Menopausal hormone therapy and risk of venous thromboembolism: The story so far.

Menopausal hormone therapy (MHT) is known to increase the risk of venous thromboembolism (VTE), which includes deep vein thrombosis, pulmonary embolism, and less frequently cerebral vein thrombosis, but the absolute risk for a given patient is very low. After starting MHT, the risk of VTE seems to be at its highest, declining to the non-HRT user baseline level of risk after stopping. Whether estrogen-only or estrogen-progestin HRT combination is linked to a similar risk of VTE is unclear from the available evidence. The aim of this study is to evaluate the risks of developing VTE in relation to different types as well as different modes of administration of MHT through a database search including PubMed, MEDLINE, Google Scholar, Cochrane Library, and others in order to provide the women carers with the up-to-date and evidence-based guidelines and recommendations while counseling the post-menopausal women enquiring on use of hormonal therapies either to alleviate the menopausal symptoms or to prevent the long-term sequelae of estrogen deficiency.

On sait que l'hormonothérapie ménopausique (MHT) augmente le risque de thromboembolie veineuse (TEV), qui comprend la thrombose veineuse profonde, l'embolie pulmonaire et, moins fréquemment, la thrombose veineuse cérébrale, mais le risque absolu pour un patient donné est très faible. Après le début du MHT, le risque de TEV semble être à son plus haut niveau, diminuant jusqu'au niveau de risque de base des non-utilisatrices de THS après l'arrêt. Les preuves disponibles ne permettent pas de savoir si un THS à base d'œstrogène seul ou d'association œstroprogestative est lié à un risque similaire de TEV. Le but de cette étude est d'évaluer les risques de développer une TEV par rapport à différents types ainsi qu'à différents modes d'administration du MHT grâce à une recherche dans des bases de données comprenant PubMed, MEDLINE, Google Scholar, Cochrane Library et autres afin de fournir aux femmes les soignants avec les lignes directrices et recommandations à jour et fondées sur des preuves tout en conseillant les femmes ménopausées qui se renseignent sur l'utilisation de thérapies hormonales, soit pour soulager les symptômes de la ménopause, soit pour prévenir les séquelles à long terme d'une carence en œstrogènes.

A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway.

Alternative polyadenylation (APA) generates mRNA isoforms and diversifies gene expression. Here we report the discovery that the mTORC1 signaling pathway balances the expression of two Trim9/TRIM9 isoforms through APA regulation in human and mouse. We showed that CFIm components, CPSF6 and NUDT21, promote the short Trim9/TRIM9 isoform (Trim9-S/TRIM9-S) expression. In addition, we identified an evolutionarily conserved twin UGUA motif, UGUAYUGUA, in TRIM9-S polyadenylation site (PAS) that is critical for its regulation by CPSF6. We found additional CPSF6-regulated PASs with similar twin UGUA motifs in human and experimentally validated the twin UGUA motif functionality in BMPR1B, MOB4, and BRD4-L. Importantly, we showed that inserting a twin UGUA motif into a heterologous PAS was sufficient to confer regulation by CPSF6 and mTORC1. Our study reveals an evolutionarily conserved mechanism to regulate gene isoform expression by mTORC1 and implicates possible gene isoform imbalance in cancer and neurological disorders with mTORC1 pathway dysregulation.

Venous thromboembolism and pregnancy: A review of the literature.

This review aims to provide the mother carers with the most recent evidence-based guidelines in the context of managing of pregnancy-associated VTE, where an extensive search through the medical journals addressing the topic including the medical database such as Pubmed, Medline, Sience direct,Embase and others using the title and key-words in order to gather the most concerned as well as the up-to-date publications concerned with the problem under research, the search resulted in recognising pregnancy as a significant risk factor for the development of VTE, both during the prenatal and postnatal periods, with an estimated increased likelihood risk of five and sixty times, respectively and concluded that venous thromboembolism (VTE) is one of the leading causes of maternal mortality hence, all pregnant women should be assessed for the risk of developing the condition as early as possible (when scheduling a booking antenatal appointment) or even in the pre-pregnancy clinic.

Mechanism of the Multistep Catalytic Cycle of 6-Hydroxynicotinate 3-Monooxygenase Revealed by Global Kinetic Analysis.

