Deficient and null variants of SERPINA1 are proteotoxic in a Caenorhabditis elegans model of α1-antitrypsin deficiency

α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregationprone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gainoffunction proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence with a heterogeneous and complex pathophysiology that presents barriers to traditional targeted therapeutic approaches. We describe an integrated quantitative systems pharmacology (QSP) platform that comprehensively and unbiasedly defines disease states, in contrast to just individual genes or pathways, that promote NAFLD progression. The QSP platform can be used to predict drugs that normalize these disease states and experimentally test predictions in a human liver acinus microphysiology system (LAMPS) that recapitulates key aspects of NAFLD. Analysis of a 182 patient-derived hepatic RNA-sequencing dataset generated 12 gene signatures mirroring these states. Screening against the LINCS L1000 database led to the identification of drugs predicted to revert these signatures and corresponding disease states. A proof-of-concept study in LAMPS demonstrated mitigation of steatosis, inflammation, and fibrosis, especially with drug combinations. Mechanistically, several structurally diverse drugs were predicted to interact with a subnetwork of nuclear receptors, including pregnane X receptor (PXR; NR1I2), that has evolved to respond to both xenobiotic and endogenous ligands and is intrinsic to NAFLD-associated transcription dysregulation. In conjunction with iPSC-derived cells, this platform has the potential for developing personalized NAFLD therapeutic strategies, informing disease mechanisms, and defining optimal cohorts of patients for clinical trials

Pelvic organ prolapse and collagen-associated disorders

Contains fulltext : 109010.pdf (publisher's version ) (Open Access)INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members. METHODS: In this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members. RESULTS: POP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82). CONCLUSIONS: POP and other collagen-associated disorders may have a common aetiology, originating at the molecular level of the collagens.1 maart 201

Quality of life after pertrochanteric femoral fractures treated with a gamma nail: a single center study of 62 patients

<p>Abstract</p> <p>Background</p> <p>Intramedullary nailing of pertrochanteric femoral fractures has grown in popularity over the past 2 decades likely because this procedure is associated with a low risk for postoperative morbidity and a fast recovery of function. The evaluation of outcomes associated with pertrochanteric nailing has mainly been based on objective measures. The purpose of the present study is to correlate patients’ health-related quality of life results after intramedullary nailing of pertrochanteric fractures with objective outcome measures.</p> <p>Methods</p> <p>We conducted a single-center study including 62 patients (mean age 80 ± 10 years) with pertrochanteric fractures treated with a Gamma 3 Nail. Health related quality of life was measured using the Short Form-36. These results were compared to both US and Austrian age and sex-adjusted population norms. The objective outcome measures studied at one year postoperatively included Harris Hip Score, range of motion, leg length, body mass index, neck-shaft angle and grade of osteoarthritis.</p> <p>Results</p> <p>According to the Harris Hip Score 43 patients (67%) had excellent or good results. There was no significant difference in the average neck-shaft angle comparing affected hip to non-affected hip at 12 months postoperatively. The average osteoarthritis score, for both the injured and uninjured hip, did not differ significantly. We found significant differences between the bodily pain, social functioning and mental health subscales and two summary scores of the Short-Form 36 in comparison to Austrian population norms. Complication rate was 8%.</p> <p>Conclusions</p> <p>The results of this study confirm that intramedullary nailing with the use of a Gamma Nail is a safe treatment option for stable and unstable pertrochanteric fractures. Despite good functional and radiographic results we noticed a substantial fall off in patients’ quality of life up to 12 months after operation.</p

Avulsion of puborectalis muscle and other risk factors for cystocele recurrence: a 2-year follow-up study

Contains fulltext : 110349.pdf (publisher's version ) (Open Access)INTRODUCTION AND HYPOTHESIS: This study aimed to determine the relationship of recurrent cystocele with avulsion of puborectalis muscle and other risk factors. METHODS: In this prospective observational cohort study, 245 women undergoing anterior colporrhaphy were invited for a 2-year follow-up visit consisting of a questionnaire, physical examination, and translabial 3D ultrasonography. Women with and without recurrent cystocele were compared to identify recurrence risk factors. RESULTS: Of the 245 women, 156 agreed to the follow-up visit (63.7%). Objective recurrence rate was 80 of 156 (51.3%). Seventeen of the 156 (10.9%) reported subjective recurrence. Risk factors for anatomical recurrence were complete avulsion of puborectalis muscle (OR, 2.4; 95% CI, 1.3, 4.7), advanced preoperative stage (OR, 2.0; 95% CI, 1.0, 4.1), family history of prolapse (OR, 2.4; 95% CI, 1.2, 4.9), and sacrospinous fixation (OR, 6.5; 95% CI, 2.0, 21.2). CONCLUSIONS: Risk factors for anatomical cystocele recurrence after anterior colporrhaphy were complete avulsion of puborectalis muscle, advanced preoperative stage, family history of prolapse, and sacrospinous fixation

A systematic review of clinical studies on hereditary factors in pelvic organ prolapse.

Contains fulltext : 108103.pdf (publisher's version ) (Open Access)INTRODUCTION AND HYPOTHESIS: There is growing evidence that pelvic organ prolapse (POP) is at least partly caused by underlying hereditary risk factors. The aim of our study was to provide a systematic literature review and meta-analysis of clinical studies on family history of POP as a risk factor for POP in individual women. METHODS: The databases PubMed and Embase were searched. Clinical studies reporting on family history of POP in relation to POP in individual women were included. RESULTS: Sixteen studies were included, of which eight enabled us to calculate a pooled odds ratio (OR). The pooled OR of POP in case of a positive family history of POP was 2.58 (95 % confidence interval 2.12-3.15). CONCLUSIONS: Women with POP are substantially more likely to have family members with the same condition compared to women without POP. This strengthens the hypothesis that genetic predisposition plays an important role in the development of POP