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Schematic illustration of AgNPs synthesis, foliar application on lettuce with morpho-anatomical characterizations.

The spread of the gameable personal computers and game consoles resulted in the diversification of the video game genre, and from the 7th generation of the gaming consoles, the experience support of the games became largely enhanced. These games are now consumable owing to their resolution, the content, the plots are so fascinating so that they tie the gamer to the seat. Gamers seek experiences in the games. Still, such a special genre called roguelike was established, which is characterized by the constant termination of this world of experience in such a way that the gamer, as a results of the high level of difficulty, is obliged to start the game again and again. These new genre games are now leading titles of the new generation consoles, such as Demon’s Souls or the Returnal, gaining huge role in the introduction and sale of the new gaming console PS5. This study aims to reveal specifications of this genre, moreover, aims to describe through empirical research how gamers relate to it, and whether features of these games contribute to the devotion to them or lead to the disappointment from this world of experience. more...

Herein, we report a simple and ecofriendly synthesis of ZnO nanoparticles (ZnO NPs) employing Digera muricata along with bioassay studies of synthesized NPs. The ZnO NPs obtained were indicated by a colour change from yellow to almost faint yellow giving whitish tinge and supported by the appearance of UV-Vis band at 373 nm and were characterized by using Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray (EDX), and scanning electron microscopy (SEM). The FT-IR spectrum confirmed the presence of biomolecules fabricated on ZnO NPs as indicated by the absorption bands at 1,378 for C–O cm−1, and ZnO NPs were also evident from the absorption bands at 440 and 670 cm−1, the former being the result of symmetric vibration of hexagonal ZnO and the latter belonged to a very weak vibration of ZnO. Its surface morphology was confirmed by SEM, and the zinc and oxygen bonds were confirmed by EDX analysis giving sharp signals for Zn and oxygen with At% of 17.58 and 30.49, respectively. The antimicrobial activity of ZnO nanoparticles was determined by the agar well diffusion method against pathogenic bacterial and fungal strains using imipenem and miconazole as standards. The results reflected that ZnO NPs enhanced the activity of plant extracts against all employed algal (E. coli, S. faecalis, P. aeruginosa, K. pneumonia, S. aureus, and B. subtilis) and fungal (T. mentogrophytes, E. floccosum, A. niger, M. canis, and F. culmorum) strains. The antibacterial and antifungal activities of extracts were enhanced by the formation of ZnO NPs. The results indicated that Digera muricata extract contains effective reducing agents for green synthesis of Digera muricata fabricated ZnO NPs, which are more potent antimicrobial than the plant extract and showed almost similar inhibition against lipoxygenase, i.e., the IC50 value of 83.82 ± 1.15, comparable to the standard. more...

Herein, a facile one step synthesis of Ni–Cu supported on TiO2 alloy nanoparticles through the polyol method, which reflect high catalytic performance in enzymeless electrochemical glucose sensing and applied onto glassy carbon, is reported. The morphology imaging and physical properties of the Ni–Cu/TiO2 nanocomposite were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis, and energy dispersive X-ray spectroscopy (EDS). The electrochemical studies/characterizations of glucose oxidation were realised in a basic medium and the new sensor was found to be a better electrochemical glucose sensor than Ni/TiO2/Ti and CuO/TiO2/Ti modified electrodes. The fabricated sensor was highly sensitive (719.9 μA mM-1 cm-2), had a wide linear range (from 0.1 to 6 mM), selective and tolerant towards endogenous species, such as ascorbic acid, uric acid, acetaminophen and sodium chloride. more...

The energy dependence on the intrinsic efficiency, absolute efficiency, full energy peak absolute efficiency and peak-to-total ratio have been studied for various wide band gap semiconductor detectors using the Geant4 based Monte Carlo simulations. The detector thickness of 1-4 mm and the area in 16-100 mm2 range were considered in this work. In excellent agreement with earlier work (Rybka et al., [20]), the Geant4 simulated values of detector efficiencies have been found to decrease with incident g-ray energy. Both for the detector thickness and the detector area, the increasing trends have been observed for total efficiency as well as for full-energy peak efficiency in 0.1 MeV-50 MeV range. For Cd1-xZnxTe, the detector response remained insensitive to changes in relative proportions of Zn. For various wide band gap detectors studied in this work, the detection efficiency of TlBr was found highest over the entire range of energy, followed by the HgI2, CdTe, and then by CZT. more...

In the title compound, C12H15N3O3S, the 4-nitro and carbonyl groups are nearly coplanar with the benzene ring [C—C—N—O = −175.72 (14) and C—C—C—O = 172.75 (14)°]. The diethylcarbamothioyl group is twisted significantly from the plane of the benzene ring [C—N—C—N = −89.79 (15)°] with the S atom pointing away from each of these groups [C—N—C—S = 91.12 (14)°]. In the crystal, an intermolecular N—H...O hydrogen bond, which forms an infinite polymeric chain along the c axis, and weak C—H...O and C—H...S hydrogen bonds are observed. more...

Abstract Introduction Gangrenous cholecystitis is a severe complication of acute cholecystitis. We present an unusual case of gangrenous cholecystitis which was totally asymptomatic, with normal pre-operative parameters, and was discovered incidentally during a laparoscopic cholecystectomy. We have not found any similar cases in the published literature. Case presentation A 79-year-old British Caucasian man presented initially with acute cholecystitis which responded to conservative management. After six weeks he was asymptomatic and had normal blood parameters. An elective laparoscopic cholecystectomy was performed and our patient was found to have a totally gangrenous gall bladder. Conclusion It is important to keep a high index of suspicion for the diagnosis of gangrenous cholecystitis in order to avoid potentially serious complications. more...

