Adaptation to respiration at birth depends upon the synthesis of pulmonary surfactant, a lipid-protein complex that reduces surface tension at the air-liquid interface in the alveoli and prevents ...lung collapse during the ventilatory cycle. Herein, we demonstrated that the gene encoding a subunit of the endoplasmic reticulum membrane complex, EMC3, also known as TMEM111 (Emc3/Tmem111), was required for murine pulmonary surfactant synthesis and lung function at birth. Conditional deletion of Emc3 in murine embryonic lung epithelial cells disrupted the synthesis and packaging of surfactant lipids and proteins, impaired the formation of lamellar bodies, and induced the unfolded protein response in alveolar type 2 (AT2) cells. EMC3 was essential for the processing and routing of surfactant proteins, SP-B and SP-C, and the biogenesis of the phospholipid transport protein ABCA3. Transcriptomic, lipidomic, and proteomic analyses demonstrated that EMC3 coordinates the assembly of lipids and proteins in AT2 cells that is necessary for surfactant synthesis and function at birth.
Direct-acting antiviral (DAA) drugs have been effective in the treatment of chronic hepatitis C virus (HCV) infection. Limited data are available on safety, tolerability, and efficacy in American ...Indian or Alaska Native people. We aim to evaluate the treatment outcomes of sofosbuvir- based regimens for treatment of HCV in a real life setting in Alaska Native/American Indian (AN/AI) people.
AN/AI patients within the Alaska Tribal Health System with confirmed positive anti-HCV and HCV RNA, who were 18 years of age and older were included in the study. Pretreatment baseline patient characteristics, treatment efficacy based on sustained virologic response (SVR) 12 weeks after treatment completion, and adverse effects were assessed. The following treatments were given according to the American Association for the Study of Liver Diseases/Infectious Disease Society of America (AASLD/IDSA) HCV Guidance: ledipasvir/sofosbuvir, sofosbuvir plus weight-based ribavirin, and sofosbuvir/velpatasvir.
We included 501 patients with a mean age of 54.3 (range 21.3-78.3) in the study. Overall SVR was achieved in 95.2% of patients who received one of the three DAA regimens. For those with cirrhosis, overall SVR was 92.8% and for those with genotype 3 91.1% achieved SVR. The most common symptom experienced during treatment was headache. Joint pain was found to decrease during treatment. One person discontinued sofosbuvir plus ribavirin due to myocardial infarction and one discontinued sofosbuvir/velpatasvir due to urticaria.
In the real-world setting, sofosbuvir-based treatment is safe, effective, and well tolerated in AN/AI patients. Sustained virologic response was high regardless of HCV genotype or cirrhosis status.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundThe development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection has been associated with specific HBV genotypes and the presence of specific ...mutations MethodsFrom a cohort of Alaska Native people with chronic HBV infection, we genotyped 47 patients with HCC and 1129 patients without HCC, and we tested patients with HCC and control patients for mutations in the basal core promoter and precore regions ResultsGenotype F was found in 68% of patients with HCC, versus 18% of those without HCC (P<.001). For patients with genotype F, the median age at diagnosis of HCC was lower than that for patients with other genotypes (22.5 vs. 60 years, respectively; P=.002). Overall, there were no significant differences in the number of basal core promoter and precore region mutations between patients with HCC and control patients ConclusionsWe found a significant association between genotype F and the development of HCC among Alaska Native people with chronic HBV infection but no significant association between HCC and basal core promoter or precore mutations in genotype F
Summary
Background
Hepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear.
Aim
To compare HCC risk between Alaska Native (AN) patients with and ...without hepatitis B surface antigen (HBsAg) seroclearance.
Methods
We selected persons with (case‐patients) and without (control‐patients) HBsAg seroclearance from a cohort of 1346 chronically HBV‐infected AN patients followed during 1982‒2013. We attempted to match two control‐patients/case‐patient on sex, HBV genotype, and age. Person‐years of follow‐up for case‐patients began on the date of HBsAg resolution and for control‐patients began on the date equivalent to the cohort entry date plus the years of HBsAg duration for their corresponding case‐patient. We compared HCC risk using a Cox proportional hazards model.
