Publications by authors named "Asif Ahmed"

114 Publications

Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1.

Sci Rep 2021 Aug 11;11(1):16344. Epub 2021 Aug 11.

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Placenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.
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http://dx.doi.org/10.1038/s41598-021-95511-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357836PMC
August 2021

Medicated multi-targeted alginate-based dressings for potential treatment of mixed bacterial-fungal infections in diabetic foot ulcers.

Int J Pharm 2021 Sep 19;606:120903. Epub 2021 Jul 19.

School of Science, Faculty of Engineering and Science, University of Greenwich, Medway, Central Ave., Chatham Maritime, Kent ME4 4TB, UK. Electronic address:

Recently developed medicated dressings target either bacterial or fungal infection only, which is not effective for the treatment of mixed infections common in diabetic foot ulcers (DFUs). This study aimed to develop advanced bioactive alginate-based dressings (films and wafers) to deliver therapeutically relevant doses of ciprofloxacin (CIP) and fluconazole (FLU) to target mixed bacterial and fungal infections in DFUs. The alginate compatibility with the drugs was confirmed by SEM, XRD, FTIR and texture analysis, while the medicated wafers showed better fluid handling properties than the films in the presence of simulated wound fluid. The dressings showed initial fast release of FLU followed by sustained release of CIP which completely eradicated E. coli, S. aureus, P. aeruginosa and reduced fungal load (C. albicans) by 10-fold within 24 h. Moreover, the medicated dressings were biocompatible (>70% cell viability over 72 h) with human primary adult keratinocytes and in-vitro scratch assay showed 65-68% wound closure within 7 days.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120903DOI Listing
September 2021

The impact of COVID-19 on pregnancy and therapeutic drug development.

Br J Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Division of Drug Development, MirZyme Therapeutics, Birmingham, UK.

Emerging data show that pregnant women with COVID-19 are at significantly higher risk of severe outcomes compared with non-pregnant women of similar age. This review discusses the invaluable insight revealed from vaccine clinical trials in women who were vaccinated and inadvertently became pregnant during the trial period. It further explores a number of clinical avenues in their management and proposes a drug development strategy in line with clinical trials for vaccines and drug treatments for the drug development community. Little is known of the long-term effects of COVID-19 on the mother and the baby. Our hypothesis that COVID-19 predisposes pregnant women to pre-eclampsia or hypertensive disorders during pregnancy is supported by a clinical study, and this may also adversely impact a woman's cardiovascular disease risk later in life. It may also increase a woman's risk of pre-eclampsia in subsequent pregnancy. This is an ever-evolving landscape, and early knowledge for healthcare providers and drug innovators is offered to ensure benefits outweigh the risks. COVID-19 mRNA vaccines appear to generate robust humoral immunity in pregnant and lactating women. This novel approach to vaccination also offers new ways to therapeutically tackle disorders of many unmet medical needs.
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http://dx.doi.org/10.1111/bph.15582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239854PMC
June 2021

Corona Collateral Damage Syndrome: Perception of the Damage.

Authors:
Asif Ahmed

Indian J Crit Care Med 2021 Apr;25(4):358-359

Department of Critical Care Medicine, Tata Main Hospital, Jamshedpur, Jharkhand, India.

Ahmed A. Corona Collateral Damage Syndrome: Perception of the Damage. Indian J Crit Care Med 2021;25(4):358-359.
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http://dx.doi.org/10.5005/jp-journals-10071-23799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138649PMC
April 2021

USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families.

BMC Ophthalmol 2021 Apr 29;21(1):191. Epub 2021 Apr 29.

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, 26000, Khyber Pakhtunkhwa, Pakistan.

Background: Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20-30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants.

Methods: We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families.

Results: Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT.

Conclusions: This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.
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http://dx.doi.org/10.1186/s12886-021-01957-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086330PMC
April 2021

Preparedness and impact of COVID 19 infection at tertiary care neurology centers in Pakistan.

J Neurol Sci 2021 06 17;425:117462. Epub 2021 Apr 17.

Aga Khan University, Karachi, Pakistan. Electronic address:

Objective: We aimed to assess the response and impact of covid 19 pandemic at tertiary care centers in Pakistan especially pertaining to neurological care, facilities and training.

Methods: A pre-tested survey form was sent to 40 neurology tertiary care centers in all the provinces in the country in the first week of July 2020. 33 filled forms were received, out of which 18 were public (government) and 15 were private hospitals.