Aims: Sacubitril/valsartan (Sac/Val) is used for treatment of heart failure. The effect of Sac/Val on regional dysfunction following myocardial infarction (MI) remains uncertain. This study aimed at understanding the effects of Sac/Val on regional function after MI., Methods and Results: MI or sham surgery was performed in Sprague-Dawley rats. Animals were randomized to treatment with Sac/Val, valsartan (Val) or vehicle (Veh). Magnetic resonance imaging was used to acquire left ventricular volumes and strain. Left ventricular tissue was obtained for wesern blotting, PCR and Masson's trichrome staining. Isolated cardiac fibroblasts were cultured with Veh, atrial natriuretic peptide (ANP), adrenomedullin (ADM) and sacubitrilat, and collagen expression assessed with droplet digital PCR., Results: Sac/Val reduced ventricular end-diastolic volume by 18% compared with Veh, and preserved circumferential systolic strain in the zone proximal to infarction compared with sham after 42 days of treatment (peak strain ± SEM: sham: -0.19 ± 0.01%; Sac/Val: -0.14 ± 0.02%; Val: -0.10 ± 0.02%; Veh: -0.10 ± 0.02%). Masson's trichrome staining demonstrated lower fibrotic deposition in the intermediate zone with Sac/Val treatment than Veh (sham: 2.29 ± 0.17%; Sac/Val: 2.31 ± 0.27%; Val: 3.22 ± 0.60%; Veh: 4.14 ± 0.48%). The amounts of the pro-apoptotic caspase 3 cleavage fragments p19/17 were 89% higher in Val than sham, with Sac/Val showing no significant increase compared with sham. Collagen expression in human fibroblast culture was lower in cells co-treated with sacubitrilat and ANP, an effect not observed with sacubitrilat/ADM co-treatment., Conclusions: Sac/Val preserves in vivo myocardial function in the region most proximal to MI in rats and reduces left ventricular dilatation. These effects may be related to a reduction in both fibrosis and pro-apoptotic signalling., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.) more...

Objective: S100A4 is a DAMP protein. S100A4 is overexpressed in patients with systemic sclerosis (SSc), and levels correlate with organ involvement and disease activity. S100A4 -/-erscript> mice are protected from fibrosis. The aim of this study was to assess the antifibrotic effects of anti-S100A4 monoclonal antibody (mAb) in murine models of SSc and in precision cut skin slices of patients with SSc., Methods: The effects of anti-S100A4 mAbs were evaluated in a bleomycin-induced skin fibrosis model and in Tsk-1 mice with a therapeutic dosing regimen. In addition, the effects of anti-S100A4 mAbs on precision cut SSc skin slices were analyzed by RNA sequencing., Results: Inhibition of S100A4 was effective in the treatment of pre-established bleomycin-induced skin fibrosis and in regression of pre-established fibrosis with reduced dermal thickening, myofibroblast counts, and collagen accumulation. Transcriptional profiling demonstrated targeting of multiple profibrotic and proinflammatory processes relevant to the pathogenesis of SSc on targeted S100A4 inhibition in a bleomycin-induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation- and fibrosis-relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP-activated protein kinase, calsequestrin-1, and phosphorylated STAT3, were validated on the protein level, and STAT3 inhibition was shown to prevent the profibrotic effects of S100A4 on fibroblasts in human skin., Conclusion: Inhibition of S100A4 confers dual targeting of inflammatory and fibrotic pathways in complementary mouse models of fibrosis and in SSc skin. These effects support the further development of anti-S100A4 mAbs as disease-modifying targeted therapies for SSc., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.) more...

A cholesteatoma is an expansion of keratinizing squamous epithelium that enters the middle ear cleft from the outer layer of the tympanic membrane or ear canal. Choleatomas are always treated surgically. Recurrence of the illness presents another challenge for the patient and the surgeon, though. There have been reports of recurrence rates as high as 30% in adults and as high as 70% in children. Here, we describe a case of persistent recurrent otorrhea following revision surgery, along with acquired recurrent cholesteatoma following canal wall down surgery. A 38-year -male with underlying Diabetes Mellitus and Hypertension presented with left scanty and foul-smelling ear discharge for 2 years and left reduced hearing. He was diagnosed with left chronic active otitis media with cholesteatoma for which he underwent left modified radical mastoidectomy, meatoplasty and tympanoplasty in 2017. Five months post operatively, he presented with left otorrhea. However, he defaulted followed up and presented in April 2018 for similar complaints. Otoscopy examination revealed left tympanic membrane perforation at poster superior quadrant of pars tensa and bluish discoloration behind pars flacida. He was diagnosed as recurrent left cholesteatoma and subsequently he underwent left mastoid exploration under general anesthesia in June 2018. Postsurgery, he developed recurrent ear discharge which was treated with topical antibiotics and ear toileting. We report a case of recurrent Cholesteatoma despite canal wall down procedure requiring a second redo procedure and with persistent recurrent otorrhea after the redo procedure.However, this case demonstrates the need for regular follow ups even after a canal wall down procedure for detecting recurrence of disease. Moreover, this case denotes some of the patient factors and surgeon factors involved in disease recurrence. Furthermore, importance of opting for an imaging study in case of high suspicion of the disease. more...

Objectives: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis., Methods: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing)., Results: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc., Conclusion: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.) more...