Results
The 238 case‐patients (4 with HCC) and 435 control‐patients (9 with HCC) were similar in age P‐value (P) = 0.30, sex (P = 0.53) and HBV genotype (P = 0.99). Case‐patients had longer person‐years of follow‐up than control‐patients (11.7 vs. 10.1 years; P = 0.04). The HCC rate/100 000 persons was similar between case‐ (132) and control‐patients (178; P = 0.65). The adjusted hazard ratio comparing case‐ and control‐patients was similar for HCC 0.7; 95% confidence interval (CI): 0.2–2.4, increased for each 1‐year increment for age (1.1; CI: 1.0–1.1; P < 0.01), and was greater if the initial HBeAg was positive (3.5; CI: 1.1–11.0; P = 0.03).
Conclusions
Hepatitis B surface antigen seroclearance was not associated with reduced HCC risk; the HCC risk estimates are limited by wide 95% confidence intervals. Persons meeting HCC surveillance indications prior to HBsAg seroclearance could benefit from continued surveillance after seroclearance.
Knowledge of the outcome of chronic hepatitis B virus (HBV) infection is limited.
To determine the incidence of and risk factors for adverse events (hepatocellular carcinoma and end-stage liver ...disease) and clearance of hepatitis B e antigen (HBeAg) and surface antigen (HBsAg) in carriers of HBV.
Population-based cohort study of hepatitis B carriers who were observed for a median of 12.3 years as part of an active surveillance program to detect carriers with hepatocellular carcinoma.
126 communities in Alaska.
1536 Alaska Natives with chronic hepatitis B.
Bivariate comparisons, multivariable models, and other statistical methods were used to examine the relationships of risk factors to outcomes and clearance of HBeAg and HBsAg.
1536 chronic HBV carriers were followed up for 19 430 person-years from their first HBsAg-positive test result. At the first serologic test, 641 were HBeAg positive and 893 were anti-HBe positive. Older carriers were more likely than younger carriers to clear HBeAg (P < 0.001). The observed probability of clearing HBeAg within 10 years of diagnosis was 72.5%. Clearance of HBsAg occurred in 106 (7%) of all carriers and was positively associated with older age and positive result on initial anti-HBe test. The incidence of adverse events was 2.3 per 1000 carrier-years, and the incidence of hepatocellular carcinoma was 1.9 per 1000 carrier-years (2.3 in men and 1.2 in women). Risk for hepatocellular carcinoma increased with age, among those of Yupik Eskimo ethnicity, and among carriers who reverted from anti-HBe to HBeAg.
In HBsAg-positive carriers, observed clearance of HBeAg was more than 70% during the first 10 years of follow-up.
Eukaryotic cells transit through the cell cycle to produce two daughter cells. Dysregulation of the cell cycle leads to cell death or tumorigenesis. Herein, we found a subunit of the ER membrane ...complex, EMC3, as a key regulator of cell cycle. Conditional deletion of Emc3 in mouse embryonic mesoderm led to reduced size and patterning defects of multiple organs. Emc3 deficiency impaired cell proliferation, causing spindle assembly defects, chromosome mis-segregation, cell cycle arrest at G2/M, and apoptosis. Upon entry into mitosis, mesenchymal cells upregulate EMC3 protein levels and localize EMC3 to the mitotic centrosomes. Further analysis indicated that EMC3 works together with VCP to tightly regulate the levels and activity of Aurora A, an essential factor for centrosome function and mitotic spindle assembly: while overexpression of EMC3 or VCP degraded Aurora A, their loss led to increased Aurora A stability but reduced Aurora A phosphorylation in mitosis.
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•EMC3 upregulates protein levels and transits to the centrosomes in mitosis•EMC3 deficiency causes spindle assembly defects, cell cycle arrest, and apoptosis•Multiple EMC3 interactors were identified by mass spectrometry including VCP•EMC3 tightly regulates the levels and activity of Aurora A during mitosis
Biological sciences; Cell biology; Molecular biology
Animal studies have demonstrated macrogol laxatives may reduce colorectal cancer (CRC) risk. This study aimed to investigate the association between macrogol prescribing and CRC risk.
A case-control ...study nested within a cohort of laxative users was conducted using data from the UK General Practice Research Database. Six controls per case were identified and to account for the lead time of CRC, additional control sets were selected on the index date backdated by 1 to 5 years. Exposure to macrogols and covariate status before each of the backdated index dates was established. Conditional logistic regression was used to calculate the risk of CRC following macrogol prescribing adjusted for potential confounders.