Results: Estimated 1300 HCW (faculty, medical officers, trainees and nurses) work at these 33 participating centers. There were 17 deaths among HCW (1.3%) at ten centers. Sufficient personal protective equipment (PPE) were provided to 158 HCW (12%). 129 (10%)HCW tested positive for COVID 19 at 31 centers including trainees/medical officers (39), consultants (29) and nursing and other staff (61). Due to low neurology admissions, 23/33 hospitals (70%) posted neurology trainees in COVID 19 units to contribute to covid care. Less than 50% hospitals did covid screening PCR before admission to neurology wards. Only 10% hospitals provide training and regular update to HCW. Neurology tele-health services were started for clinically stable patients at 15 (45%) centers. Only 60% neurology training programs were able to start online training. Ongoing research studies and trials focusing neurological manifestations of COVID-19 were done at 10 (30%) centers. Modification of facilities for COVID patients showed that 24(72%) hospitals strictly reduced the number of attendants accompanying patients. Only 10 (30%) centers had neurophysiological tests being conducted on COVID-19 patients. Mental health support services to HCW were provided at 12 (36%) centers.

Conclusions: Among HCW 10% tested positive for covid and 1.3% died. Mental health support services offered for HCW were available in 36% institutions. Neurology training was substantially affected due to low admissions, limited ward rounds and limited availability of online training.
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http://dx.doi.org/10.1016/j.jns.2021.117462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052505PMC
June 2021

Potential detrimental role of soluble ACE2 in severe COVID-19 comorbid patients.

Rev Med Virol 2021 Jan 10. Epub 2021 Jan 10.

Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumour necrosis factor-α-converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1-7), to balance the renin angiotensin system. Membrane-bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS-CoV-2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non-primed virus-sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II-angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines.
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http://dx.doi.org/10.1002/rmv.2213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014495PMC
January 2021

Dietary intake of artificial food color additives containing food products by school-going children.

Saudi J Biol Sci 2021 Jan 21;28(1):27-34. Epub 2020 Aug 21.

Department Food Science and Nutrition, College of Food and Agriculture Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia.

Nutritional risk in children is associated with food safety. This is the first study to identify the food type consumed by 6-17-year-old school-going children in Saudi Arabia. Eight permitted artificial food color additives, including Tartrazine (E102), Sunset Yellow (E110), Carmoisine (E122), Allura Red (E129), Indigo Carmine (E132), Brilliant Blue (E133), Fast Green (E143), and Black PN (E151), and two non-permitted ones, Erythrosine (E127) and Red 2G (E128), were determined using 24-h dietary recall questionnaires. Artificial color additives in 839 food products were divided into nine categories, including biscuits, cakes, chocolates, chips, ice cream, juices and drinks, candy, jelly, and chewing gum, are determined using high performance liquid chromatography and diode array detector. The results indicated a high intake of juices and drinks, ice cream, and cakes, but low consumption of chewing gum among school-going children. Among the permitted artificial food color additives, Brilliant Blue (E133) (54.1%) and Tartrazine (E102) (42.3%) were the most commonly used. Sunset Yellow (E110) in one chocolate sample, Tartrazine (E102) and Sunset Yellow (E110) in one and two juice and drink samples, respectively, and Brilliant Blue (E133) in two candy samples exceeded the permitted level. Therefore, further investigations are needed to provide insights into the possible adverse health effects of high intake of these additives in artificial food coloring on the test population are warranted.
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http://dx.doi.org/10.1016/j.sjbs.2020.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783677PMC
January 2021

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

Health Technol Assess 2020 12;24(72):1-252

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management.

Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers.

Design: This was an individual participant data meta-analysis of cohort studies.

Setting: Source data from secondary and tertiary care.

Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey.

Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia.

Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using and τ. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals.

Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia.

Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data.

Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings.

Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate.

Study Registration: This study is registered as PROSPERO CRD42015029349.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780127PMC
December 2020

Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model.

Redox Biol 2021 01 28;38:101814. Epub 2020 Nov 28.

Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; King Fahad Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia; President's Office, University of Southampton, University Road, Southampton, UK. Electronic address:

An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (HS) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (HS)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that HS released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial.
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http://dx.doi.org/10.1016/j.redox.2020.101814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744945PMC
January 2021

screening of bioactive phytopeptides for novel anti-ageing therapeutics.

J Biomol Struct Dyn 2020 Dec 15:1-13. Epub 2020 Dec 15.