The class A flavoenzyme 6-hydroxynicotinate 3-monooxygenase (NicC) catalyzes a rare decarboxylative hydroxylation reaction in the degradation of nicotinate by aerobic bacteria. While the structure and critical residues involved in catalysis have been reported, the mechanism of this multistep enzyme has yet to be determined. A kinetic understanding of the NicC mechanism would enable comparison to other phenolic hydroxylases and illuminate its bioengineering potential for remediation of N-heterocyclic aromatic compounds. Toward these goals, transient state kinetic analyses by stopped-flow spectrophotometry were utilized to follow rapid changes in flavoenzyme absorbance spectra during all three stages of NicC catalysis: (1) 6-HNA binding; (2) NADH binding and FAD reduction; and (3) O2 binding with C4a-adduct formation, substrate hydroxylation, and FAD regeneration. Global kinetic simulations by numeric integration were used to supplement analytical fitting of time-resolved data and establish a kinetic mechanism. Results indicate that 6-HNA binding is a two-step process that substantially increases the affinity of NicC for NADH and enables the formation of a charge-transfer-complex intermediate to enhance the rate of flavin reduction. Singular value decomposition of the time-resolved spectra during the reaction of the substrate-bound, reduced enzyme with dioxygen provides evidence for the involvement of C4a-hydroperoxy-flavin and C4a-hydroxy-flavin intermediates in NicC catalysis. Global analysis of the full kinetic mechanism suggests that steady-state catalytic turnover is partially limited by substrate hydroxylation and C4a-hydroxy-flavin dehydration to regenerate the flavoenzyme. Insights gleaned from the kinetic model and determined microscopic rate constants provide a fundamental basis for understanding NicC's substrate specificity and reactivity.

13C and 15N chemical shift assignments of A117V and M129V human Y145Stop prion protein amyloid fibrils.

The C-terminally truncated Y145Stop variant of prion protein (PrP23-144) has been linked to a heritable prionopathy in humans and is also capable of triggering a transmissible prion disease in mice. PrP23-144 can be converted from soluble monomeric form to amyloid under physiological conditions, providing an in vitro model for investigating the molecular basis of amyloid strains and cross-seeding barriers. Here, we use magic-angle spinning solid-state NMR to establish the sequential backbone and sidechain 13C and 15N chemical shift assignments for amyloid fibrils formed by the A117V and M129V mutants of human PrP23-144, which in the context of full length PrP in vivo are among the specific residues associated with development of Gerstmann-Straüssler-Scheinker disease. The chemical shift data are utilized to identify amino acids comprising the rigid amyloid core regions and to predict the protein secondary structures for human PrP23-144 A117V and M129V fibrils.

Quality of life of elderly patients with polypharmacy in the out-patient department of a tertiary hospital

Background@#Quality of Life (QoL) is an indicator of an elderly patient’s health status in achieving optimum care. However, no available local studies focused on QoL in elderly patients with polypharmacy. Better knowledge on this may help healthcare practitioners design and modify interventions that will suit elderly patients’ needs to improve both care and well-being. This study examined the QoL of elderly patients with polypharmacy and evaluated its relationship with demographic and clinical profile.@*Methods@#A descriptive cross-sectional study was done among 333 elderly patients with polypharmacy seen at Region 1 Medical Center-Family and Community Medicine Out-Patient Department (R1MC-FCM OPD) from January to June 2019 using a self-administered EuroQoL-5 Dimension 5-Level (EQ-5D-5L) questionnaire to elicit the domains of QoL. The following statistical tests were utilized: Frequency count and percentage for analyzing gathered data; Spearman’s rank correlation for determining correlation between ordinal and continuous variables; and Mann-Whitney U and Kruskal-Wallis H tests for comparison of mean ranks. All analyses were performed using SPSS version 25. @*Results@#Majority of the respondents were 60-69 years old (59.5%), female (55.3%), married (65.5%), attained at least elementary level education (38%), diagnosed with two illnesses (53%), taking four medications (65.5%) with an average monthly income below Php 10,000.00 (82.6%). Most of the respondents reported “no problems” in all five dimensions of EQ-5D-5L; however, decrease in usual activities (49.8%), pain (49.5%), and mobility (39%) were noted to be the common problems. Lower EQ-5D index and EQ-Visual Analogue Scale (EQ-VAS) scores were observed among respondents aged 80-90 years old, attained at least elementary level education, with three diagnosed illnesses, taking more than four medications, suffering mild cognitive impairment, partially dependent on activities in daily living, and mildly depressed (p <0.05).@*Conclusion@#The quality of life was reduced in the ageing population with low educational attainment, polypharmacy, multimorbidity, functional incapacity, cognitive impairment, and emotional problem.

Infectious diseases pre-transplant evaluation improves vaccination rates for liver transplant candidates.

