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Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. © 2013 The American Society of Human Genetics.

This paper addresses the problem of estimating the quantile function in a multiple-sample set up when the data are left-truncated and right-censored (LTRC). Assuming an uncertain prior non-sample information on the value of the quantile, we propose improved estimators based on Stein-type shrinkage estimators. A test statistic is also proposed to define improved estimators for the quantile function. The asymptotic bias and risk of the estimators are derived and compared with the benchmark estimator analytically. For several choices of parameters, a Monte Carlo simulation experiment is conducted to appraise the risk reduction of the proposed estimators at different levels of censoring and truncation. We demonstrate that the proposed estimators have superior performance in terms of risk reduction over the benchmark estimator.

ObjectiveTo evaluate whether the clinical benefit and relapse rates in anti-muscle-specific kinase (MuSK) myasthenia gravis (MG) differ depending on the protocol of rituximab followed. MethodsThis retrospective multicentre study in patients with MuSK MG compared three rituximab protocols in terms of clinical status, relapse, changes in treatment, and adverse side effects. The primary effectiveness endpoint was clinical relapse requiring a further infusion of rituximab. Survival curves were estimated using Kaplan-Meier methods and survival analyses were undertaken using Cox proportional-hazards models. ResultsTwenty-five patients were included: 11 treated with protocol 4 + 2 (375 mg/m(2)/4 weeks, then monthly for 2 months), five treated with protocol 1 + 1 (two 1 g doses 2 weeks apart), and nine treated with protocol 4 (375 mg/m(2)/4 weeks). Mean follow-up was 5.0 years (SD 3.3). Relapse occurred in 18.2%, 80%, and 33.3%, and mean time to relapse was 3.5 (SD 1.5), 1.1 (SD 0.4), and 2.5 (SD 1.4) years, respectively. Based on Kaplan-Meier estimates, patients treated with protocol 4 + 2 had fewer and later relapses than patients treated with the other two protocols (log-rank test P = 0.0001). Patients treated with protocol 1 + 1 had a higher risk of relapse than patients treated with protocol 4 + 2 (HR 112.8, 95% CI, 5.7-2250.4, P = 0.002). Patients treated with protocol 4 showed a trend to a higher risk of relapse than those treated with protocol 4 + 2 (HR 9.2, 95% CI 0.9-91.8, P = 0.059). InterpretationThis study provides class IV evidence that the 4 + 2 rituximab protocol has a lower clinical relapse rate and produces a more durable response than the 1 + 1 and 4 protocols in patients with MuSK MG.

AbstractThere is now widespread acceptance of the universal coverage approach, presented in the 2010 World Health Report. There are more and more voices for the benefit of creating a single national risk pool. Now, a body of literature is emerging on institutional design and organizational practice for universal coverage, related to management of the three health-financing functions: collection, pooling and purchasing. While all countries can move towards universal coverage, lower-income countries face particular challenges, including scarce resources and limited capacity. Recently, the Lao PDR has been preparing options for moving to a single national health insurance scheme. The aim is to combine four different social health protection schemes into a national health insurance authority (NHIA) with a single national fund- and risk-pool. This paper investigates the main institutional and organizational challenges related to the creation of the NHIA. The paper uses a qualitative approach, drawing on the World Health Organization's institutional and Organizational Assessment for Improving and Strengthening health financing (OASIS) conceptual framework for data analysis. Data were collected from a review of key health financing policy documents and from 17 semi-structured key informant interviews. Policy makers and advisors are confronting issues related to institutional arrangements, funding sources for the authority and government support for subsidies to the demand-side health financing schemes. Compulsory membership is proposed, but the means for covering the informal sector have not been resolved. While unification of existing schemes may be the basis for creating a single risk pool, challenges related to administrative capacity and cross-subsidies remain. The example of Lao PDR illustrates the need to include consideration of national context, the sequencing of reforms and the time-scale appropriate for achieving universal coverage.

AbstractOnly a few studies have assessed the long-term duration of the humoral immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).In this nationwide longitudinal study from the Faroe Islands with close to full participation of all individuals on the Islands with PCR confirmed COVID-19 during the two waves of infections in the spring and autumn 2020 (n=172 & n=233), samples were drawn at three longitudinal time points (3, 7 and 12 months and 1, 3 and 7 months after disease onset, respectively).Serum was analyzed with a direct quantitative IgG antibody binding ELISA to detect anti–SARS-CoV-2 spike RBD antibodies and a commercially available qualitative sandwich RBD ELISA kit measuring total antibody binding.The seropositive rate in the convalescent individuals was above 95 % at all sampling time points for both assays. There was an overall decline in IgG titers over time in both waves (p < 0.001). Pairwise comparison showed that IgG declined significantly from the first sample until approximately 7 months in both waves (p < 0.001). After that, the antibody level still declined significantly (p < 0.001), but decelerated with an altered slope remaining fairly stable from 7 months to 12 months after infection. Interestingly, the IgG titers followed a U-shaped curve with higher antibody levels among the oldest (67+) and the youngest (0– 17) age groups compared to intermediate groups (p < 0.001).Our results indicate that COVID-19 convalescent individuals are likely to be protected from reinfection up to 12 months after symptom onset and maybe even longer. We believe our results can add to the understanding of natural immunity and the expected durability of SARS-CoV-2 vaccine immune responses.

This chapter provides a review of the general theory of electric machines. It discusses the principles of electric machine operation, magnetic modeling, and characteristics of materials. Various classical electric machine topologies, including brushed DC, and different AC machines are discussed.

Benign lymphoid polyps are uncommon lesions of the small bowel and the colon to a lesser degree that are mostly found in children. There are only few reported cases in adults in which the lesions were predominantly polypoid and described as lymphonodular hyperplasia. We present a case of a large benign lymphoid polyp in the transverse colon of a 64-year-old lady who was referred to our care for a history of alteration in her bowel habit and anemia. Colonoscopy showed a 3 cm (Paris 1p) friable polyp which was excised and retrieved. Histopathology examination confirmed its benign nature supported by immunohistochemical studies. Benign lymphoid polyp is a rare condition posing a diagnostic challenge as it can be misinterpreted as a malignant lesion.

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. http://purl.org/eprint/status/PeerReviewed published version Article