Biotechnology and Genetic Engineering Discipline, Life Science School, Khulna University, Khulna, Bangladesh.

A metabolic network of energy-sensing molecular pathways drives the biological ageing process. Regulating certain network elements can help decelerate the ageing process and ameliorate ageing associated disorders. Bioactive phytopeptides are a prospective avenue for anti-ageing therapeutics and rejuvenation biotechnology. The present study investigates the potential of therapeutic plant peptides against cellular senescence by targeting three key proteins in the ageing network - target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). This investigation screened a library of reported bioactive peptides using standard cheminformatic methods including ADMET, molecular docking, molecular dynamics simulation and molecular mechanics calculation. The retrieved simulation data predict 25 diverse phytopeptides as potential safe and drug-like anti-ageing biologics with half-lives >20 h and bioavailability scores >0.40. The best docked peptide, Cycloleonuripeptide B, exhibited strong binding affinity and stable complex formation with mTOR (-17.5 kCal/mol), SIRT1 (-28.54 kCal/mol) and two active sites in AMPK (-41.8 kCal/mol; -36.0 kCal/mol) during molecular dynamics simulations. The computational study acts as a foundation for future laboratory and clinical research into the potential of repurposing therapeutic phytopeptides against cellular senescence and associated pathophysiology. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1859411DOI Listing
December 2020

Predicting multi-enzyme inhibition in the arachidonic acid metabolic network by extracts.

J Biomol Struct Dyn 2020 Dec 7:1-14. Epub 2020 Dec 7.

Biotechnology and Genetic Engineering Discipline, Life Science School, Khulna University, Khulna, Bangladesh.

is a mangrove plant with a rich history of ethnomedicinal usage against chronic inflammation. Biochemical analyses of have exposed a plethora of bioactive phytochemicals that contribute to this therapeutic effect by perturbing enzymes of a complex inflammatory network mediated by arachidonic acid (AA) metabolism. This study is the first instance of utilizing cheminformatic approaches to elucidate a molecular linkage between these phytochemical interventions and the multi-enzyme AA metabolic network regulation. Analysis of the simulations reflects as a functional reservoir of multiple safe and potent natural anti-inflammatory compounds. The investigation suggests two phytocompounds extracted from the plant: a sesquiterpene lactone and a flavone glycoside, as candidate inhibitors of multiple catalytic checkpoints of the inflammatory network. The outcomes of this research act as a primary guideline for future laboratory and clinical testing of anti-inflammatory potentials of as an exploitable source of safe and potent drug-like molecules.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1855248DOI Listing
December 2020

Lifestyle Acquired Immunity, Decentralized Intelligent Infrastructures, and Revised Healthcare Expenditures May Limit Pandemic Catastrophe: A Lesson From COVID-19.

Front Public Health 2020 5;8:566114. Epub 2020 Nov 5.

Department of Medical Biotechnology, Bangladesh University of Health Sciences, Dhaka, Bangladesh.

Throughout history, the human race has often faced pandemics with substantial numbers of fatalities. As the COVID-19 pandemic has now affected the whole planet, even countries with moderate to strong healthcare support and expenditure have struggled to contain disease transmission and casualties. Countries affected by COVID-19 have different demographics, socioeconomic, and lifestyle health indicators. In this context, it is important to find out to what extent these parametric variations are modulating disease outcomes. To answer this, this study selected demographic, socioeconomic, and health indicators e.g., population density, percentage of the urban population, median age, health expenditure per capita, obesity, diabetes prevalence, alcohol intake, tobacco use, case fatality of non-communicable diseases (NCDs) as independent variables. Countries were grouped according to these variables and influence on dependent variables e.g., COVID-19 positive tests, case fatality, and case recovery rates were statistically analyzed. The results suggested that countries with variable median age had a significantly different outcome on positive test rate ( < 0.01). Both the median age ( = 0.0397) and health expenditure per capita ( = 0.0041) showed a positive relation with case recovery. An increasing number of tests per 100 K of the population showed a positive and negative relationship with the number of positives per 100 K population ( = 0.0001) and the percentage of positive tests ( < 0.0001), respectively. Alcohol intake per capita in liter ( = 0.0046), diabetes prevalence ( = 0.0389), and NCDs mortalities ( = 0.0477) also showed a statistical relation to the case fatality rate. Further analysis revealed that countries with high healthcare expenditure along with high median age and increased urban population showed more case fatality but also had a better recovery rate. Investment in the health sector alone is insufficient in controlling the severity of the pandemic. Intelligent and sustainable healthcare both in urban and rural settings and healthy lifestyle acquired immunity may reduce disease transmission and comorbidity induced fatalities, respectively.
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http://dx.doi.org/10.3389/fpubh.2020.566114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674625PMC
May 2021

MZe786, a hydrogen sulfide-releasing aspirin prevents preeclampsia in heme oxygenase-1 haplodeficient pregnancy under high soluble flt-1 environment.