4734 incident CRC cases were identified; 2722, 2195, 1789, 1481 and 1214 had received a laxative prescription before the index dates backdated by 1 to 5 years. A suggestion of a non-significant reduction in CRC risk associated with 'macrogol after other laxative' prescribing was observed when the index date was backdated by 1 and 2 years, ORadj = 0.87 (CI950.74-1.03) and ORadj = 0.80 (CI950.65-1.00) compared to non-macrogol laxative exposure. The odds ratios reduced further and were significant when backdated by 3, 4 and 5 years, ORadj = 0.68 (CI950.50-0.92), ORadj = 0.60 (CI950.40-0.90) and ORadj = 0.30 (CI950.14-0.64) respectively. This reduction in risk was not observed, however, for 'macrogol only' and 'macrogol before other laxative' exposure categories.
In this study we observed a reduced CRC risk associated with macrogol prescribing after accounting for the lead time for CRC. Further studies are required to determine whether the association is causal and whether it can partly be explained by selective prescribing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Hepatitis A vaccine is recommended for children ≥1 year old to prevent hepatitis A virus (HAV) infection. However, the duration of vaccine‐induced immunity is unknown. We evaluated a cohort ...of Alaska Native persons 20 years after HAV vaccination. Children aged 3‐6 years had been previously randomized to receive three doses of HAV vaccine (360 ELISA units/dose) at: (i) 0,1,2 months; (ii) 0,1,6 months; and (iii) 0,1,12 months. We measured anti‐HAV antibody concentrations every 2‐3 years; described geometric mean concentrations (GMC) and the proportion with protective antibody (≥20 mIU mL‐1) over time; and modelled the change in GMC using fractional polynomial regression. Of the 144 participants, after 20 years 52 (36.1%) were available for the follow‐up (17, 18, 17 children in Groups A, B and C, respectively). Overall, 46 (88.5%) of 52 available participants had anti‐HAV antibody concentrations ≥20 mIU mL‐1, and overall GMC was 107 mIU mL‐1. Although GMC levels were lower in Group A (60; CI 34‐104) than in Group B (110; CI 68‐177) or Group C (184; CI 98‐345) (B vs C: P=.168; A vs B/C: P=.011), there was no difference between groups after adjusting for peak antibody levels post‐vaccination (P=.579). Models predicted geometric mean concentrations of 124 mIU mL‐1 after 25 years, and 106 mIU mL‐1 after 30 years. HAV vaccine provides protective antibody levels 20 years after childhood vaccination. Lower antibody levels in Group A may be explained by a lower initial peak response. Our results suggest a booster vaccine dose is unnecessary for at least 25‐30 years.
Asthma is commonly treated during pregnancy, yet data on the safety of asthma medicines used during pregnancy are sparse.
The objective of this study was to evaluate the safety of the inhaled ...corticosteroid (ICS) fluticasone propionate (FP), alone and in fixed-dose combination with salmeterol (FSC) in terms of the risk of all major congenital malformations (MCMs), compared with all other non-FP ICS.
Women with asthma who had a pregnancy between January 1, 2000, and December 31, 2010, were identified in the United Kingdom's Clinical Practice Research Datalink. Exposure to asthma medicines during the first trimester of pregnancy was based on issued prescriptions. The mothers' and infants' medical records were linked where possible, and pregnancy outcomes with an MCM diagnosed by age 1 year were identified based on medical codes in the mother's and infant's medical records, including those MCMs prenatally diagnosed that ended in an induced pregnancy termination. The absolute and relative risks of an MCM after different ICS exposures, stratified by the asthma treatment intensity level, were calculated.
A total of 14,654 mother-infant pairs were identified, of which 6,174 received an ICS prescription during the first trimester, in addition to 13 first trimester ICS exposed pregnancies that ended in an induced termination after a prenatal MCM diagnosis. In total, 5,362 pregnancies were eligible for the primary analysis at age 1 year. The absolute risk of an MCM after any first trimester FP exposure was 2.4% (CI95 0.8-4.1) and 2.7% (CI95 1.8-3.6) for the "moderate" and "considerable/severe" asthma treatment intensity levels, respectively. The adjusted odds ratios when compared with non-FP ICS were 1.1 (CI95 0.5-2.3) and 1.2 (CI95 0.7-2.0) for the "moderate" and "considerable/severe" intensity levels; risks for any FP and for FSC did not differ substantially.