Agricultural intensification is a major threat to farmland biodiversity and associated ecosystem services. Semi-natural habitats are integral to the preservation of farmland biodiversity and ecosystem services, however, the extent in which they contribute to specific services is largely unclear. We studied predation rates of ground-dwelling predatory arthropods, and pollination success within old permanent grasslands, newly established grasslands and arable fields near and far from new grasslands. We evaluated whether grassland restoration can enhance pollination and biological control in crop fields. For this purpose, we established new grassland strips within cereal fields, which directly bordered existing permanent grasslands. We evaluated if the distance to these old and new grasslands affects the delivery of the two ecosystem services within crop fields. We found significantly higher seed numbers and seed weight in sentinel plants placed in old grasslands, new grasslands and nearby arable fields compared to distant arable fields. We also found significantly decreasing seed numbers and seed weight in sentinel plants placed in distant arable fields with increasing distance from old grasslands, while pollination success was not affected by distance in nearby arable fields. Contrary, we did not find any significant effects of new grasslands on biological control. Our study showed that 3 years after establishing grasslands arable fields benefited from the proximity of flower-rich new grasslands through increased pollination success though not regarding biological control. This indicates that, on a short term, establishing new grasslands can support beneficial arthropods in providing ecosystem services such as pollination. Predators, in contrast, might take longer to establish effective populations that denote higher predation rates. Our study provides a baseline for future long-term studies to better evaluate pollination and pest control patterns within arable fields., Supplementary Information: The online version contains supplementary material available at 10.1007/s11829-023-10034-5., Competing Interests: Competing interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© The Author(s) 2024.) more...

Objectives: We have studied the damage-associated molecular pattern protein S100A4 as a driver of fibroblast activation in systemic sclerosis (SSc)., Methods: S100A4 protein concentration was measured by ELISA in serum of SSc (n=94) and healthy controls (n=15). Protein expression in skin fibroblast cultures from diffuse cutaneous SSc (SScF, n=6) and healthy controls (normal fibroblasts (NF), n=6) was assessed. Recombinant S100A4 and a high affinity anti-S100A4 neutralising monoclonal antibody (AX-202) were tested on SScF and NF., Results: Median (range) S100A4 (ng/mL) was higher in serum of SSc (89.9 (15.0-240.0)) than healthy controls (71.4 (7.9-131.8); p=0.027). There was association with SSc-interstitial lung disease (p=0.025, n=55), scleroderma renal crisis (p=0.026, n=4). Median (range) S100A4 (ng/mL) was higher in culture supernatants of SScF (4.19 (0.52-8.42)) than NF controls (0.28 (0.02-3.29); p<0.0001). AX-202 reduced the constitutive profibrotic gene and protein expression phenotype of SScF. Genome-wide RNA sequencing analysis identified an S100A4 activated signature in NF overlapping the hallmark gene expression signature of SScF. Thus, 464 differentially expressed genes (false discovery rate (FDR) <0.001 and fold change (FC) >1.5) induced in NF by S100A4 were also constitutively overexpressed, and downregulated by AX-202, in SScF. Pathway mapping of these S100A4 dependent genes in SSc showed the most significant enriched Kegg pathways (FDR <0.001) were regulation of stem cell pluripotency (4.6-fold) and metabolic pathways (1.9-fold)., Conclusion: Our findings provide compelling evidence for a profibrotic role for S100A4 in SSc and suggest that serum level may be a biomarker of major organ manifestations and disease severity. This study supports examining the therapeutic potential of targeting S100A4 in SSc., Competing Interests: Competing interests: CPD has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline, consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron, and honoraria from Janssen, Boehringer Ingelheim and Corbus. SB, RIH, JK and JH are employees of Arxx Therapeutics. Other authors have no relevant disclosures., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Aims: ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF)., Methods: ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment., Results: At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non-S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non-S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient-years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient-years in the non-S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non-S/V, S/V, and rS/V groups, respectively., Conclusions: This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real-world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.) more...

Establishment of semi-natural grasslands offers a valuable approach to the conservation of threatened grassland biodiversity. We established new grassland strips on former crop fields adjacent to old semi-natural grasslands and monitored the development of plant, carabid, spider, and wild bee communities over 3 years. The studied plant and arthropods communities were significantly different between newly established grassland strips and old grassland. Our results suggest that restoring plant and arthropod communities takes longer than 3 years to become similar to old semi-natural grasslands., (© 2022 The Authors. Restoration Ecology published by Wiley Periodicals LLC on behalf of Society for Ecological Restoration.) more...

Aims: To compare baseline characteristics of patients with heart failure with reduced ejection fraction (HFrEF) initiated on sacubitril/valsartan compared with patients continued on conventional heart failure (HF)-treatment in a European out-patient setting., Methods and Results: Between July 2016 and July 2019, ARIADNE enrolled 8787 outpatients aged ≥18 years with HFrEF from 17 European countries. Choice of therapy was solely at the investigators' discretion. In total, 4173 patients were on conventional HF-treatment (non-S/V group), while 4614 patients were on sacubitril/valsartan either at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). Of these, 2108 patients started sacubitril/valsartan treatment ±1 month around enrolment [restricted S/V (rS/V) group]. The average age of the patients was 68 years. Patients on S/V were more likely to have New York Heart Association (NYHA) class III or IV symptoms (50.3%, 44.6%, 32.1% in rS/V, S/V, and non-S/V, respectively) and had lower left ventricular ejection fraction (LVEF; 32.3%, 32.7%, and 35.4% in rS/V, S/V, and non-S/V, respectively; P < 0.0001). The most frequently received HF treatments were angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB; ∼84% in non-S/V), followed by β-blockers (∼80%) and mineralocorticoid receptor antagonists (MRAs; 53%). The use of triple HF therapy (ACEI/ARB/angiotensin receptor neprilysin inhibitor with β-blockers and MRA) was higher in the S/V groups than non-S/V group (48.2%, 48.2%, and 40.2% in rS/V, S/V, and non-S/V, respectively)., Conclusion: In this large multinational HFrEF registry, patients receiving sacubitril/valsartan tended to be younger with lower LVEF and higher NYHA class. Fewer than half of the patients received triple HF therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.) more...

