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After cessation of lactation, the mammary gland undergoes involution, which is characterized by a massive epithelial cell death and proteolytic degradation of the extracellular matrix. Whereas the expression patterns and also the function of TGF-beta isoforms during mammary gland branching morphogenesis and lactation are well understood, their expression during postlactational involution and therefore a possible role in this process is poorly known. In this study we show that TGF-beta3 expression is dramatically induced (>fivefold) during mouse mammary gland involution when compared to that of virgin mouse, reaching a maximal expression level at day 4 after weaning. In contrast, other TGF-beta isoforms do not display significant increase in expression during involution (TGF-beta1, 1.3-fold and TGF-beta2, <1.5-fold) when compared to that of virgin or lactating mice. During mammary gland involution, TGF-beta3 is expressed in the epithelial layer and particularly in myoepithelial cells. A comparison of the kinetics of TGF-beta3 expression to that of programmed cell death and degradation of the basement membrane suggests that TGF-beta3 functions in the remodeling events of the extracellular matrix during the second stage of involution. 相似文献
94.
Clément Fran?ois Nora Rahhali Ylana Chalem Per S?rensen Amandine Luquiens Henri-Jean Aubin 《PloS one》2015,10(6)
Background
The objective of this article was to investigate the effect of as-needed nalmefene on health-related quality of life (HRQoL) in patients with alcohol dependence, and to relate changes in drinking behavior and status to HRQoL outcomes.Methods
This post hoc analysis was conducted on a pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) who participated in one of two randomized controlled 6-month studies, ESENSE 1 and ESENSE 2. Patients received nalmefene 18 mg or placebo on an as-needed basis, in addition to a motivational and adherence-enhancing intervention (BRENDA). At baseline and after 12 and 24 weeks questionnaires for the Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36), European Quality of life-5 Dimensions (EQ-5D) and the Drinker Inventory of Consequences (DrInC-2R) were completed.Results
The pooled population consisted of 667 patients (nalmefene: 335; placebo: 332), with no notable between-group differences in baseline patient demographics/characteristics. At week 24, nalmefene had a superior effect compared to placebo in improving SF-36 mental component summary scores (mean difference [95% CI], p-value: 3.09 [1.29, 4.89]; p=0.0008), SF-36 physical component summary scores (1.23 [0.15, 2.31]; p=0.026), EQ-5D utility index scores (0.03 [0.00, 0.06]; p=0.045), EQ-5D health state scores (3.46 [0.75, 6.17]; p=0.012), and DrInC-2R scores (-3.22 [-6.12, 0.33]; p=0.029). The improvements in SF-36 mental component summary scores at week 24, and the DrInC-2R total score change from baseline to week 24, were significantly correlated to reductions in heavy drinking days and total alcohol consumption at week 24.Conclusions
As-needed nalmefene significantly improved almost all patient-reported HRQoL measures included in SF-36 and EQ-5D compared with placebo. These HRQoL gains were significantly correlated to reduced drinking behavior, as determined by reductions in heavy drinking days and total alcohol consumption. 相似文献95.
Gabriella Juhasz Xenia Gonda Gabor Hullam Nora Eszlari David Kovacs Judit Lazary Dorottya Pap Peter Petschner Rebecca Elliott John Francis William Deakin Ian Muir Anderson Peter Antal Klaus-Peter Lesch Gyorgy Bagdy 《PloS one》2015,10(3)
Background
Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.Methods
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.Results
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.Limitations
Our study is cross-sectional and applies self-report questionnaires.Conclusions
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups. 相似文献96.
Panayotis K. Thanos Mike Michaelides Mike Subrize Mike L. Miller Robert Bellezza Robert N. Cooney Lorenzo Leggio Gene-Jack Wang Ann M. Rogers Nora D. Volkow Andras Hajnal 《PloS one》2015,10(6)
Background
Roux-en-Y gastric bypass (RYGB) surgery is a very effective bariatric procedure to achieve significant and sustained weight loss, yet little is known about the procedure’s impact on the brain. This study examined the effects of RYGB on the brain’s response to the anticipation of highly palatable versus regular food.Methods
High fat diet-induced obese rats underwent RYGB or sham operation and were then tested for conditioned place preference (CPP) for the bacon-paired chamber, relative to the chow-paired chamber. After CPP, animals were placed in either chamber without the food stimulus, and brain-glucose metabolism (BGluM) was measured using positron emission tomography (μPET).Results
Bacon CPP was only observed in RYGB rats that had stable weight loss following surgery. BGluM assessment revealed that RYGB selectively activated regions of the right and midline cerebellum (Lob 8) involved in subjective processes related to reward or expectation. Also, bacon anticipation led to significant activation in the medial parabrachial nuclei (important in gustatory processing) and dorsomedial tegmental area (key to reward, motivation, cognition and addiction) in RYGB rats; and activation in the retrosplenial cortex (default mode network), and the primary visual cortex in control rats.Conclusions
RYGB alters brain activity in areas involved in reward expectation and sensory (taste) processing when anticipating a palatable fatty food. Thus, RYGB may lead to changes in brain activity in regions that process reward and taste-related behaviors. Specific cerebellar regions with altered metabolism following RYGB may help identify novel therapeutic targets for treatment of obesity. 相似文献97.