No increase in the overall risk of MCMs was identified after first trimester FP exposure compared with non-FP ICS.
Abstract Objective Human skin is the first line of defence from environmental factors such as solar radiation and is susceptible to premature ageing, including a disruption in epidermal ...differentiation and homeostasis. We evaluated the impact of a Galactomyces Ferment Filtrate (GFF) on epidermal differentiation and response to oxidative stress. Methods We used transcriptomics, both spatial and traditional, to assess the impact of GFF on epidermal biology and homeostasis in keratinocytes (primary or immortalized) and in ex vivo skin explant tissue. The effect of GFF on cell adhesion rates, cellular ATP levels and proliferation rates were quantitated. Oxidative phosphorylation and glycolytic rates were measured under normal and stress‐induced conditions. Results Transcriptomics from keratinocytes and ex vivo skin explants from multiple donors show GFF induces keratinocyte differentiation, skin barrier development and cell adhesion while simultaneously repressing cellular stress and inflammatory related processes. Spatial transcriptomics profiling of ex vivo skin indicated basal keratinocytes at the epidermal‐dermal junction and cornifying keratinocytes in the top layer of the epidermis as the primary cell types influenced by GFF treatment. Additionally, GFF significantly increases crosstalk between suprabasal and basal keratinocytes. To support these findings, we show that GFF can significantly increase cell adhesion and proliferation in keratinocytes. GFF also protected overall cellular bioenergetics under metabolic or oxidative stress conditions. Conclusion Our findings provide novel insights into cellular differences and epidermal spatial localization in response to GFF, supporting previous findings that this filtrate has a significant impact on epidermal biology and homeostasis, particularly on spatially defined crosstalk. We propose that GFF can help maintain epidermal health by enhancing keratinocyte crosstalk and differentiation/proliferation balance as well as promoting an enhanced response to stress.
Abstrait Objectif La peau humaine constitue la première ligne de défense contre les facteurs environnementaux tels que le rayonnement solaire et est susceptible de vieillir prématurément, notamment d’une perturbation de la différenciation épidermique et de l’homéostasie. Nous avons évalué l'impact d'un filtrat de ferment Galactomyces (GFF) sur la différenciation épidermique et la réponse au stress oxydatif. Méthodes Nous avons utilisé la transcriptomique, à la fois spatiale et traditionnelle, pour évaluer l'impact du GFF sur la biologie épidermique et l'homéostasie des kératinocytes (primaires ou immortalisés) et des explants cutanés ex vivo. L'effet du GFF sur les taux d'adhésion cellulaire, les niveaux d'ATP cellulaire et les taux de prolifération ont été quantifiés. La phosphorylation oxydative et les taux de glycolytique ont été mesurés dans des conditions normales et induites par le stress. Résultats La transcriptomique des kératinocytes et des explants cutanés ex vivo provenant de plusieurs donneurs montrent que le GFF induit la différenciation des kératinocytes, le développement de la barrière cutanée et l'adhésion cellulaire tout en réprimant simultanément le stress cellulaire et les processus inflammatoires associés. Le profilage transcriptomique spatial de la peau ex vivo a indiqué que les kératinocytes basaux à la jonction épidermique‐dermique et les kératinocytes cornifiants dans la couche supérieure de l'épiderme étaient les principaux types de cellules influencés par le traitement GFF. De plus, le GFF augmente considérablement la diaphonie entre les kératinocytes suprabasaux et basaux. Pour étayer ces résultats, nous montrons que le GFF peut augmenter considérablement l’adhésion cellulaire et la prolifération des kératinocytes. Le GFF a également protégé la bioénergétique cellulaire globale dans des conditions de stress métabolique ou oxydatif. Conclusion Nos résultats fournissent de nouvelles informations sur les différences cellulaires et la localisation spatiale épidermique en réponse au GFF, confortant les découvertes précédentes selon lesquelles ce filtrat a un impact significatif sur la biologie épidermique et l'homéostasie, en particulier sur la diaphonie spatialement définie. Nous proposons que le GFF puisse aider à maintenir la santé de l'épiderme en améliorant la diaphonie des kératinocytes et l'équilibre de différenciation/prolifération, ainsi qu'en favorisant une réponse améliorée au stress.
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