pubarche

Objective: The aim of this study is to clarify, in girls with premature pubarche (PP), the influence of premature androgenization on the prevalence of polycystic ovary syndrome (PCOS). Design and patients: Ninety-nine PP girls, 63 who developed PCOS and 36 who did not develop PCOS, were retrospectively included. Clinical, anthropometric, and metabolic parameters were evaluated at the time of diagnosis of PP and after 10 years from menarche to find predictive factors of PCOS. Results: Young females with PP showed a PCOS prevalence of 64% and showed a higher prevalence of familial history of diabetes (P = 0.004) and a lower prevalence of underweight (P = 0.025) than PP-NO-PCOS. In addition, girls with PP-PCOS showed higher BMI (P < 0.001), waist circumference (P < 0.001), total testosterone (P = 0.026), visceral adiposity index (VAI) (P = 0.013), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), non-HDL cholesterol (P < 0.001) and lower age of menarche (P = 0.015), ISI-Matsuda (P < 0.001), DIo (P = 0.002), HDL cholesterol (P = 0.026) than PP-NO-PCOS. Multivariate analysis showed that WC (P = 0.049), ISI-Matsuda (P < 0.001), oral disposition index (DIo) (P < 0.001), VAI (P < 0.001), total testosterone (P < 0.001) and LDL-cholesterol (P < 0.001) are independent predictive factors for PCOS in girls with PP. Conclusions: Our study established a strong association between multiple risk factors and development of PCOS in PP girls. These risk factors are predominantly related to the regulation of glucose, lipid, and androgen metabolism. Among these factors, WC, ISI-Matsuda, DIo, VAI, total testosterone, and LDL-cholesterol predict PCOS

Calcium Binds to Transthyretin with Low Affinity

The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its aggregation propensity. The association between free calcium ions (Ca2+) and TTR is still debated, although recent work seems to suggest that calcium induces structural destabilization of TTR and promotes its aggregation at non-physiological low pH in vitro. We apply high-resolution NMR spectroscopy to investigate calcium binding to TTR showing the formation of labile interactions, which leave the native structure of TTR substantially unaltered. The effect of calcium binding on TTR-enhanced aggregation is also assessed at physiological pH through the mechano-enzymatic mechanism. Our results indicate that, even if the binding is weak, about 7% of TTR is likely to be Ca2+-bound in vivo and therefore more aggregation prone as we have shown that this interaction is able to increase the protein susceptibility to the proteolytic cleavage that leads to aggregation at physiological pH. These events, even if involving a minority of circulating TTR, may be relevant for ATTR, a pathology that takes several decades to develop

Functional and dysfunctional conformers of human neuroserpin Characterized by optical spectroscopies and molecular dynamics

Neuroserpin (NS) is a serine protease inhibitor (SERPIN) involved in different neurological pathologies, including the Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), related to the aberrant polymerization of NS mutants. Here we present an in vitro and in silico characterization of native neuroserpin and its dysfunctional conformation isoforms: the proteolytically cleaved conformer, the inactive latent conformer, and the polymeric species. Based on circular dichroism and fluorescence spectroscopy, we present an experimental validation of the latent model and highlight the main structural features of the different conformers. In particular, emission spectra of aromatic residues yield distinct conformational fingerprints, that provide a novel and simple spectroscopic tool for selecting serpin conformers in vitro. Based on the structural relationship between cleaved and latent serpins, we propose a structural model for latent NS, for which an experimental crystallographic structure is lacking. Molecular Dynamics simulations suggest that NS conformational stability and flexibility arise from a spatial distribution of intramolecular salt-bridges and hydrogen bonds

On the molecular structure of human neuroserpin polymers

The polymerization of serpins is at the root of a large class of diseases; the molecular structure of serpin polymers has been recently debated. Here, we study the polymerization kinetics of human neuroserpin by Fourier Transform Infra Red spectroscopy and by time-lapse Size Exclusion Chromatography. Firstly we show that two distinct neuroserpin polymers, formed at 45 and 85 °C, display the same isosbestic points in the Amide I′ band, and therefore share common secondary structure features. We also find a concentration independent polymerization rate at 45 °C, suggesting that the polymerization rate-limiting step is the formation of an activated monomeric species. The polymer structures are consistent with a model that predicts the bare insertion of portions of the reactive center loop into the A β-sheet of neighboring serpin molecule, although with different extents at 45 and 85 °C

Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? A randomized controlled trial

<br>Background: Loss of muscle mass and strength with ageing is a major cause for falls, disability, and morbidity in older people. Previous studies have found that angiotensin-converting enzyme inhibitors (ACEi) may improve physical function in older people. It is unclear whether ACEi provide additional benefit when added to a standard exercise training program. We examined the effects of ACEi therapy on physical function in older people undergoing exercise training.</br> <b>Methods:</b> Community-dwelling people aged ≥65 years with functional impairment were recruited through general (family) practices. All participants received progressive exercise training. Participants were randomized to receive either 4 mg perindopril or matching placebo daily for 20 weeks. The primary outcome was between-group change in 6-minute walk distance from baseline to 20 weeks. Secondary outcomes included changes in Short Physical Performance Battery, handgrip and quadriceps strength, self-reported quality of life using the EQ-5D, and functional impairment measured using the Functional Limitations Profile.<p></p> <b>Results:</b> A total of 170 participants (n = 86 perindopril, n = 84 placebo) were randomized. Mean age was 75.7 (standard deviation [SD] 6.8) years. Baseline 6-minute walk distance was 306 m (SD 99). Both groups increased their walk distance (by 29.6 m perindopril, 36.4 m placebo group) at 20 weeks, but there was no statistically significant treatment effect between groups (−8.6m [95% confidence interval: −30.1, 12.9], p = .43). No statistically significant treatment effects were observed between groups for the secondary outcomes. Adverse events leading to withdrawal were few (n = 0 perindopril, n = 4 placebo).<p></p> <b>Interpretation:</b> ACE inhibitors did not enhance the effect of exercise training on physical function in functionally impaired older people.<p></p&gt

C. elegans expressing human β2-microglobulin: a novel model for studying the relationship between the molecular assembly and the toxic phenotype.

Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β(2)-microglobulin (β(2)-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β(2)-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β(2)-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β(2)-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β(2)-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β(2)-m