Ocular manifestations of diabetes mellitus: a general overview

Introduction: Diabetes is on the rise – according to the World Health Organization (WHO) over 400 million people worldwide are affected. Elevated blood sugar levels pose a risk for the lives of these patients as well as a serious deterioration in their quality of life. Apart from diabetic retinopathy, which poses an immediate risk to vision, virtually any part of the visual-sensory system can be irreversibly damaged. The objective of the study is to evaluate the prevalence of different eye complications in patients with type two diabetes and to propose guidelines for early diagnosis, clinical evaluation and treatment.Contingent and Methods: A total of 1654 adult patients hospitalized at the Clinic of Ophthalmology in the Alexandrovska Hospital were clinically evaluated including OCT scanning and visual field testing. Results: Approximately 13% of the patients (212) had type two diabetes as a concomitant disease. The most common eye manifestation of diabetes was cataract found in 73% of the patients. Other ocular manifestations of diabetes included primary open-angle glaucoma (POAG), secondary glaucoma, retinopathy and vitreal bleeding, retinal detachment, ischemic optic neuropathy, oculomotor dysfunction and eye-lid inflammation.Conclusion: Diabetes mellitus bears a significant risk for ocular complications and visual disability. The disease can affect any part of the visual system ‒ the sensory, the oculomotor and the adjacent tissues (eyelids and tear production and outflow). Patients with diabetes require regular follow up and timely intervention to prevent irreversible damage to the visual system

Double versus single intrauterine insemination (IUI) in stimulated cycles for subfertile couples

Background In subfertile couples, couples who have tried to conceive for at least one year, intrauterine insemination (IUI) with ovarian hyperstimulation (OH) is one of the treatment modalities that can be offered. When IUI is performed a second IUI in the same cycle might add to the chances of conceiving. In a previous update of this review in 2010 it was shown that double IUI increases pregnancy rates when compared to single IUI. Since 2010, different clinical trials have been published with differing conclusions about whether double WI increases pregnancy rates compared to single IUI. Objectives To determine the effectiveness and safety of double intrauterine insemination (IUI) compared to single IUI in stimulated cycles for subfertile couples. Search methods We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLI NE, Embase and CINAHL in July 2020 and LILACS, Google scholar and Epistemoni kos in February 2021, together with reference checking and contact with study authors and experts in the field to identify additional studies. Selection criteria We included randomised controlled, parallel trials of double versus single lUls in stimulated cycles in subfertile couples. Data collection and analysis Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Main results We identified in nine studies involving subfertile women. The evidence was of low quality; the main limitations were unclear risk of bias, inconsistent results for some outcomes and imprecision, due to small trials with imprecise results. We are uncertain whether double IUI improves live birth rate compared to single IUI (odds ratio (OR) 1.15, 95% confidence interval (CI) 0.71 to 1.88; I-2 = 29%; studies= 3, participants =468; low quality evidence). The evidence suggests that if the chance of live birth following single IUI is 16%, the chance of live birth following double IUI would be between 12% and 27%. Performing a sensitivity analysis restricted to only randomised controlled trials (RCTs) with low risk of selection bias showed similar results. We are uncertain whether double IUI reduces miscarriage rate compared to single IUI (OR 1.78, 95% CI 0.98 to 3.24; I-2 = 0%; studies = 6, participants = 2363; low quality evidence). The evidence suggests that chance of miscarriage following single IUI is 1.5% and the chance following double IUI would be between 1.5% and 5%. The reported clinical pregnancy rate per woman randomised may increase with double 11.11 group (OR 1.51, 95% CI 1.23 to 1.86; I-2 = 34%; studies = 9, participants = 2716; low quality evidence). This result should be interpreted with caution due to the low quality of the evidence and the moderate inconsistency. The evidence suggests that the chance of a pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%. We are uncertain whether double IUI affects multiple pregnancy rate compared to single IUI (OR 2.04, 95% CI 0.91 to 4.56; I-2 = 8%; studies = 5; participants = 2203; low quality evidence). The evidence suggests that chance of multiple pregnancy following single IUI is 0.7% and the chance following double ILA would be between 0.85% and 3.7%. We are uncertain whether double IUI has an effect on ectopic pregnancy rate compared to single IUI (OR 1.22, 95% CI 0.35 to 4.28; I-2 = 0%; studies =4, participants= 1048; low quality evidence). The evidence suggests that the chance of an ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%. Authors' conclusions Our main analysis, of which the evidence is low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. Our sensitivity analysis restricted to studies of low risk of selection bias for both outcomes is consistent with the main analysis. Clinical pregnancy rate may increase in the double IUI group, but this should be interpreted with caution due to the low quality evidence. We are uncertain whether double IUI has an effect on multiple pregnancy rate and ectopic pregnancy rate compared to single IUI

Análisis del Maltrato Físico en la Familia y su Influencia en Variables del Contexto Educativo [Analysis of the Physical Abuse in the Family and its Influence in Variables of the Educational Context]

This study analyzes the relationship between physical abuse in the family context and its influence on the educational context variables (academic performance and social behavior). A total of 2.852 students aged between 12 and 17 years participated in the study. The results highlight that the students who were abused in the family have higher numbers of fail marks, a lower level of social acceptance in the peer group as well as a greater involvement in the dynamics of bullying in both, the role of aggressor and as the victim. The results are discussed in relation to the importance of the type of family socialization based on coercion and abuse and behavior of students in the classroom

Targeted expression of human FSH receptor Asp567Gly mutant mRNA in testis of transgenic mice: role of the human FSH receptor promoter.