Marina Fugmann Olaf Uhl Christian Hellmuth Holger Hetterich Nora N. Kammer Uta Ferrari Klaus G. Parhofer Berthold Koletzko Jochen Seissler Andreas Lechner 《PloS one》2015,10(5)
BackgroundNonesterified fatty acids (NEFA) play pathophysiological roles in metabolic syndrome and type 2 diabetes (T2D). In this study, we analyzed the fasting NEFA profiles of normoglycemic individuals at risk for T2D (women with a recent history of gestational diabetes (GDM)) in comparison to controls (women after a normoglycemic pregnancy). We also examined the associations of NEFA species with overweight/obesity, body fat distribution and insulin sensitivity.ResultsWomen after GDM had a lower molar percentage of total saturated fatty acids (SFA; 38.55% vs. 40.32%, p = 0.0002) than controls. At an explorative level of significance several NEFA species were associated with post-GDM status (with and without adjustment for body mass index (BMI) and HbA1c): The molar percentages of 14:0, 16:0, 18:0 and 18:4 were reduced, whereas those of 18:1, 18:2, 20:2, 24:4, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and total n-6 NEFA were increased. BMI and the amount of body fat correlated inversely with several SFA and MUFA and positively with various PUFA species over the whole study cohort (abs(ρ)≥0.3 for all). 14:0 was inversely and BMI-independently associated with abdominal visceral adiposity. We saw no correlations of NEFA species with insulin sensitivity and the total NEFA concentration was similar in the post-GDM and the control group.ConclusionIn conclusion, we found alterations in the fasting NEFA profile associated with a recent history of gestational diabetes, a risk marker for T2D. NEFA composition also varied with overweight/obesity and with body fat distribution, but not with insulin sensitivity. 相似文献
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99.
Timothy Abuya Charlotte E. Warren Nora Miller Rebecca Njuki Charity Ndwiga Alice Maranga Faith Mbehero Anne Njeru Ben Bellows 《PloS one》2015,10(4)
Background
Poor quality of care including fear of disrespect and abuse (D&A) perpetuated by health workers influences women’s decisions to seek maternity care. Key manifestations of D&A include: physical abuse, non-consented care, non-confidential care, non-dignified care, discrimination, abandonment, and detention in facilities. This paper describes manifestations of D&A experienced in Kenya and measures their prevalence.Methods
This paper is based on baseline data collected during a before-and-after study designed to measure the effect of a package of interventions to reduce the prevalence of D&A experienced by women during labor and delivery in thirteen Kenyan health facilities. Data were collected through an exit survey of 641 women discharged from postnatal wards. We present percentages of D&A manifestations and odds ratios of its relationship with demographic characteristics using a multivariate fixed effects logistic regression model.Results
Twenty percent of women reported any form of D&A. Manifestations of D&A includes: non-confidential care (8.5%), non-dignified care (18%), neglect or abandonment (14.3%), Non-consensual care (4.3%) physical abuse (4.2%) and, detainment for non-payment of fees (8.1). Women aged 20-29 years were less likely to experience non-confidential care compared to those under 19; OR: [0.6 95% CI (0.36, 0.90); p=0.017]. Clients with no companion during delivery were less likely to experience inappropriate demands for payment; OR: [0.49 (0.26, 0.95); p=0.037]; while women with higher parities were three times more likely to be detained for lack of payment and five times more likely to be bribed compared to those experiencing there first birth.Conclusion
One out of five women experienced feeling humiliated during labor and delivery. Six categories of D&A during childbirth in Kenya were reported. Understanding the prevalence of D&A is critical in developing interventions at national, health facility and community levels to address the factors and drivers that influence D&A in facilities and to encourage clients’ future facility utilization. 相似文献100.
Alienor Berges Jonathan Bullman Stewart Bates David Krull Nicola Williams Chao Chen 《PloS one》2015,10(2)
Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease with a high unmet medical need. In this context, a potential therapy should be brought to patients in the most expeditious way and early exploration of pharmacology is highly beneficial. Ozanezumab, a humanised IgG monoclonal antibody against Nogo-A protein which is an inhibitor of neurite outgrowth, is currently under development for the treatment of ALS and has been recently assessed in 76 patients in a first-in-human study. Inadequate target engagement has been recognised as a major contributing reason for drug trial failures. In this work, we describe the development of a pharmacokinetic-pharmacodynamic (PKPD) model using immunohistochemistry (IHC) data of co-localization of ozanezumab with Nogo-A in skeletal muscle as a surrogate measure of target engagement. The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non-linear mixed-effect approach. The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle. Diagnostic plots showed a satisfactory fit of both PK and IHC data. The model was used as a simulation tool to design a dose regimen for sustained drug-target co-localization in a phase II study. 相似文献