Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Comparison of two independent systematic reviews of trials of recombinant human bone morphogenetic protein-2 (rhBMP-2) : The Yale Open Data Access Medtronic Project

Background: It is uncertain whether the replication of systematic reviews, particularly those with the same objectives and resources, would employ similar methods and/or arrive at identical findings. We compared the results and conclusions of two concurrent systematic reviews undertaken by two independent research teams provided with the same objectives, resources, and individual participant-level data. Methods: Two centers in the USA and UK were each provided with participant-level data on 17 multi-site clinical trials of recombinant human bone morphogenetic protein-2 (rhBMP-2). The teams were blinded to each other's methods and findings until after publication. We conducted a retrospective structured comparison of the results of the two systematic reviews. The main outcome measures included (1) trial inclusion criteria; (2) statistical methods; (3) summary efficacy and risk estimates; and (4) conclusions. Results: The two research teams' meta-analyses inclusion criteria were broadly similar but differed slightly in trial inclusion and research methodology. They obtained similar results in summary estimates of most clinical outcomes and adverse events. Center A incorporated all trials into summary estimates of efficacy and harms, while Center B concentrated on analyses stratified by surgical approach. Center A found a statistically significant, but small, benefit whereas Center B reported no advantage. In the analysis of harms, neither showed an increased cancer risk at 48 months, although Center B reported a significant increase at 24 months. Conclusions reflected these differences in summary estimates of benefit balanced with small but potentially important risk of harm. Conclusions: Two independent groups given the same research objectives, data, resources, funding, and time produced broad general agreement but differed in several areas. These differences, the importance of which is debatable, indicate the value of the availability of data to allow for more than a single approach and a single interpretation of the data. Systematic review registration: PROSPERO CRD42012002040and CRD42012001907

Respective impacts of Arctic sea ice decline and increasing greenhouse gases concentration on Sahel precipitation

The impact of climate change on Sahel precipitation is uncertain and has to be widely documented. Recently, it has been shown that Arctic sea ice loss leverages the global warming effects worldwide, suggesting a potential impact of Arctic sea ice decline on tropical regions. However, defining the specific roles of increasing greenhouse gases (GHG) concentration and declining Arctic sea ice extent on Sahel climate is not straightforward since the former impacts the latter. We avoid this dependency by analysing idealized experiments performed with the CNRM-CM5 coupled model. Results show that the increase in GHG concentration explains most of the Sahel precipitation change. We found that the impact due to Arctic sea ice loss depends on the level of atmospheric GHG concentration. When the GHG concentration is relatively low (values representative of 1980s), then the impact is moderate over the Sahel. However, when the concentration in GHG is levelled up, then Arctic sea ice loss leads to increased Sahel precipitation. In this particular case the ocean-land meridional gradient of temperature strengthens, allowing a more intense monsoon circulation. We linked the non-linearity of Arctic sea ice decline impact with differences in temperature and sea level pressure changes over the North Atlantic Ocean. We argue that the impact of the Arctic sea ice loss will become more relevant with time, in the context of climate change

HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors

Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed whether specific HCV-genotypes are differently prone to develop resistance to linear and macrocyclic protease-inhibitors (PIs)

Anti–Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis

\ua9 2024Objectives: This study aimed to evaluate the cost-effectiveness of anti–vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. Methods: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. Results: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of \ua33688, with a net health benefit of −0.214 at a \ua320 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. Conclusions: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties

Anti-VEGF drugs compared with laser photocoagulation for the treatment of diabetic retinopathy: a systematic review and meta-analysis