Redox Biol 2021 01 24;38:101768. Epub 2020 Oct 24.

Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham, B7 4BB, United Kingdom; Aston Medical Research Institute, Aston Medical School, Birmingham, United Kingdom; Department of Biochemistry, ESC Research Unit, Faculty of Science, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; President's Office, University of Southampton, University Road, Southampton, SO17 1BJ, UK. Electronic address:

Preeclampsia affects one in twelve of the 130 million pregnancies a year. The lack of an effective therapeutic to prevent or treat it is responsible for an annual global cost burden of 100 billion US dollars. Preeclampsia also affects these women later in life as it is a recognised risk factor for cardiovascular disease, stroke and vascular dementia. Our laboratory demonstrated that preeclampsia is associated with high soluble fms-like tyrosine kinase 1 (sFlt-1) and low heme oxygenase-1 (HO1/Hmox1) expression. Here we sought to determine the therapeutic value of a novel HS-releasing aspirin (MZe786) in HO-1 haploid deficient (Hmox1) pregnant mice in a high sFlt-1 environment. Pregnant Hmox1 mice were injected with adenovirus encoding sFlt-1 or control virus at gestation day E11.5. Subsequently, Hmox1 dams were treated daily with a number of treatment regimens until E17.5, when maternal and fetal outcomes were assessed. Here we show that HO-1 compromised mice in a high sFlt-1 environment during pregnancy exhibit severe preeclampsia signs and a reduction in antioxidant genes. MZe786 ameliorates preeclampsia by reducing hypertension and renal damage possibly by stimulating antioxidant genes. MZe786 also improved fetal outcome in comparison with aspirin alone and appears to be a better therapeutic agent at preventing preeclampsia than aspirin alone.
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http://dx.doi.org/10.1016/j.redox.2020.101768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610044PMC
January 2021

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BMC Med 2020 11 2;18(1):302. Epub 2020 Nov 2.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting.

Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis.

Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%.

Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice.

Trial Registration: PROSPERO ID: CRD42015029349 .
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http://dx.doi.org/10.1186/s12916-020-01766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604970PMC
November 2020

Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells.

Sci Rep 2020 09 25;10(1):15810. Epub 2020 Sep 25.

Aston Medical Research Institute, Aston Medical School, Birmingham, UK.

Endothelial dysfunction is a hallmark of preeclampsia, a life-threatening complication of pregnancy characterised by hypertension and elevated soluble Fms-Like Tyrosine Kinase-1 (sFlt-1). Dysregulation of hydrogen sulfide (HS) by inhibition of cystathionine γ-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE/HS pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE/HS pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted HS donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial HS metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting HS to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.
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http://dx.doi.org/10.1038/s41598-020-72371-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519095PMC
September 2020

Spiritual Health Among Pakistani Religious and Non-Religious Professional: A Comparative Cross-Sectional Study Highlighting the Role of Regional Beliefs and Practices.

Adv Mind Body Med 2020 Summer;34(3):18-24

Background: Spiritual health forms the core of health and is associated with better physical and mental health. Spiritual health and wellbeing has been shown to be significantly associated with better mental outcomes, yet there's lack of understanding of the determinants of spiritual health. Religious practices have been shown to improve health and have been assumed to be associated with spirituality, yet there remains a gap between religious practices and spiritual health. It is therefore, crucial to understand the role of religious beliefs and practices in improving spiritual health.

Purpose: To assess spiritual wellbeing between religious and non-religious professionals and assess how regional religious beliefs and practices are associated with spiritual wellbeing.

Methods: We examined spiritual health among religious and non-religious professionals. A comparative cross sectional study was done with a sample size of 210. Differences of spiritual health and spiritual experiences, perceived spiritual traits and psychological parameters were observed.