The coronavirus disease 2019 (COVID-19) pandemic and its effects on an individual's life have altered the consumer behavior. In the context of purchase and consumption, a shift from conventional to green purchase has been noticed. Although the factors underlying this shift were relatively unexplored, the study aimed to identify the factors that influenced a significant role in the green purchases during the outbreak and the relationship of these factors with green purchase behavior (GPB). Subsequently, this study investigates and interprets the role of fear of COVID-19 (FCV), psychological distress (PD), and mortality salience (MS) in predicting consumer's GPB. This research adopted a quantitative methodology using data collected from 432 respondents in various cities across Pakistan. Smart-PLS 3 was used to evaluate the measurement model, structural model, and multi-group analysis (MGA). Despite having the negative psychological and physical impact of the pandemic, a significant proportion of customers have switched to healthier and sustainable products. This research revealed that the FCV, PD, and MS plays a substantial role in adopting GPB. All the direct relationships were positive and significant. In addition, MS and PD partially mediate the effect of FCV on GPB. Furthermore, the MGA revealed that the infected respondents were interested in purchasing green products than uninfected respondents due to their FCV; conversely, the PD and MS were higher in uninfected individuals than infected ones. However, there is a vast literature on GPB, but little has investigated the cumulative impact of FCV, PD, and MS on GPB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sajid, Hussain, Hussain and Mustafa.) more...

The world needs to get out of the COVID-19 pandemic smoothly through a thorough socio-economic recovery. The first and the foremost step forward in this direction is the health recovery of the people infected. Our empirical study addresses this neglected point in the recent research on COVID-19 and specifically aims at exploring the impact of the environment on health recovery from COVID-19. The sample data are taken during the lockdown period in Wuhan, i.e., from 23rd January 2020 to 8th April 2020. The recently developed econometric technique of Quantile-on-Quantile regression, proposed by Shin and Zhu (2016) is employed to capture the asymmetric association between environmental factors (TEMP, HUM, PM 2.5 , PM 10 , CO, SO 2 , NO 2 , and O 3 ) and the number of recovered patients from COVID-19. We observe significant heterogeneity in the association among variables across various quantiles. The findings suggest that TEMP, PM 2.5 , PM 10 , CO, NO 2, and O 3 are negatively related to the COVID-19 recovery, while HUM and SO 2 show a positive association at most quantiles. The study recommends that maintaining a safe and comfortable environment for the patients may increase the chances of recovery from COVID-19. The success story of Wuhan, the initial epicenter of the novel coronavirus in China, can serve as an important case study for other countries to bring the outbreak under control. The current study could be conducive for the policymakers of those countries where the COVID-19 pandemic is still unrestrained., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.) more...

Objective: To assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy., Methods: PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist's referral and no later than 6 months after the baseline visit. Based on futility interim analysis, the study was terminated early., Results: In total, 1415 HFrEF patients from 223 PCs from 18 countries in Europe were enrolled. Of these, 1324 (96.9%) were considered clinically stable and 920 (65.0%) had NT-pro-BNP ≥600 pg/mL (mean: 2631 pg/mL). In total, 861 (60.8%) patients fulfilled both criteria and were referred to a cardiologist. Before cardiologist consultation, 10.1% of patients were on ESC guideline-recommended HFrEF medications and 2.7% were on recommended dosages of HFrEF medication (defined as ≥50% of ESC guideline-recommended dose). Postreferral, prescribed HFrEF drugs remained largely unchanged except for an increase in diuretics (+4.6%) and mineralocorticoid receptor antagonists (+7.9%). No significant increase in patients' adherence to guideline-defined drug combinations (11.2% post-referral vs 10.1% baseline) or drug combinations and dosages (3.3% postreferral vs 2.7% baseline) was observed after cardiologist consultation., Conclusions: PREFER demonstrates substantial suboptimal treatment of HFrEF patients in the real world. Referral of patients with elevated NT-pro-BNP levels from PC to cardiologist did not result in meaningful treatment optimisation for treatments with known mortality and morbidity benefit., Competing Interests: Competing interests: RH acknowledges his part-funding from the National Institute for Health Research (NIHR) School for Primary Care Research, the NIHR Collaboration for Leadership in Health Research and Care (CLARHC) Oxford, the NIHR Oxford Biomedical Research Centre (BRC, UHT), and the NIHR Oxford Medtech and In-Vitro Diagnostics Co-operative (MIC) and has received occasional fees for consulting or speaking from companies including Novartis. RH and PF are employees of Novartis. HB receives research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 & PI17/01799), Astra-Zeneca, BMS, Janssen and Novartis and has received consulting fees from Astra-Zeneca, Bayer, BMS-Pfizer, Novartis; and speaking fees or support for attending scientific meetings from Astra-Zeneca, Bayer, BMS-Pfizer, Novartis, and MEDSCAPE-the heart.og. YMP received consultancy fees from Novartis, Roche Diagnostics and holds minority shares in a University spin-off. FG has received fees for consulting and speaking honoraria from Novartis, Carmat, Orion and fees for consulting, speaking and as an investigator from Abbott. He has also received research grant from Orion and speaking honoraria from Boehringer-Ingelheim and received fees for consulting from Bayer and Pfizer. MO has been contracted by Novartis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Ongoing intensification and fragmentation of European agricultural landscapes dramatically reduce biodiversity and associated functions. Enhancing perennial noncrop areas holds great potential to support ecosystem services such as ant-mediated pest control.To study the potential of newly established grassland strips to enhance ant diversity and associated functions, we used hand collection data and predation experiments to investigate differences in (a) ant community composition and (b) biocontrol-related functional traits, and (c) natural pest control across habitats in cereal fields, old grasslands, and new grassland transects of three years of age.Ant species diversity was similar between new and old grasslands, but significantly higher in new grasslands than in surrounding cereal fields. Contrary, ant community composition of new grasslands was more similar to cereal fields and distinct from the species pool of old grasslands. The functional trait space covered by the ant communities showed the same distribution between old and new grasslands. Pest control did not differ significantly between habitat types and therefore could not be linked to the prevalence of functional ant traits related to biocontrol services in new grasslands.Our findings not only show trends of convergence between old and new grasslands, but also indicate that enhancing ant diversity through new grasslands takes longer than three years to provide comparable biodiversity and functionality. Synthesis and applications : Newly established grasslands can increase ant species richness and abundance and provide a consistent amount of biocontrol services in agroecosystems. However, three years after their establishment, new grasslands were still dominated by common agrobiont ant species and lacked habitat specialists present in old grasslands, which require a constant supply of food resources and long colony establishment times. New grasslands represent a promising measure for enhancing agricultural landscapes but must be preserved in the longer term to promote biodiversity and resilience of associated ecosystem services., Competing Interests: The authors have no conflict of interest to declare., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.) more...