AIM: To specifically express the Asp567Gly human follicle-stimulating hormone receptor (FSHR) under the control of its promoter to evaluate the phenotypic consequences in the presence of normal pituitary function. METHODS: We produced transgenic mice overexpressing the Asp567Gly human FSHR under the control of a 1.5kb 5'-flanking region fragment of its promoter. RESULTS: Mice were phenotypically normal and fertile. In males, mRNA could be detected in the testis and the brain, indicating that the 1.5kb promoter fragment drives expression not only in the gonads. The testis weight/body weight ratio and the testosterone levels in transgenic and non-transgenic littermates were similar. By in situ hybridisation we found that the transgenic FSHR was highly expressed in Sertoli cells, spermatocytes and round spermatids. However, a radioligand receptor assay failed to show a significant difference in total FSHR binding sites in testis homogenates of transgenic and wild type animals, suggesting that the transgenic FSHR is probably not translated into functional receptor protein. CONCLUSION: A 1.5kb 5'-region of the human FSHR drives mRNA expression of the transgene in the testis but leads to ectopic expression in germ cells and in the brain. No phenotypic consequences could be documented due to the lack of protein expression

The construct of institutional distance through the lens of different institutional perspectives:Review, analysis, and recommendations

This paper presents a review and critique of the 20-year-old literature on institutional distance, which has greatly proliferated. We start with a discussion of the three institutional perspectives that have served as a theoretical foundation for this construct: organizational institutionalism, institutional economics, and comparative institutionalism. We use this as an organizing framework to describe the different ways in which institutional distance has been conceptualized and measured, and to analyze the most common organizational outcomes that have been linked to institutional distance, as well as the proposed explanatory mechanisms of those effects. We substantiate our qualitative review with a meta-analysis, which synthesizes the main findings in this area of research. Building on our review and previous critical work, we note key ambiguities in the institutional distance literature related to underlying theoretical perspectives and associated mechanisms, distance versus profile effects, and measurement. We conclude with actionable recommendations for improving institutional distance research

Storage and processing in working memory : a single, domain-general resource explains multi-tasking

An ongoing major debate centers around whether multitasking in working memory, that is, performing several mental activities at once, is supported by multiple specialized domain-specific or by a single-purpose domain-general cognitive resources. Working memory theories differ in their explanations and predictions about when performing two mental tasks causes performance failures, versus when two processes can be carried out concurrently with negligible cognitive costs. In particular, the predictions of domain-specific and domain-general views on working memory are in conflict with one another when it comes to the cognitive cost associated with concurrent verbal and visuospatial processing and storage tasks. Previous tests of these predictions using traditional methods have led to ambiguous and inconsistent conclusions, however. To make critical progress in this theoretical debate, we used a radically different approach combining Bayesian state-trace analysis with an experimental design fully crossing processing and storage tasks differing only in the domain of representation (verbal vs. visuospatial). Across two experiments, we show unambiguously that a single, domain-general factor can account for briefly maintaining verbal and visuospatial information in a multitasking scenario

Stage-specific sensitivity to p53 restoration during lung cancer progression

2011 May 25Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1, 2, 3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)American Cancer Society (New England Area Fellow)Leukemia & Lymphoma Society of America (Fellow)Massachusetts Institute of Technology. Undergraduate Research Program (John Reed Fund)Damon Runyon Cancer Research Foundation (Merck Fellow)Genentech, Inc. (Postdoctoral Fellow)Howard Hughes Medical Institut

Chemical Tuning Enhances Both Potency Toward Nrf2 and In Vitro Therapeutic Index of Triterpenoids

The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf

Chemical tuning enhances both potency toward Nrf2 and<em> in vitro</em> therapeutic index of triterpenoids

The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf2.</p

Impact of the COVID-19 pandemic on the incidence and prognosis of acute myocardial infarction - a single-center restrospective analysis

Introduction: COVID-19 pandemic has led to a signifi cant change in the incidence and prognosis of acute myocardial infarction (AMI) by indirect and direct mechanisms. Aim: To assess the impact of the COVID-19 pandemic on the incidence and prognosis of AMI. Material and methods: We performed a retrospective analysis of consecutive patients with AMI (STEMI and NSTEMI) during two time periods &amp;ndash; the complete lockdown in Bulgaria and one of the waves of the pandemic. We compared patients&amp;rsquo; risk profi le, index event, investigations and treatment to a control group from the pre-pandemic period. Results: During the fi rst period we included 52 patients with AMI without COVID-19 and compared them to a control group of 66 patients. We found a decrease primarily in the number of patients with STEMI. The scores for assessing diseaseseverity (GRACE, APACHE II, SOFA) were higher in 2020 compared to the pre-pandemic period. More patients presented with acute congestive heart failure, mortality was similar. During the second period we included 83 patients, 21 of them with COVID-19 infection. System delay was increased in all patients. Disease severity scores and baseline troponin were higher especially in the COVID-19 group. In-hospital mortality was substantially higher in patients with COVID-19 compared to controls (23,8% versus 9%, &amp;#1088; = 0,0375), probably due to increased incidence of cardiogenic shock and need for mechanical ventilation. Conclusion: During the complete lockdown there was a reduction in the number of patients admitted with AMI, higher incidence of acute congestive heart failure and similar mortality. During one of the waves of the pandemic we found a signifi cant increase in system delay, not exceeding the recommended time frame of 120 minutes, and in disease severity in all patients. Concomitant COVID-19 infection was associated with higher in-hospital mortality due to increased incidence of cardiogenic shock and need for mechanical ventilation