Results: Religious professionals were found to be more spiritually healthy than non-religious professionals (P < .05). Spiritual experiences weakly contribute to spiritual health (r = 0.39, P < .05). Perceived spiritual traits including frequency of prayer (β = 5.25, CI = 1.80-8.70, P < .01) and belief in the presence of Supreme Being (β = 1.001, CI = 0.120-1.883, P < .05) influenced spiritual wellbeing and spiritual wellbeing showed a negative association with psychological parameters including anger (OR = 0.95, CI = 0.929-0.987, P < .05).

Conclusion And Implications: The findings from this study show that religious professionals tend to be more spiritually healthy than non-religious professionals highlighting the importance of incorporating religious practices to ensure spiritual wellbeing. Improving spiritual wellbeing can provide an important tool for promoting holistic healing.
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October 2020

MZe786 Rescues Cardiac Mitochondrial Activity in High sFlt-1 and Low HO-1 Environment.

Antioxidants (Basel) 2020 Jul 9;9(7). Epub 2020 Jul 9.

Aston Medical Research Institute, Aston Medical School, Birmingham B4 7ET, UK.

Hypertensive disorder in pregnancy is a major cause of maternal and perinatal mortality worldwide. Women who have had preeclampsia are at three to four times higher risk in later life of developing high blood pressure and heart disease. Soluble Flt-1 (sFlt-1) is elevated in preeclampsia and may remain high postpartum in women with a history of preeclampsia. Heme oxygenase-1 (Hmox1/HO-1) exerts protective effects against oxidative stimuli and is compromised in the placenta of pregnant women with preeclampsia. We hypothesized that sFlt-1 inhibits cardiac mitochondrial activity in HO-1 deficient mice. HO-1 haplo-insufficient mice (Hmox1) were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) or control virus (Ad-CMV). Subsequently, they were treated daily with either placebo or MZe786 for six days, when the heart tissue was harvested to assess cardiac mitochondrial activity. Here, we show that the loss of HO-1 disturbed cardiac mitochondrial respiration and reduced mitochondrial biogenesis. The overexpression of sFlt-1 resulted in the inhibition of the cardiac mitochondrial activity in Hmox1 mice. The present study demonstrates that the hydrogen sulfide (HS) releasing molecule, MZe786, rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defense in Hmox1 mice and in Hmox1 mice exposed to a high sFlt-1 environment.
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http://dx.doi.org/10.3390/antiox9070598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402164PMC
July 2020

Ethnobotany and Antimicrobial Peptides From Plants of the Solanaceae Family: An Update and Future Prospects.

Front Pharmacol 2020 7;11:565. Epub 2020 May 7.

Pharmacy Discipline, Life Science School, Khulna University, Khulna, Bangladesh.

The Solanaceae is an important plant family that has been playing an essential role in traditional medicine and human nutrition. Members of the Solanaceae are rich in bioactive metabolites and have been used by different tribes around the world for ages. Antimicrobial peptides (AMPs) from plants have drawn great interest in recent years and raised new hope for developing new antimicrobial agents for meeting the challenges of antibiotic resistance. This review aims to summarize the reported AMPs from plants of the Solanaceae with possible molecular mechanisms of action as well as to correlate their traditional uses with reported antimicrobial actions of the peptides. A systematic literature study was conducted using different databases until August 2019 based on the inclusion and exclusion criteria. According to literature, a variety of AMPs including defensins, protease inhibitor, lectins, thionin-like peptides, vicilin-like peptides, and snaking were isolated from plants of the Solanaceae and were involved in their defense mechanism. These peptides exhibited significant antibacterial, antifungal and antiviral activity against organisms for both plant and human host. , , , , and are the most commonly studied genera for AMPs. Among these genera, and the ranked top according to the total number of studies (35%-38% studies) for different AMPs. The mechanisms of action of the reported AMPs from Solanaceae was not any new rather similar to other reported AMPs including alteration of membrane potential and permeability, membrane pore formation, and cell aggregation. Whereas, induction of cell membrane permiabilization, inhibition of germination and alteration of hyphal growth were reported as mechanisms of antifungal activity. Plants of the Solanaceae have been used traditionally as antimicrobial, insecticidal, and antiinfectious agents, and as poisons. The reported AMPs from the Solanaceae are the products of chemical shields to protect plants from microorganisms and pests which unfold an obvious link with their traditional medicinal use. In summary, it is evident that AMPs from this family possess considerable antimicrobial activity against a wide range of bacterial and fungal pathogens and can be regarded as a potential source for lead molecules to develop new antimicrobial agents.
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http://dx.doi.org/10.3389/fphar.2020.00565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232569PMC
May 2020

Spectrum of neurological disorders in neurology outpatients clinics in urban and rural Sindh, Pakistan: a cross sectional study.