Background: Diabetic retinopathy is a major cause of sight loss in people with diabetes. The most severe form, proliferative diabetic retinopathy, carries a high risk of vision loss, vitreous haemorrhage, macular oedema and other harms. Panretinal photocoagulation is the primary treatment for proliferative diabetic retinopathy. Anti-vascular endothelial growth factor drugs are used to treat various eye conditions and may be beneficial for people with diabetic retinopathy. Objective: To investigate the efficacy and safety of anti-vascular endothelial growth factor therapy for the treatment of diabetic retinopathy when compared to panretinal photocoagulation. Methods: A systematic review and network meta-analysis of all published randomised controlled trials comparing anti-vascular endothelial growth factor (alone or in combination with panretinal photocoagulation) to panretinal photocoagulation in people with diabetic retinopathy. The database searches were updated in May 2023. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Results: A total of 14 trials were included: 3 of aflibercept, 5 of bevacizumab and 6 of ranibizumab. Two trials were of patients with non-proliferative diabetic retinopathy; all others were in proliferative diabetic retinopathy. Overall, anti-vascular endothelial growth factor was slightly better than panretinal photocoagulation at preventing vision loss, measured as best corrected visual acuity, at up to 2 years follow-up [mean difference in the logarithm of the minimum angle of resolution -0.089 (or 3.6 Early Treatment Diabetic Retinopathy Study letters), 95% confidence interval -0.180 to -0.019]. There was no clear evidence of any difference between the anti-vascular endothelial growth factors, but the potential for bias complicated the comparison. One trial found no benefit of anti-vascular endothelial growth factor over panretinal photocoagulation after 5 years. Anti-vascular endothelial growth factor was superior to panretinal photocoagulation at preventing macular oedema (relative risk 0.29, 95% confidence interval 0.18 to 0.49) and vitreous haemorrhage (relative risk 0.77, 95% confidence interval 0.61 to 0.99). There was no clear evidence that the effectiveness of anti-vascular endothelial growth factor varied over time. Conclusions: Anti-vascular endothelial growth factor injections reduce vision loss when compared to panretinal photocoagulation, but the benefit is small and unlikely to be clinically meaningful. Anti-vascular endothelial growth factor may have greater benefits for preventing complications such as macular oedema. Observational studies extending follow-up beyond the 1-year duration of most trials are needed to investigate the longer-term effects of repeated anti-vascular endothelial growth factor injections. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.People with diabetes are at risk of gradually losing their sight. This is because blood vessels in the part of the eye called the retina may become damaged, leading to sight loss. This condition is called diabetic retinopathy. People with a more severe type of retinopathy, called proliferative diabetic retinopathy, are usually offered laser treatment to reduce the risk of further sight loss. Recently, drugs called anti-vascular endothelial growth factor drugs, which are injected directly into the eye, have been used to treat other eye conditions, and might be useful to treat retinopathy. This project investigated whether anti-vascular endothelial growth factor therapy is effective by identifying and re-analysing all the clinical trials that used the three main anti-vascular endothelial growth factor drugs (called aflibercept, bevacizumab and ranibizumab) to treat diabetic retinopathy. We identified 14 relevant clinical trials, including approximately 1800 persons. Our analyses found that anti-vascular endothelial growth factor injections were slightly better than laser therapy at maintaining vision. After 1 year, people with proliferative retinopathy who received anti-vascular endothelial growth factor injections could, on average, read three or four more letters on a standard eye test chart than people who had received laser therapy. This difference may be too small to make anti-vascular endothelial growth factor injections worthwhile. People with less severe forms of retinopathy saw no benefit in vision after receiving anti-vascular endothelial growth factor therapy. We did find that people who received anti-vascular endothelial growth factor injections were substantially less likely to experience some of the more severe consequences of vision loss, including where vision is lost in the centre of the eye (called diabetic macular oedema), and where blood leaks into the eye (called vitreous haemorrhage). Most of the trials lasted for 1 year or less, so the long-term impact of using anti-vascular endothelial growth factor injections is still not well understood. This long-term impact of anti-vascular endothelial growth factor use requires further clinical research

Anti-VEGF drugs compared with laser photocoagulation for the treatment of proliferative diabetic retinopathy: a systematic review and individual participant data meta-analysis