Aims: Sacubitril/valsartan (sac/val) has shown superior effect compared with blockade of the renin-angiotensin-aldosterone system in heart failure with reduced ejection fraction. We aimed to investigate effects of sac/val compared with valsartan in a pressure overload model of heart failure with preserved ejection fraction (HFpEF)., Methods and Results: Sprague-Dawley rats underwent aortic banding or sham (n = 16) surgery and were randomized to sac/val (n = 28), valsartan (n = 29), or vehicle (n = 26) treatment for 8 weeks. Sac/val reduced left ventricular weight by 11% compared with vehicle (P = 0.01) and 9% compared with valsartan alone (P = 0.04). Only valsartan reduced blood pressure compared with sham (P = 0.02). Longitudinal early diastolic strain rate was preserved in sac/val compared with sham, while it was reduced by 23% in vehicle (P = 0.03) and 24% in valsartan (P = 0.02). Diastolic dysfunction, measured by E/e'SR, increased by 68% in vehicle (P < 0.01) and 80% in valsartan alone (P < 0.001), while sac/val showed no increase. Neither sac/val nor valsartan prevented interstitial fibrosis. Although ejection fraction was preserved, we observed mild systolic dysfunction, with vehicle showing a 28% decrease in longitudinal strain (P < 0.01). Neither sac/val nor valsartan treatment improved this dysfunction., Conclusions: In a model of HFpEF induced by cardiac pressure overload, sac/val reduced hypertrophy compared with valsartan alone and ameliorated diastolic dysfunction. These effects were independent of blood pressure. Early systolic dysfunction was not affected, supporting the notion that sac/val has the largest potential in conditions characterized by reduced ejection fraction. Observed anti-hypertrophic effects in preserved ejection fraction implicate potential benefit of sac/val in the clinical setting of hypertrophic remodelling and impaired diastolic function., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.) more...

Aims: OUTSTEP-HF compared the effect of sacubitril/valsartan vs. enalapril on 6-min walk test (6MWT) distance, non-sedentary daytime physical activity and heart failure (HF) symptoms in patients with HF with reduced ejection fraction (HFrEF)., Methods and Results: Ambulatory patients (n = 621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (n = 310) or enalapril (n = 311). Changes in physical activity and mean daily non-sedentary daytime activity from baseline to Week 12 were measured using 6MWT and a wrist-worn accelerometer device, respectively. After 12 weeks, 6MWT improved by 35.09 m with sacubitril/valsartan [97.5% confidence interval (CI) 27.85, 42.32] and by 26.11 m with enalapril (97.5% CI 18.78, 33.43); however, there was no significant difference between groups [least squares means treatment difference: 8.98 m (97.5% CI -1.31, 19.27); P = 0.0503]. Mean daily non-sedentary daytime activity decreased by 27 min with sacubitril/valsartan and by 21 min with enalapril [least squares means treatment difference: -6 min (97.5% CI -25.7, 13.4), P = 0.4769] after 12 weeks. 6MWT improved by ≥30 m in 51% of patients in the sacubitril/valsartan group vs. 44% of patients treated with enalapril (odds ratio 1.251, 95% CI 0.895, 1.748). At Week 4, non-sedentary daytime activity increased by ≥10% in 58% of patients treated with sacubitril/valsartan vs. 64% with enalapril; 58% of patients treated with sacubitril/valsartan reported improved HF symptoms as assessed by patient global assessment vs. 43% with enalapril. However, these differences did not persist at Week 12., Conclusion: After 12 weeks of treatment, there was no significant benefit of sacubitril/valsartan on either 6MWT or daytime physical activity measured by actigraphy compared with enalapril., (© 2020 European Society of Cardiology.) more...

Operational and financial sustainability have, over time, remained as issues in the microfinance industry. The microfinance industry is struggling to gain self-sufficiency in Pakistan due to non-performing loans and operating costs. Simultaneously, deliberation on corporate social responsibility (CSR) is also considered in academic literature and organizational practices. However, studies on CSR and financial performance in the microfinance sector are scarce, especially in Pakistan. CSR will develop customer attraction and loyalty, employee attraction, motivation and commitment, MFIs' reputation and access to capital, and eventually build financial performance. Interviews were conducted with branch managers of microfinance institutions to test previous questionnaires. A self-administered survey was conducted to collect data from the managers of the microfinance banks operating in Punjab. Descriptive and inferential statistics were performed to answer research questions using Smart PLS. Most of the microfinance institutions believe in social responsibilities but lacks fund allocation and approval from higher management, and results are in line with prior studies. These empirical findings lead to the perception that CSR is not a barrier performance in microfinance banks as they have access to capital. The results indicated a strong positive correlation between CSR and the financial performance of the MFIs. CSR also positively correlates with customer retention, employees' motivation and attraction, and business reputation. CSR was associated with access to capital but was found to be weak. The research also narrated the limitation and practical implications of the study. The study also discusses further research directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Hussain, Bashir and Hussain.) more...