BMC Neurol 2019 Aug 13;19(1):192. Epub 2019 Aug 13.

Department of Medicine and Neurology, Aga Khan University, Karachi, Pakistan.

Background: Neurological disorders are the most common cause of morbidity and mortality in developing countries. Available evidence on urban-rural differences on neurological diseases is scare in such countries. Our study objective was to determine the prevalence of neurological diseases in urban and rural tertiary care hospitals of Sindh, Pakistan.

Methods: This was a cross sectional study conducted in selected urban and rural region of tertiary care hospitals of Sindh, Pakistan. The outpatients medical records of adults (18 years and above) was obtained from January 1st, 2014 to December 31st, 2014.

Results: A total of 10,786 outpatients visit were recorded in this period. Mean age of the participants was 40.6 ± 15 years; majority was females 6104 (56.6%). About three-fourth of the patients were from rural hospital 7828 (72.6%). Common neurological diseases were headache disorders 3613 (33.4%), nerve and root lesion 2928 (27.1%), vascular diseases 1440 (13.3%), epilepsies 566 (5.2%), muscle disorders 424 (3.9%), psychiatric disorders 340 (3.1%) and CNS infection 303 (2.8%). Comparison between the urban and rural samples showed that ischaemic stroke (72.7% vs. 82%) and psychiatric disorders (2.1% vs. 3.5%) were more prevalent in rural area as compared to urban setting.

Conclusion: Stroke, headache and nerve and root lesion are major causes of neurological disorders in urban and rural settings of Sindh, Pakistan. The policy and planning must be focus on primary care, preventive measures and the promotion of health.
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http://dx.doi.org/10.1186/s12883-019-1424-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691523PMC
August 2019

Establishment of porcine and human expanded potential stem cells.

Nat Cell Biol 2019 06 3;21(6):687-699. Epub 2019 Jun 3.

Key Laboratory of Regenerative Biology of Chinese Academy of Sciences, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.
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http://dx.doi.org/10.1038/s41556-019-0333-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035105PMC
June 2019

Clofazimine-induced methemoglobinemia: A rare incidence.

J Family Med Prim Care 2018 Nov-Dec;7(6):1573-1575

Department of Medicine, Tata Main Hospital, Jamshedpur, Jharkhand, India.

Clofazimine is commonly used for the treatment of leprosy and chronic use of it can lead to methemoglobinemia, which is a rare but major concern. Iron of hemoglobin remains in the form of ferric (Fe3+) in methemoglobinemia as compared with ferrous form (Fe2+) in normal situation. This transformation prevents oxygen carriage and results in higher level of MetHb in blood which could be dangerous to life. In normal patients the level of MetHb is <1%. We report a case where acute ingestion of many tablets of clofazimine resulted in methemoglobinemia. Cyanosis was not apparent in this case leading to delayed diagnosis, and despite >30% MetHb levels, the clinical presentation was not very suggestive. Because of the nonavailability of intravenous methylene blue and parenteral ascorbic acid, tablet ascorbic acid was used for the management. Gradual decrease of MetHb levels was observed, with amelioration of symptoms and improvement in patient's condition. Review of the literature failed to reveal publication of acute methemoglobinemia with such presentation in the past. Awareness about possibility of methemoglobinemia and its possible contributors will help primary care physician and emergency physician suspect this condition early in patients presenting with history of unknown drug overdose and work in proper direction.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_296_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293906PMC
January 2019

Survival after cardiac resynchronization therapy: results from 50 084 implantations.

Europace 2019 May;21(5):754-762

Queen Elizabeth Hospital, Birmingham, UK.

Aims: Randomized controlled trials have shown that cardiac resynchronization therapy (CRT) prolongs survival in patients with heart failure. No studies have explored survival after CRT in relation to individuals in the general population (relative survival, RS). We sought to determine observed and RS after CRT in a nationwide cohort undergoing CRT.