Background: Proliferative diabetic retinopathy is a major cause of sight loss in people with diabetes, with a high risk of vitreous haemorrhage, tractional retinal detachment and other complications. Panretinal photocoagulation is the primary established treatment for proliferative diabetic retinopathy. Anti-vascular endothelial growth factor drugs are used to treat various eye conditions and may be beneficial for people with proliferative diabetic retinopathy. Objective: To investigate the efficacy and safety of anti-vascular endothelial growth factor therapy for the treatment of proliferative diabetic retinopathy when compared to panretinal photocoagulation. Methods: A systematic review and network meta-analysis of randomised controlled trials comparing anti-vascular endothelial growth factor (alone or in combination) to panretinal photocoagulation in people with proliferative diabetic retinopathy. The database searches were updated in May 2023. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Key outcomes were best corrected visual acuity, diabetic macular oedema and vitreous haemorrhage. Individual participant data were obtained and analysed for three large, high-quality trials in combination with published data from other trials. Network meta-analyses of best corrected visual acuity and meta-analyses of other outcomes combined individual participant data with published data from other trials; regression analyses against patient covariates used just the individual participant data. Results: Twelve trials were included: one of aflibercept, five of bevacizumab and six of ranibizumab. Individual participant data were available from 1 aflibercept and 2 ranibizumab trials, representing 624 patients (33% of the total). When considered together, anti-vascular endothelial growth factors produced a modest, but not clinically meaningful, benefit over panretinal photocoagulation in best corrected visual acuity, after 1 year of follow-up (mean difference in logarithm of the minimum angle of resolution -0.116, 95% credible interval -0.183 to -0.038). There was no clear evidence of a difference in effectiveness between the anti-vascular endothelial growth factors. The benefit of anti-vascular endothelial growth factor appears to decline over time. Analysis of the individual participant data trials suggested that anti-vascular endothelial growth factor therapy may be more effective in people with poorer visual acuity, in those who have vitreous haemorrhage and, possibly, in people with poorer vision generally. Anti-vascular endothelial growth factor was superior to panretinal photocoagulation at preventing macular oedema after 1 year (relative risk 0.48, 95% confidence interval 0.28 to 0.83) and possibly at preventing vitreous haemorrhage (relative risk 0.72, 95% confidence interval 0.47 to 1.10). Anti-vascular endothelial growth factor reduced the incidence of retinal detachment when compared to panretinal photocoagulation (relative risk 0.41, 95% confidence interval 0.22 to 0.77). Data on other adverse events were generally too limited to identify any differences between anti-vascular endothelial growth factor and panretinal photocoagulation. Conclusions: Anti-vascular endothelial growth factor has no clinically meaningful benefit over panretinal photocoagulation for preserving visual acuity. However, anti-vascular endothelial growth factor therapy appears to delay or prevent progression to macular oedema and vitreous haemorrhage. The possibility that anti-vascular endothelial growth factor therapy may be more effective in patients with poorer health and poorer vision merits further clinical investigation. The long-term effectiveness and safety of anti-vascular endothelial growth factor treatment are unclear, particularly as additional panretinal photocoagulation and anti-vascular endothelial growth factor treatment will be required over time. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.People with diabetes are at risk of gradually losing their sight because blood vessels in the part of the eye called the retina may become damaged. This condition is called diabetic retinopathy. People with a more severe type of retinopathy, called proliferative diabetic retinopathy are usually offered laser treatment to reduce the risk of further sight loss. Recently, drugs called anti-vascular endothelial growth factors, which are injected directly into the eye, have been used to treat other eye conditions, and might be useful to treat retinopathy. This paper investigates whether anti-vascular endothelial growth factor therapy is effective by identifying and reanalysing the clinical trials that used the three main anti-vascular endothelial growth factor drugs (called aflibercept, bevacizumab and ranibizumab) to treat proliferative diabetic retinopathy. We identified 12 relevant clinical trials, including approximately 1100 persons, and obtained and reanalysed the data from three of the trials. We found that, after 1 year, people with proliferative retinopathy who received anti-vascular endothelial growth factor injections could, on average, read three or four more letters on a standard eye test chart than people who had received laser therapy. This difference may be too small to make anti-vascular endothelial growth factor injections worthwhile. The benefit of anti-vascular endothelial growth factor injections may also decline over time. Anti-vascular endothelial growth factor injections may be more beneficial in people with poorer vision when treatment starts. We also found that people who received anti-vascular endothelial growth factor injections were substantially less likely to experience some of the more severe consequences of vision loss, including where vision is lost in the centre of the eye (called diabetic macular oedema), and where blood leaks into the eye (called vitreous haemorrhage). The long-term impact of using anti-vascular endothelial growth factor injections repeatedly is still not well understood and requires further clinical research. Further trials that treat people with poorer vision or health generally would be useful