Aim: In PARADIGM-HF, sacubitril/valsartan demonstrated superiority to enalapril in reducing mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several patient-centred outcomes like improved physical activity and quality of life have been emphasised as important treatment goals in HF management. OUTSTEP-HF has been designed to evaluate the effect of sacubitril/valsartan compared with enalapril on non-sedentary daytime physical activity in patients with HFrEF., Methods: OUTSTEP-HF is a randomised, actively controlled, double-blind, double-dummy study that plans to enrol 600 ambulatory patients with symptomatic HFrEF in 19 European countries. Patients will be randomised 1:1 to receive sacubitril/valsartan 97/103 mg bid or enalapril 10 mg bid. The primary objective of the study is to assess changes from baseline (Week 0) to Week 12 in exercise capacity measured by the 6-min walk test and in daily non-sedentary daytime activity. Physical activity and objective sleep parameters will be measured by accelerometry using a wrist-worn device, worn continuously from screening (Week -2) until the end of study (Week 12). As a co-primary outcome, changes from baseline in sub-maximal exercise capacity will be assessed by the 6-min walk test. Patient- and physician-reported questionnaires will be used to assess quality of life, changes in signs and symptoms of HF and sleep parameters., Conclusion: OUTSTEP-HF will be the largest randomised trial in HF to date to use non-invasive accelerometry to assess whether treatment with sacubitril/valsartan improves patients' daily physical activity and exercise capacity compared with enalapril., (© 2020 European Society of Cardiology.) more...

Associations between biodiversity, human health and well-being have never been discussed with reference to agriculturally managed, species-rich mountainous meadows. We evaluated these associations between extensively managed (one mowing a year, no fertilization) and abandoned (no mowing since more than 80 years, no fertilization) semi-dry meadows located in the Austrian and Swiss Alps. We quantified the richness and abundance of plants, grasshoppers, true bugs, bumblebees, syrphids and landscape characteristics in the surroundings of the meadows. Associations between these biodiversity attributes and short-term psychological and physiological human health effects were assessed with 22 participants (10 males, 12 females; mean age 27 years). Participants´ pulse rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were not affected during visits to managed or abandoned meadows. However, perceived health benefits (e.g., stress reduction, attention restoration) were higher during their stays in managed than in abandoned meadows. Also, the attractiveness of the surrounding landscape and the recreation suitability were rated higher when visiting managed meadows. Perceived naturalness was positively correlated with plant richness and flower cover. A positive correlation was found between SBP and forest cover, but SBP was negatively correlated with the open landscape. A negative association was found between grasshoppers and recreational and landscape perceptions. We suggest to discuss biodiversity attributes not only in connection with agricultural management but also with cultural ecosystem services and health benefits to raise more awareness for multifaceted interrelationships between ecosystems and humans. more...

The aim was to identify kinase activities involved in the phosphorylation of regulatory light chain (RLC) in situ in cardiomyocytes. In electrically stimulated rat cardiomyocytes, phosphatase inhibition by calyculin A unmasked kinase activities evoking an increase of phosphorylated RLC (P-RLC) from about 16% to about 80% after 80 min. The phosphorylation rate in cardiomyocytes was reduced by about 40% by the myosin light chain kinase (MLCK) inhibitor, ML-7. In rat ventricular muscle strips, calyculin A induced a positive inotropic effect that correlated with P-RLC levels. The inotropic effect and P-RLC elevation were abolished by ML-7 treatment. The kinase activities phosphorylating RLC in cardiomyocytes were reduced by about 60% by the non-selective kinase inhibitor staurosporine and by about 50% by the calmodulin antagonist W7. W7 eliminated the inhibitory effect of ML-7, suggesting that the cardiac MLCK is Ca(2+)/calmodulin (CaM)-dependent. The CaM-dependent kinase II (CaMKII) inhibitor KN-93 attenuated the calyculin A-induced RLC phosphorylation by about 40%, indicating a contribution from CaMKII. The residual phosphorylation in the presence of W7 indicated that also CaM-independent kinase activities might contribute. RLC phosphorylation was insensitive to protein kinase C inhibition. In conclusion, in addition to MLCK, CaMKII phosphorylates RLC in cardiomyocytes. Involvement of other kinases cannot be excluded., (Copyright © 2016 Elsevier Inc. All rights reserved.) more...

Objective: The aim of this study was to compare the use of semi-automated (Medax Velox 2; Poggio Rusco, Italy) and automated (Bard Magnum Biopsy Instrument; Covington, GA, USA) core biopsy needles, for ultrasound guided breast biopsy., Materials and Methods: A 14G semi-automatic spring loaded core biopsy needle with a 22-mm-throw (Medax Velox 2; Poggio Rusco, Italy) and 14-gauge automated needle device with a 22-mm-throw biopsy gun (Bard-Magnum Biopsy Instrument, Covington, GA, USA) were used for breast biopsies under ultrasound guidance on alternate months during the study period between July 2009 and May 2011. One hundred and sixty lesions were biopsied and specimens were sent for histological evaluation., Results: The automated needle obtained a higher number of histology reports at 84% (67/80) as compared with the semiautomated needle at 60% (48/80) (Fisher exact test, p value=0.023). Inadequate samples with the automated needle were much less at 9% (7/60) than with the semiautomated needle at 23% (18/60) (Fisher exact test, p value=0.028). The semi-automated needle showed slightly less fragmented samples. However, the number of fragmented samples with definitive diagnosis was slightly higher with the automated compared with the semiautomated needle, at 16% (13/80) and 13% (10/80) respectively. Compared with histology of 29 lesions that were excised, the semi-automated needle had higher sensitivity (100%) but lower specificity (75%) and accuracy (90%) compared with the automated needle (88% sensitivity, 100% specificity, 95% accuracy)., Conclusion: Definitive diagnosis from the study samples slightly favours the use of automated core biopsy needle as compared to semi-automated core biopsy needle. more...

