Disorders of sex development : timing of diagnosis and management in a single large tertiary center

Background: We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center. Methods: DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts. Results: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 +/- 5.5 years), Klinefelter syndrome (14.5%, 6.8 +/- 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P <0.001). Conclusions: Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients' adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.Peer reviewe

Asymptotic expansions of the solutions of the Cauchy problem for nonlinear parabolic equations

Let $u$ be a solution of the Cauchy problem for the nonlinear parabolic equation $$\partial_t u=\Delta u+F(x,t,u,\nabla u) \quad in \quad{\bf R}^N\times(0,\infty), \quad u(x,0)=\varphi(x)\quad in \quad{\bf R}^N,$$ and assume that the solution $u$ behaves like the Gauss kernel as $t\to\infty$. In this paper, under suitable assumptions of the reaction term $F$ and the initial function $\varphi$, we establish the method of obtaining higher order asymptotic expansions of the solution $u$ as $t\to\infty$. This paper is a generalization of our previous paper, and our arguments are applicable to the large class of nonlinear parabolic equations

Influence of temperature gradients on tunnel junction thermometry below 1 K: cooling and electron-phonon coupling

We have studied thermal gradients in thin Cu and AlMn wires, both experimentally and theoretically. In the experiments, the wires were Joule heated non-uniformly at sub-Kelvin temperatures, and the resulting temperature gradients were measured using normal metal-insulator-superconducting tunnel junctions. The data clearly shows that even in reasonably well conducting thin wires with a short ($\sim 10 \mu$m) non-heated portion, significant temperature differences can form. In most cases, the measurements agree well with a model which includes electron-phonon interaction and electronic thermal conductivity by the Wiedemann-Franz law.Comment: J. Low Temp. Phys. in pres

Protective distal side-to-side neurorrhaphy in proximal nerve injury-an experimental study with rats

Background Side-to-side neurorrhaphy may protect the denervated end organ and preserve the initial connection with proximal stump. We examined the effect of protective side-to-side anastomosis on nerve and end organ regeneration in proximal nerve injury model.Methods The left common peroneal nerve of 24 Sprague Dawley rats was proximally transected. In groups B and C, side-to-side neurorrhaphy was performed distally between the peroneal and tibial nerves without (group B) and with (group C) partial donor nerve axotomy inside the epineural window. Group A served as an unprotected control. After 26 weeks, the proximal transection was repaired with end-to-end neurorrhaphy on all animals. Regeneration was followed during 12 weeks with the walk track analysis. Morphometric studies and wet muscle mass calculations were conducted at the end of the follow-up period.Results The results of the walk track analysis were significantly better in groups B and C compared to group A. Groups B and C showed significantly higher wet mass ratios of the tibialis anterior and extensor digitorum longus muscle compared to group A. Group C showed significantly higher morphometric values compared to group A. Group B reached higher values of the fibre count, fibre density, and percentage of the fibre area compared to group A.Conclusions Protective distal side-to-side neurorrhaphy reduced muscle atrophy and had an improving effect on the morphometric studies and walk track analysis. Distal side-to-side neurorrhaphy does not prevent the regenerating axons to grow from the proximal stump to achieve distal nerve stump

Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia:Results of a 24week, double-blind, randomized Phase 3 trial

Background:Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy. Methods In a Phase 3, randomized, double-blind, double-dummy study (NCT01644474), patients (low-density lipoprotein cholesterol [LDL-C] 100–190 mg/dL, 10-year risk of fatal cardiovascular events = 1%–&lt;5% [systemic coronary risk estimation]) were randomized to ezetimibe 10 mg/day (n = 51) or alirocumab 75 mg subcutaneously (via 1­mL autoinjector) every 2 weeks (Q2W) (n = 52), with dose up-titrated to 150 mg Q2W (also 1 mL) at week 12 if week 8 LDL-C was = 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks, analyzed using all available data (intent-to-treat approach, ITT). Analyses using on-treatment LDL-C values were also conducted.Results: Mean (SD) baseline LDL-C levels were 141.1 (27.1) mg/dL (alirocumab) and138.3 (24.5) mg/dL (ezetimibe). The 24-week treatment period was completed by 85% of alirocumab and 86% of ezetimibe patients. Least squares mean (SE) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe (ITT; p &lt; 0.0001) and 54 (2)% versus 17 (2)% (on-treatment; p &lt; 0.0001).At week 12, before up-titration, alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% (on-treatment). Injection site reactions were infrequent (&lt; 2% and &lt; 4% of alirocumab and ezetimibe patients, respectively). Conclusions: Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide = 50% LDL-C reduction in the majority of the patients. Adverse events were comparable between groups.</p

Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure

ObjectivesImpaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Inadequate understanding of the pathological mechanisms limits the development of therapeutic approaches. We aimed to identify the key cardiac kinases and signaling pathways in patients with IHD with an effort to discover potential therapeutic strategies.MethodsCardiac kinase activity in IHD left ventricle (LV) and the related signaling pathways were investigated by kinomics, transcriptomics, proteomics, and integrated multi-omics approach.ResultsProtein kinase A (PKA) and protein kinase G (PKG) ranked on top in the activity shift among the cardiac kinases. In the IHD LVs, PKA activity decreased markedly compared with that of controls (62% reduction, p = 0.0034), whereas PKG activity remained stable, although the amount of PKG protein increased remarkably (65%, p = 0.003). mRNA levels of adenylate cyclases (ADCY 1, 3, 5, 9) and cAMP-hydrolysing phosphodiesterases (PDE4A, PDE4D) decreased significantly, although no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). The gene expression of natriuretic peptide CNP decreased remarkably, whereas those of BNP, ANP, and neprilysin increased significantly in the IHD LVs. Proteomics analysis revealed a significant reduction in protein levels of “Energy metabolism” and “Muscle contraction” in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway.ConclusionThe deficiency in cAMP/PKA signaling pathway is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling.Peer reviewe