Coffee resistance to the main diseases : leaf rust and coffee berry disease

Sucesso considerável tem sido obtido no uso do melhoramento clássico para o controle de doenças de plantas economicamente importantes, tais como a ferrugem alaranjada das folhas e a antracnose dos frutos do cafeeiro (CBD). Há um grande consenso de que o uso de plantas geneticamente resistentes é o meio mais apropriado e eficaz em termos de custos do controle das doenças das plantas, sendo também um dos elementos chave do melhoramento da produção agrícola. Tem sido também reconhecido que um melhor conhecimento do agente patogênico e dos mecanismos de defesa das plantas permitirá o desenvolvimento de novas abordagens no sentido de aumentar a durabilidade da resistência. Após uma breve descrição de conceitos na área da resistência das plantas às doenças, nesta revisão tentou-se dar uma idéia do progresso na investigação da ferrugem alaranjada do cafeeiro e do CBD relativamente ao processo de infecção e variabilidade dos agentes patogênicos, melhoramento do cafeeiro para a resistência e mecanismos de resistência do cafeeiro

Hepatitis C virus genotype frequency in Isfahan province of Iran: a descriptive cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Hepatitis C is an infectious disease affecting the liver, caused by the hepatitis C virus (HCV). The hepatitis C virus is a small, enveloped, single-stranded, positive sense RNA virus with a large genetic heterogeneity. Isolates have been classified into at least eleven major genotypes, based on a nucleotide sequence divergence of 30-35%. Genotypes 1, 2 and 3 circulate around the world, while other genotypes are mainly restricted to determined geographical areas. Genotype determination of HCV is clinically valuable as it provides important information which can be used to determine the type and duration of therapy and to predict the outcome of the disease.</p> <p>Results</p> <p>Plasma samples were collected from ninety seven HCV RNA positive patients admitted to two large medical laboratory centers in Isfahan province (Iran) from the years 2007 to 2009. Samples from patients were subjected to HCV genotype determination using a PCR based genotyping kit. The frequency of HCV genotypes was determined as follows: genotype 3a (61.2%), genotype 1a (29.5%), genotype 1b (5.1%), genotype 2 (2%) and mixed genotypes of 1a+3a (2%).</p> <p>Conclusion</p> <p>Genotype 3a is the most frequent followed by the genotype 1a, genotype 1b and genotype 2 in Isfahan province, Iran.</p

Novel Positive-Sense, Single-Stranded RNA (+ssRNA) Virus with Di-Cistronic Genome from Intestinal Content of Freshwater Carp (Cyprinus carpio)

A novel positive-sense, single-stranded RNA (+ssRNA) virus (Halastavi árva RNA virus, HalV; JN000306) with di-cistronic genome organization was serendipitously identified in intestinal contents of freshwater carps (Cyprinus carpio) fished by line-fishing from fishpond “Lőrinte halastó” located in Veszprém County, Hungary. The complete nucleotide (nt) sequence of the genomic RNA is 9565 nt in length and contains two long - non-in-frame - open reading frames (ORFs), which are separated by an intergenic region. The ORF1 (replicase) is preceded by an untranslated sequence of 827 nt, while an untranslated region of 139 nt follows the ORF2 (capsid proteins). The deduced amino acid (aa) sequences of the ORFs showed only low (less than 32%) and partial similarity to the non-structural (2C-like helicase, 3C-like cystein protease and 3D-like RNA dependent RNA polymerase) and structural proteins (VP2/VP4/VP3) of virus families in Picornavirales especially to members of the viruses with dicistronic genome. Halastavi árva RNA virus is present in intestinal contents of omnivorous freshwater carps but the origin and the host species of this virus remains unknown. The unique viral sequence and the actual position indicate that Halastavi árva RNA virus seems to be the first member of a new di-cistronic ssRNA virus. Further studies are required to investigate the specific host species (and spectrum), ecology and role of Halastavi árva RNA virus in the nature