264 research outputs found
Assessment of the impact of race and proxies of socioeconomic status on the prevalence and health outcome of peripartum cardiomyopathy (PPCM) using the âAll of Usâ Databank
Background: Peripartum Cardiomyopathy (PPCM) is a form of cardiomyopathy occurring during the last month of pregnancy or within months after giving birth in women with previously normal hearts. PPCM is an idiopathic systolic dysfunction that causes a reduced left ventricle ejection fraction. The estimated incidence of PPCM worldwide is 1 diagnosis out of 2,000 live births, and the causes of PPCM remain unknown. A retrospective cohort study conducted at the University of Pennsylvania Health System by Getz et al. showed that black race and socioeconomic proxies (like neighborhood disadvantage index (NDI)) were independently associated with sustained cardiac dysfunction (Getz et al., Am Heart J 2021). This study also showed that from all the components of NDI (education, high rental occupied housing, annual income below poverty line, female headed household, adults unemployed, adults on public assistance), low education and high rental occupied housing were significantly associated with sustained cardiac dysfunction. The central aim of the present project is to assess the effect of socioeconomic proxies (including NDI, lack of access to health care and food insecurity) on the prevalence of sustained cardiac dysfunction from PPCM across the US using the âAll of Usâ databank. A secondary aim is to test the compliance of the All of Us database capacity to interrogate this potential association. Lastly, we aim to compare the results obtained from the All of Us database with the UK Biobank.
Methods: The All of Us databank (Ramirez et al., Patterns 2022; The All of US Research Program, NEJM 2019) will be used to conduct a retrospective cohort study to assess how proxies of socioeconomic status may affect the incidence and prevalence of sustained cardiac dysfunction from PPCM across different ethnicities in the US. The All of Us database focuses on enrolling people in the US from diverse groups that have historically been underrepresented in medical research. Therefore, it includes a more diverse population than the population targeted in the retrospective study conducted at the University of Pennsylvania in which only black women from Philadelphia, PA, were included. To further interrogate the impact that geographic location and population ethnicity may have on the prevalence of sustained cardiac dysfunction from PPCM, the results obtained from the âAll of Usâ database will be compared against data obtained from the UK Biobank.
Expected Results: We expect that the socioeconomic proxies interrogated in this study will have a significant impact on the prevalence of sustained cardiac dysfunction from PPCM. Current knowledge is limited on how socioeconomic status affects sustained cardiac dysfunction resulting from PPCM. Previous studies have been done on populations restricted to small geographic areas and did not analyze factors such as food security, access to care, or disability status. Understanding how these factors affect the incidence and prevalence of sustained cardiac dysfunction from PPCM may be used to improve prevention, early diagnosis, and management of PPCM
Coupled plasma filtration adsorption (CPFA) plus continuous veno-venous haemofiltration (CVVH) versus CVVH alone as an adjunctive therapy in the treatment of sepsis
To compare the efficacy of Coupled
Plasma Filtration and Adsorption (CPFA) plus
Continuous Veno-Venous Haemofiltration (CVVH) versus CVVH alone as an adjunct treatment of sepsis in terms of haemodynamic stability, inotropic requirement and inflammatory mediators. Design and Methods: Prospective randomized controlled trial involving septic patients with/without acute kidney injury (AKI) whom were randomized to receive CPFA + CVVH or CVVH alone. Haemodynamic parameters including inotropic requirements and inflammatory mediators [procalcitonin (PCT) and C reactive protein (CRP)] were measured. Results: Twenty-three patients [CPFA + CVVH (n = 11), CVVH (n = 12)] were enrolled. Haemodynamic stability occurred earlier and sustained in the CPFA + CVVH group with an increase in diastolic blood pressure (p = 0.001 vs. p = 0.226) and mean arterial pressure (p = 0.001 vs. p = 0.575) at the end of treatment with no increment in inotropic requirement.
Both groups had a reduction in PCT and CRP (CPFA + CVVH: p = 0.003, p = 0.026 and CVVH: p = 0.008, p = 0.071 respectively). The length of intensive care unit stay, hospital stay and 30 day outcomes were similar between the groups. There was an inverse association between serum albumin and CRP (p = 0.018). Serum albumin positively correlated with systolic blood pressure (p = 0.012) and diastolic blood pressure (p = 0.009). We found a trend between CRP and length of hospital stay (p = 0.056). Patients with a lower PCT at 24 h had a
better outcome (survival) than those with a higher PCT (p = 0.045). Conclusion: CPFA is a feasible, albeit expensive adjunctive extracorporeal treatment that may be superior to CVVH alone in the treatment of severe sepsis
Progressive ataxia with oculo-palatal tremor and optic atrophy
The final publication is available at Springer via doi: 10.â1007/âs00415-013-7136-
Corrigendum to Assessment of the Global Potential for Renewable Energy Storage Systems on Small Islands EGYPRO 46C (2014) 294â 300
The authors regret that the printed version of the above article contained a number of errors. The correct and final version follows. The authors would like to apologise for any inconvenience caused
Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis.