Immunization rates in pre-liver transplant patients have been historically below rates for immunocompetent patients. At Cleveland Clinic, an infectious diseases (ID) consult is required for all patients during the liver transplant evaluation and may beneficially impact vaccination rates. The goal of this study was to evaluate pre-transplant vaccination rates in pre-liver transplant candidates. This single-center, retrospective chart review included adults transplanted between January 1, 2013, and December 31, 2016. Prior to transplant, rates of vaccination and/or documented seropositivity were 35% for hepatitis B vaccine, 92% for hepatitis A vaccine, 57% for pneumococcal conjugate vaccine, 62% for pneumococcal polysaccharide vaccine, and 77% for influenza vaccine. Vaccination rates were higher than to previously reported. Rates were also higher for several vaccines compared to transplant candidates for other organs without ID consult. With ongoing ID consult requirements for liver transplant candidates, combined with standardization of vaccine recommendations via technology, and increased multi-disciplinary collaboration, vaccination rates should improve further.

Epidemiology of Uveitis in a Tertiary Eye Center in Myanmar.

PURPOSE: To identify the characteristics of uveitis in a tertiary eye center in Myanmar. METHODS: A retrospective study was undertaken to obtain the characteristics of uveitis in a tertiary eye center in Myanmar from September 2013 to September 2014, using a standard clinical protocol and tailored laboratory investigations. RESULTS: A total of 139 patients were included in this epidemiologic study; 71 (51.1%) men and 68 (48.9%) women. The mean age of onset was 36.3 ± 15.5 years. Infectious uveitis constituted 76/139 (54.7%) cases and non-infectious etiologies accounted for 63/139 (45.3%) cases. The most common non-infectious etiologies were idiopathic, followed by HLA-B27-associated anterior uveitis and multifocal choroiditis with panuveitis, while tuberculosis was the most common infectious etiology. CONCLUSIONS: Tuberculosis was the most frequent cause of uveitis among the infectious group of patients in this tertiary eye center as a result of endemic disease in Myanmar.

Vector-induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury.

Rewiring the injured corticospinal tract (CST) by promoting connections between CST axons and spared neurons is a strategy being explored experimentally to achieve improved recovery of motor function after spinal cord injury (SCI). Reliable interventions to promote and direct growth of collaterals from injured CST axons are in high demand to promote functionally relevant detour pathways. A promising tool is neurotrophin-3 (NT-3), which has shown growth-stimulating and chemo-attractive effects for spared CST axons caudal to a CST lesion. Yet, efforts to promote growth of injured CST axons rostral to a SCI with NT-3 have been less successful to date. Evidence indicates that immune activation in the local growth environment, either intrinsic or induced by the endotoxin lipopolysaccharide (LPS), can play a decisive role in the CST's responsiveness to NT-3. Here, we test the potential of NT-3 as a tool to enhance and direct collateral growth from the injured CST rostral to a SCI (1) using long-term expression of NT-3 by adeno-associated viral vectors, (2) with and without stimulating the immune system with LPS. Our results indicate that inducing a growth response from injured CST axons into a region of vector-mediated NT-3 expression is possible in the environment of the spinal cord rostral to a SCI, but seems dependent on the distance between the responding axon and the source of NT-3. Our findings also suggest that injured CST axons do not increase their growth response to NT-3 after immune activation with LPS in this environment. In conclusion, this is to our knowledge the first demonstration that NT-3 can be effective at promoting growth of injured CST collaterals far rostral to a SCI. Making NT-3 available in close proximity to CST target axons may be the key to success when using NT-3 to rewire the injured CST in future investigations.

Comparison of stroke ward care versus mobile stroke teams in the Hungarian stroke database project.

Although previous studies have proved that both stroke wards and mobile stroke teams are considerably better than non-specialized stroke care, an unresolved debate in vascular neurology is whether or not stroke wards provide better outcomes in some specific cases to stroke victims. Our prospective, multicenter, cohort study compared dedicated stroke wards versus specialist stroke team care at general hospital wards in 11 centers nationwide for 8743 consecutive stroke events during 18 months. Twenty-eight-day case-fatality rate was 12.6% at stroke wards versus 15.2% at stroke teams for all patients (P = 0.002), and stroke ward care also predicted better outcome when analyzed with multivariate logistic regression model (odds ratio 1.701; confidence interval: 1.025-2.822). Case-fatality rates were not significantly different in patients with modified Rankin score > or = 2 (case-fatality rate: 17.8% vs. 20.3%; P = 0.163), and over 60 (case-fatality rate: 14.8% vs. 15.9%; P = 0.250), however these patients were more probably at home after 4 weeks when treated at stroke wards (56.1% vs. 50.6%; P = 0.03, and 69.5% vs. 64.5%; P = 0.004). In our study, stroke ward admission provided lower case-fatality rate below 60 and for those independent prior to their strokes, and lower institutionalization over 60 and amongst previously dependent patients, when compared with stroke teams.