Studies suggest that increased activity of Gi contributes to the reduced β-adrenoceptor-mediated inotropic response (βAR-IR) in failing cardiomyocytes and that β2AR-IR but not β1AR-IR is blunted by dual coupling to Gs and Gi. We aimed to clarify the role of Gi upon the β1AR-IR and β2AR-IR in Sham and failing myocardium by directly measuring contractile force and cAMP accumulation. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation in cardiomyocytes from rats with post-infarction heart failure (HF) or sham operates (Sham). The β2AR-IR in Sham and HF was small and was amplified by simultaneously inhibiting phosphodiesterases 3 and 4 (PDE3&4). In HF, the inotropic response and cAMP accumulation evoked by β1AR- or β2AR-stimulation were reduced. Inactivation of Gi with pertussis toxin (PTX) did not restore the β1AR-IR or β2AR-IR in HF to Sham levels but did enhance the maximal β2AR-IR. PTX increased both β1AR- and β2AR-evoked cAMP accumulation more in Sham than that in HF, and HF levels approached those in untreated Sham. The potency of agonists at β1 and at β2ARs (only under PDE3&4 inhibition) was increased in HF and by PTX in both HF and Sham. Without PDE3&4 inhibition, PTX increased only the maximal β2AR-IR, not potency. We conclude that Gi regulates both β1AR- and β2AR-IR independent of receptor coupling with Gi. Gi together with PDE3&4 tonically restrict the β2AR-IR. Gi inhibition did not restore the βAR-IR in HF despite increasing cAMP levels, suggesting that the mechanism of impairment resides downstream to cAMP signalling. more...

Objective: The aim of this study was to investigate the intra- and inter-rater reliability of ultrasonography (US) to measure anterior translation of the humeral head (ATHH) among healthy subjects and patients with sacroiliac joint dysfunction., Methods: The study included a total of 22 shoulder joints from 11 subjects. Six subjects were healthy and 5 had sacroiliac joint dysfunction. Anterior translation of the humeral head was measured twice using US by two different investigators. Intraclass correlation coefficient (ICC3,1), standard error of measurements (SEMs), coefficient of variations (CVs) and Bland-Altman plot were used as analytical tests to investigate intra- and inter-rater reliability, amount of error and agreeability of the measurements between investigators., Results: Intraclass correlation coefficient was 0.94, showing a high level of intra-rater reliability of the first investigator with SEMs (0.01 cm) and CV (5.1%) in measuring ATHH. Intra-rater reliability of the second investigator was 0.84 with SEMs (0.03 cms) and CV (9.6%), indicating a high level of reliability. Inter-rater reliability was high, with an ICC value of 0.92 with SEMs (0.02 cms) and CV (5.9%)., Conclusion: The use of US as a measurement of ATHH has good levels of intra- and inter-rater reliability in clinical practice. more...

Background and Purpose: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium., Experimental Approach: Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁ adrenoceptors (β₂ adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂ adrenoceptors (β₁ adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC₅₀s., Key Results: Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients., Conclusions and Implications: Metoprolol induces a control by PDE3 of ventricular effects mediated through both β₁ and β₂ adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β₂ adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle., (© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.) more...

Beta-adrenergic receptor (βAR) inotropic effects are attenuated and muscarinic receptor-mediated inhibition thereof is enhanced in heart failure. We investigated if increased G(i) activity contributes to attenuated βAR-inotropic effects and potentiates muscarinic accentuated antagonism in failing rat ventricle. Contractility was measured in ventricular strips and adenylyl cyclase (AC) activity in ventricular membranes from rats with post-infarction heart failure (HF) or Sham-operated controls (Sham). The maximal βAR-mediated inotropic effect of isoproterenol was reduced by ~70% and basal, βAR- & forskolin-stimulated AC activity was significantly lower in HF vs. Sham. Carbachol-evoked antagonism of the βAR-mediated inotropic response was complete only in HF despite a ~40% reduction in the ability of carbachol to inhibit βAR-stimulated AC. However, neither the relative efficacy (contractility decreased by ~46%) nor the potency of carbachol to inhibit the βAR inotropic response differed between Sham and HF ventricle. Pertussis toxin (PTX) inactivation of G(i) did not increase the maximal βAR inotropic effect or the attenuated basal, βAR- & forskolin-stimulated AC activity in HF, but increased the potency of isoproterenol only in Sham (~0.5 log unit). In HF ventricle pretreated with PTX, simultaneous inhibition of phosphodiesterases 3,4 (PDE3,4) alone produced a larger inotropic response than isoproterenol in ventricle untreated with PTX (84% and 48% above basal respectively). In the absence of PTX, PDE3,4 inhibition evoked negligible inotropic effects in HF. These data are not consistent with the hypothesis that increased G(i) activity contributes to the reduced βAR-mediated inotropic response and AC activity in failing ventricle. The data, however, support the hypothesis that G(i), through chronic receptor independent inhibition of AC, together with PDE3,4 activity, is necessary to maintain a low basal level of contractility., (Copyright © 2012 Elsevier Ltd. All rights reserved.) more...