Methods And Results: A national administrative database was used to quantify observed mortality for patients undergoing CRT. Relative survival (RS) was quantified using life tables. In 50 084 patients [age 72.1 ± 11.6 years (mean ± standard deviation)] undergoing CRT with (CRT-D) (n = 25 273) or without (CRT-P) defibrillation (n = 24 811) over 8.8 years (median follow-up 2.7 years, interquartile range 1.3-4.8), expected survival decreased with age. Device type, male sex, ischaemic heart disease, diabetes, and chronic kidney disease predicted excess mortality. In multivariate analyses, excess mortality (analogue of RS) was lower after CRT-D than after CRT-P in all patients [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.76-0.84] as well as in subgroups with (aHR 0.79, 95% CI 0.74-0.84) or without (aHR 0.82, 95% CI 0.74-0.91) ischaemic heart disease. A Charlson Comorbidity Index (CCI) ≥3 portended a higher excess mortality (aHR 3.04, 95% CI 2.76-3.34). Relative survival was higher in 2015-2017 than in 2009-2011 (aHR 0.64, 95% CI 0.59-0.69).

Conclusion: Reference RS data after CRT is presented. Sex, ischaemic heart disease, diabetes, chronic kidney disease, and CCI were major determinants of RS after CRT. CRT-D was associated with a higher RS than CRT-P in patients with or without ischaemic heart disease. Relative survival after CRT improved from 2009 to 2017.
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http://dx.doi.org/10.1093/europace/euy267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479423PMC
May 2019

The size dependant behaviour of particles driven by a travelling surface acoustic wave (TSAW).

Lab Chip 2018 12;18(24):3926-3938

Laboratory for Micro Systems, Department of Mechanical and Aerospace Engineering, Monash University, Clayton, Victoria 3800, Australia.

The use of travelling surface acoustic waves (TSAW) in a microfluidic system provides a powerful tool for the manipulation of particles and cells. In a TSAW driven system, acoustophoretic effects can cause suspended micro-objects to display three distinct responses: (1) swirling, driven by acoustic streaming forces, (2) migration, driven by acoustic radiation forces and (3) patterning in a spatially periodic manner, resulting from diffraction effects. Whilst the first two phenomena have been widely discussed in the literature, the periodic patterning induced by TSAW has only recently been reported and is yet to be fully elucidated. In particular, more in-depth understanding of the size-dependant nature of this effect and the factors involved are required. Herein, we present an experimental and numerical study of the transition in acoustophoretic behaviour of particles influenced by relative dominance of these three mechanisms and characterise it based on particle diameter, channel height, frequency and intensity of the TSAW driven microfluidic system. This study will enable better understanding of the performance of TSAW sorters and allow the development of TSAW systems for particle collection and patterning.
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http://dx.doi.org/10.1039/c8lc01155aDOI Listing
December 2018

Towards the effective E-waste management in Bangladesh: a review.

Environ Sci Pollut Res Int 2019 Jan 19;26(2):1250-1276. Epub 2018 Nov 19.

Department of Mechanical Engineering, Rajshahi University of Engineering & Technology, Rajshahi, 6204, Bangladesh.

Nowadays, the electrical and electronic products are a crucial commodity for different purposes of daily life and they are multiplying five times faster than human like mobile phones, which has reached zero to 7.2 billion in only three decades. A 5-10% yearly increase in the amount of used electrical and electronic equipment that are disposed of prudently can cause environmental hazards that have an aversive effect on human health, marine life, contamination of groundwater, and reduces soil's fertility. Management of this enormous influx of electrical and electronic waste is a challenge for developing countries like Bangladesh with barebones solid waste management infrastructure. Inadequacy of public awareness, policies and poor budget in the field of waste management are few of the key factors behind this delineating scenario. In this study, the picture electrical and electronic waste productions in Bangladesh along with the recent E-waste management systems have been presented comprehensively. Based on the study, it was concluded that most of the adapted E-waste management methods are conversational and detached from current technological capability. A set of sustainable E-waste management system has been suggested along with the challenges, which might appear during the implementation of these strategies. Successful implementation of these suggested systems would advance the quality of E-waste management in Bangladesh increasing the current 35% overall E-waste recycling rate and offer enormous energy from the waste.
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http://dx.doi.org/10.1007/s11356-018-3626-2DOI Listing
January 2019

Hormone Replacement Therapy: Would it be Possible to Replicate a Functional Ovary?

Int J Mol Sci 2018 Oct 14;19(10). Epub 2018 Oct 14.

Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK.