In June 1999, the Association of British Neurologists (ABN) first published guidelines for the use of the licensed multiple sclerosis (MS) disease-modifying treatments (at that time β-interferon and glatiramer acetate). The guidelines were revised in 2001 and have been periodically updated since then. In 2002, following the negative assessment of these treatments by the National Institute for Health and Care Excellence (NICE), the MS risk-sharing scheme started, in which patients eligible according to the 2001 ABN guidelines were provided with treatment funded through the UK National Health Service (NHS), and monitored annually for up to 10â
years.1 Recruitment to the risk-sharing scheme cohort is complete. Pending a future final evaluation, the UK Department of Health's instruction to NHS funders remains in place: that patients who fulfil the ABN criteria should continue to receive treatment funded through the NHS. The British neurological community has fully accepted the risk-sharing scheme for prescribing β-interferon and glatiramer acetate. Approximately 70 âtreating centresâ have recruited >5000 patients between 2002 and 2005, and these have been monitored annually for 10â
years; many more patients have received these treatments since 2005. The ABN published revised guidelines in 2007, and then again in 2009, following the licensing of natalizumab and mitoxantrone. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab): we suggest they are reviewed after an interval of no longer than 12â
months. The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS; we refer prescribing neurologists to the relevant summaries of product characteristics.PostprintPeer reviewe
Physical activity monitoring to assess disability progression in multiple sclerosis
Background: Clinical outcome measurement in multiple sclerosis (MS) usually requires a physical visit. Remote activity monitoring (RAM) using wearable technology provides a rational alternative, especially desirable when distance is involved or in a pandemic setting. Objective: To validate RAM in progressive MS using (1) traditional psychometric methods (2) brain atrophy. Methods: 56 people with progressive MS participated in a longitudinal study over 2.5 years. An arm-worn RAM device measured activity over six days, every six months, and incorporated triaxial accelerometry and transcutaneous physiological variable measurement. Five RAM variables were assessed: physical activity duration, step count, active energy expenditure, metabolic equivalents and a composite RAM score incorporating all four variables. Other assessments every six months included EDSS, MSFC, MSIS-29, Chalder Fatigue Scale and Beckâs Depression Inventory. Annualized brain atrophy was measured using SIENA. Results: RAM was tolerated well by people with MS; the device was worn 99.4% of the time. RAM had good convergent and divergent validity and was responsive, especially with respect to step count. Measurement of physical activity over one day was as responsive as six days. The composite RAM score positively correlated with brain volume loss. Conclusion: Remote activity monitoring is a valid and acceptable outcome measure in MS
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GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump.
The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. We report that the G protein-coupled receptor GPR35 interacted with the ι chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner. Deletion of Gpr35 increased baseline Ca2+ to maximal levels and reduced Src activation and overall metabolic activity in macrophages and intestinal epithelial cells (IECs). In contrast, a common T108M polymorphism in GPR35 was hypermorphic and had the opposite effects to Gpr35 deletion on Src activation and metabolic activity. The T108M polymorphism is associated with ulcerative colitis and primary sclerosing cholangitis, inflammatory diseases with a high cancer risk. GPR35 promoted homeostatic IEC turnover, whereas Gpr35 deletion or inhibition by a selective pepducin prevented inflammation-associated and spontaneous intestinal tumorigenesis in mice. Thus, GPR35 acts as a central signaling and metabolic pacesetter, which reveals an unexpected role of Na/K-ATPase in macrophage and IEC biology.European Research Council Consolidator Grant n° 648889 to A.K.
Scientia Fellowship (FP7-PEOPLE-2013-COFUND) grant agreement n° 609020 to G.S.
Addenbrookeâs Charitable Trust (ACT 25/16A) to J.E.E.
UniNA and Compagnia Di San Paolo âSTAR program for young researchersâ fellowship to E.P
Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimerâs disease
Background: Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimerâs disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations. Methods: Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs. Results: ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Îβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq. Conclusions: Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimerâs disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing
FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle
Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohnâs disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC
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