Prostanoid-modulatory approaches in heart failure patients have displayed effects which may seem to be mutually incompatible. Both treatment with prostanoids and inhibition of prostanoid synthesis have resulted in increased mortality in heart failure patients. Currently, it is unknown if prostanoids mediate contractile effects in failing human heart and if this can explain some of the clinical effects seen after prostanoid modulatory treatments. Therefore, the objectives of this study were to determine if prostanoids could elicit direct inotropic responses in human ventricle, and if so to determine if they are modified in failing ventricle. Contractile force was measured in left ventricular strips from non-failing or failing human and rat hearts. The ratio of phosphorylated to non-phosphorylated myosin light chain 2 (MLC-2) was measured by Western blotting in myocardial strips, and the levels of prostanoid FP receptor mRNA and protein were measured in rat by real-time RT-PCR and receptor binding assays. In non-failing human hearts, prostanoids evoked a positive inotropic effect and an increase of MLC-2 phosphorylation which was absent in failing human hearts. In failing rat heart, the prostanoid FP receptor-mediated inotropic response and prostanoid FP receptor-density was reduced by ~40-50% compared to non-failing rat heart. Prostanoids mediate a sustained positive inotropic response in non-failing heart, which appears to be down regulated in failing heart. The pathophysiological significance of changes in prostanoid-mediated inotropic support in the failing heart remains to be determined., (Copyright © 2012 Elsevier B.V. All rights reserved.) more...

Congestive heart failure (CHF) induces changes in the neurohumoral system and gene expression in viable myocardium. Several of these genes encode G protein-coupled receptors (GPCRs) involved in mechanisms which compensate for impaired myocardial function. We used real-time quantitative RT-PCR (Q-RT-PCR) to investigate the expression of mRNA encoding 15 different GPCRs possibly involved in CHF, and the effect of normalisation to GAPDH mRNA (GAPDH) or 18S rRNA (18S). CHF was induced in rats by coronary artery ligation, with sham-operated controls (Sham). After 6 weeks, mRNA expression in viable left ventricular myocardium was determined using both 18S and GAPDH as the normalisation standard. An apparent 30% reduction in GAPDH mRNA levels vs. 18S in CHF compared to Sham, although not significant in itself, influenced the interpretation of regulation of other genes.Thus, levels of mRNA encoding receptors for angiotensin II (AT(1)), endothelin (ET(A), ET(B)) and the muscarinic acetylcholine (mACh) receptor M(1) increased significantly in CHF only when normalised to GAPDH. Levels of mRNA encoding the mACh receptors M(3) and M(4) and the serotonin receptors 5-HT(2A) and 5-HT(4) increased, whereas alpha(1D)-adrenoceptor mRNA decreased in CHF irrespective of the normalisation standard. No significant change was detected for M2 and M5 mACh receptors or alpha(1A)-, alpha(1B)-, beta(1)- or beta(2)-adrenoceptors. Q-RT-PCR is a sensitive and powerful method to monitor changes in GPCR mRNA expression in CHF. However, the normalisation standard used is important for the interpretation of mRNA regulation. more...

Objectives: To assess the prevalence of four categories (domains) of menopausal symptoms as markers for quality of life in nine ethnic groups of Asian women. To evaluate changes in quality of life (MENQOL scores) in Asian women following hormone therapy., Methods: A prospective, randomized, double-blind, multinational clinical trial in 1028 healthy postmenopausal women of nine ethnic groups from 11 Asian countries/regions. Following 2 weeks of baseline observation, the women received one of three conjugated estrogens (CE)/medroxyprogesterone acetate (MPA) doses (in mg) daily for 24 weeks: 0.625/2.5, 0.45/1.5, or 0.3/1.5. At baseline and at the end of weeks 4, 12 and 24 following the start of therapy, the study participants were asked to record, on a menopause-specific quality of life (MENQOL) questionnaire, 29 menopausal symptoms, as experienced during the preceding month. The symptoms were categorized into four domains: vasomotor, psychosocial, physical and sexual., Results: The baseline (pretreatment) symptom scores in each of the four domains varied substantially among the different ethnic groups, ranging from 2.21 to 5.71 in the vasomotor, 2.37-5.96 in the psychosocial, 2.66-5.39 in the physical, and 2.11-6.55 in the sexual domain. Overall, Vietnamese and Pakistani women had the highest baseline scores, i.e. were most afflicted by each set of symptoms in a given domain, and Indonesian, Malay, Taiwanese and Thai women were least afflicted. In the overall population, intervention resulted in statistically significant decreases in the scores of all four domains within 4 weeks of intervention. The beneficial effects were similar in the three dose groups., Conclusions: The prevalence of four domains of menopausal symptoms, representative of quality of life as recorded on a MENQOL questionnaire, varies considerably among ethnic groups of Asian women. The MENQOL scores in the overall population were significantly lowered in the course of the study, indicating an improvement in quality of life. In the absence of a placebo group, the relative contribution of hormones and placebo in our intervention is unknown. more...

Genetic studies in Alzheimer's disease (AD), have indicated that the apolipoprotein E locus (APO E) is a major susceptibility factor, but that it can only account for approximately 50% of AD cases. Several other studies have attempted to identify additional genetic loci associated with disease development, often based on a candidate gene approach. As several lines of evidence indicate that oxidative stress and free radical damage occur in AD, the transferrin gene (TF) has been suggested as a candidate locus for AD since it is the major transport protein for iron, which itself is a major factor in free radical generation. Previous studies have shown elevated TF C2 allele frequencies in AD, this being specifically associated with carriers of the APO E varepsilon4 allele. We have therefore determined the influence of the common polymorphisms in TF, C1 and C2, in dementia. The frequency of the C2 allele was not significantly associated with AD. Stratification of cases according to the APO E varepsilon4 allele showed a highly significant excess of the C2 allele in AD cases without the varepsilon4 allele, contrasting with previous studies. Given the contrasting findings between reports of altered TF C2 allele frequencies, the TF locus would not appear to be a strong risk factor for AD in this population. more...