Background: Throughout history, menopause has been regarded as a transition in a woman's life. With the increase in life expectancy, women now spend more than a third of their lives in menopause. During these years, women may experience intolerable symptoms both physically and mentally, leading them to seek clinical advice. It is imperative for healthcare providers to improve the quality of life by reducing bothersome menopausal symptoms and preventing disorders such as osteoporosis and atherosclerosis. The current treatment in the form of hormone replacement therapy (HRT) is sometimes inadequate with several limitations and adverse effects. Objective and rationale: The current review aims to discuss the need, efficacy, and limitations of current HRT; the role of other ovarian hormones, and where we stand in comparison with ovary-in situ; and finally, explore towards the preparation of an HRT model by regeneration of ovaries tissues through stem cells which can replicate a functional ovary.

Search Methods: Four electronic databases (MEDLINE, Embase, Web of Science and CINAHL) were searched from database inception until 26 April 2018, using a combination of relevant controlled vocabulary terms and free-text terms related to 'menopause', 'hormone replacement therapy', 'ovary regeneration', 'stem cells' and 'ovarian transplantation'.

Outcomes: We present a synthesis of the existing data on the efficacy and limitations of HRT. HRT is far from adequate in postmenopausal women with symptoms of hormone deprivation as it fails to deliver all hormones secreted by naïve ovarian tissue. Moreover, the pharmacokinetics of synthetic hormones makes them substantially different from natural ones. Not only does the number and type of hormones given in HRT matter, but the route of delivering and their release in circulation are also imperative. The hormones are delivered either orally or topically in a non-physiological uniform manner, which brings along with it several side effects. These identify the need for a hormone delivery system which replicates, integrates and reacts as per the requirement of the female body. Wider implications: The review outlines the strengths and weaknesses of HRT and highlights the potential areas for future research. There is a tremendous potential for research in this field to understand the collective roles of the various ovarian hormones and to devise an auto-regulated hormone delivery system which replicates the normal physiology. Its clinical applications can prove to be transformative for postmenopausal women helping them to lead a healthy and productive life.
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http://dx.doi.org/10.3390/ijms19103160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214095PMC
October 2018

Differential phase-shift-keying demodulation by coherent perfect absorption in silicon photonics.

Opt Lett 2018 Aug;43(16):4061-4064

We demonstrate a novel differential phase-shift-keying (DPSK) demodulator based on coherent perfect absorption (CPA). Our DPSK demodulator chip device, which incorporates a silicon ring resonator, two bus waveguide inputs, and monolithically integrated detectors, operates passively at a bit rate of 10 Gbps at telecommunication wavelengths, and fits within a mm-scale footprint. Critical coupling is used to achieve efficient CPA by tuning the gap between the ring and bus waveguides. The device has a vertical eye opening of 12.47 mV and a quality factor exceeding 3×10. The fundamental principle behind this photonic circuit can be extended to other formats of integrated demodulators.
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http://dx.doi.org/10.1364/OL.43.004061DOI Listing
August 2018

Soluble Fms-Like Tyrosine Kinase-1 Alters Cellular Metabolism and Mitochondrial Bioenergetics in Preeclampsia.

Front Physiol 2018 6;9:83. Epub 2018 Mar 6.

Traslational Biomedical Research Group, Fundación Cardiovascular de Colombia, Santander, Colombia.

Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.
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http://dx.doi.org/10.3389/fphys.2018.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845757PMC
March 2018

Calcium alginate-based antimicrobial film dressings for potential healing of infected foot ulcers.

Ther Deliv 2018 02;9(3):185-204

Department of Pharmaceutical, Chemical & Environmental Sciences, Faculty of Engineering & Science, University of Greenwich, Medway, Central Ave Chatham Maritime, Kent, ME4 4TB, UK.

Aim: Diabetic foot ulcers are susceptible to infection and nonmedicated dressings are ineffective because they have no antimicrobial activity. This study aimed to develop antimicrobial films to deliver ciprofloxacin for treating bacterial infection. Results/methodology: Ciprofloxacin-loaded calcium alginate films were characterized for porosity, swelling, equilibrium water content, water absorption, water vapor transmission, evaporative water loss, moisture content, mechanical strength, adhesion, IR spectroscopy, scanning electron microscopy, x-ray diffraction, drug release, cytotoxicity and antimicrobial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Films were transparent, flexible, uniform, with ideal moisture handling, maximum drug release within 90 min, killing bacteria within 24 h and highly biocompatible with human keratinocyte cells.

Conclusion: The results confirmed successful design of biocompatible dressings effective against Gram-positive and Gram-negative bacteria. [Formula: see text].
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http://dx.doi.org/10.4155/tde-2017-0104DOI Listing
February 2018
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