A vital role for glycosphingolipid synthesis during development and differentiation

Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking. We have investigated their roles in development and differentiation by eliminating the major synthesis pathway of GSLs through targeted disruption of the Ugcg gene encoding glucosylceramide synthase. In the absence of GSL synthesis, embryogenesis proceeded well into gastrulation with differentiation into primitive germ layers and patterning of the embryo but was abruptly halted by a major apoptotic process. In vivo, embryonic stem cells deficient in GSL synthesis were again able to differentiate into endodermal, mesodermal, and ectodermal derivatives but were strikingly deficient in their ability to form well differentiated tissues. In vitro, however, hematopoietic and neuronal differentiation could be induced. The results demonstrate that the synthesis of GSL structures is essential for embryonic development and for the differentiation of some tissues and support the concept that GSLs are involved in crucial cell interactions mediating these processes.     

Alcohol use and mortality in older men and women

Aims To compare the effect of alcohol intake on 10‐year mortality for men and women over the age of 65 years. Design, setting and participants Two prospective cohorts of community‐dwelling men aged 65–79 years at baseline in 1996 (n = 11 727) and women aged 70–75 years in 1996 (n = 12 432). Measurements Alcohol was assessed according to frequency of use (number of days alcohol was consumed per week) and quantity consumed per day. Cox proportional hazards models were compared for men and women for all‐cause and cause‐specific mortality. Findings Compared with older adults who did not consume alcohol every week, the risk of all‐cause mortality was reduced in men reporting up to four standard drinks per day and in women who consumed one or two drinks per day. One or two alcohol‐free days per week reduced this risk further in men, but not in women. Similar results were observed for deaths due to cardiovascular disease. Conclusions In people over the age of 65 years, alcohol intake of four standard drinks per day for men and two standard drinks per day for women was associated with lower mortality risk. For men, the risk was reduced further if accompanied with 1 or 2 alcohol‐free days per week.     

Differential relative effect potencies of some dioxin-like compounds in human peripheral blood lymphocytes and murine splenic cells

Human risk assessment for dioxin-like compounds is typically based on the concentration measured in blood serum multiplied by their assigned toxic equivalency factor (TEF). Consequently, the actual value of the TEF is very important for accurate human risk assessment. In this study we investigated the effect potencies of three polychlorinated dibenzo-p-dioxins (PCDDs), six polychlorinated dibenzofurans (PCDFs) and 10 polychlorinated biphenyls (PCBs) relative to the reference congener 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) in in vitro exposed primary human peripheral blood lymphocytes (PBLs) and mouse splenic cells. REPs were determined based on cytochrome P450 (CYP) 1A1, 1B1 and aryl hydrocarbon receptor repressor (AhRR) gene expression as well as CYP1A1 activity in human PBLs and Cyp1a1 gene expression in murine splenic cells. Estimated median human REPs for 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (1234678-HpCDD), 2,3,4,7,8,-pentachlorodibenzofuran (23478-PeCDF), 1,2,3,4,7,8-hexachlorodibenzofuran (123478-HxCDF) and 1,2,3,4,7,8,9-heptachlorodibenzofuran (1234789-HpCDF) were with 0.1, 1.1, 1 and 0.09, respectively, significantly higher compared to those estimated for mouse with REPs of 0.05, 0.45, 0.09 and 0.04, respectively. Opposite to these results, the estimated median human REP of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), was with 0.001 30-fold lower compared to the mouse REP of 0.03. Furthermore, human REPs for 1234678-HpCDD, 23478-PeCDF, 123478-HxCDF, 1234789-HpCDF and PCB 126 were all outside the ± half log uncertainty range that is taken into account in the WHO-assigned TEFs. Together, these data show congener- and species-specific differences in REPs for some, but not all dioxin-like congeners tested. This suggests that, more emphasis should be placed on human-tissue derived REPs in the establishment of a TEF for human risk assessment.     

Taking small steps towards targets – perspectives for clinical practice in diabetes,cardiometabolic disorders and beyond

Big changes are hard. When trying to achieve guideline targets in diabetes and cardiometabolic disorders, patients can lack commitment or suffer despondency. It is much easier to make small changes in lifestyle or treatment, which are less noticeable and easier to manage long‐term. Obesity is central to the cardiometabolic disorders, and even small weight losses of 2–5% can improve the cardiometabolic risk profile and substantially reduce the risk of developing type 2 diabetes. Likewise, small increases in physical activity, such as 15–30 min of brisk walking per day, can cut the risk of heart disease by 10%. Lifestyle or treatment changes that lead to small improvements in metabolic parameters also impact patient outcome – for example, a 5 mmHg decrease in blood pressure can translate into significant reductions in the rates of myocardial infarction and cardiovascular mortality. Benefits of small changes can also be seen in health economic outcome models. Implementing change at an individual versus a population level has different implications for overall benefit and patient motivation. Even very small steps taken in trying to reach guideline targets should represent a positive achievement for patients. Patient engagement is essential – only when patients commit themselves to change can benefits be maintained, and physicians should recognise their influence. Small changes in individual parameters can result in significant beneficial effects; however, a major impact can occur when small changes are made together in multiple parameters. More research is required to elucidate the full impact of small changes on patient outcome.     

BDNF rs6265 Genotype Influences Outcomes of Pharmacotherapy and Subthalamic Nucleus Deep Brain Stimulation in Early-Stage Parkinson's Disease

IntroductionThe efficacy of pharmacotherapy and deep brain stimulation of the subthalamic nucleus in treating Parkinson's disease motor symptoms is highly variable and may be influenced by patient genotype. The relatively common (prevalence about one in three) and protein-altering rs6265 single nucleotide polymorphism (C > T) in the gene BDNF has been associated with different clinical outcomes with levodopa.ObjectiveWe sought to replicate this reported association in early-stage Parkinson's disease subjects and to examine whether a difference in clinical outcomes was present with subthalamic nucleus deep brain stimulation.Materials and MethodsFifteen deep brain stimulation and 13 medical therapy subjects were followed for 24 months as part of the Vanderbilt DBS in Early Stage PD clinical trial (NCT00282152, FDA IDE #G050016). Primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire-39.ResultsOutcomes with drug therapy in subjects carrying the rs6265 T allele were significantly worse following 12 months of treatment compared to C/C subjects (UPDRS: +20 points, p = 0.019; PDQ-39: +16 points, p = 0.018). In contrast, rs6265 genotype had no effect on overall motor response to subthalamic nucleus deep brain stimulation at any time point; further, rs6265 C/C subjects treated with stimulation were associated with worse UPDRS part II scores at 24 months compared to medical therapy.ConclusionsGenotyping for the rs6265 polymorphism may be useful for predicting long-term response to drug therapy and counseling Parkinson's disease patients regarding whether to consider earlier subthalamic nucleus deep brain stimulation. Validation in a larger cohort of early-stage Parkinson's disease subjects is warranted.     

The relationship of organizational culture, stress, satisfaction, and burnout with physician-reported error and suboptimal patient care: results from the MEMO study

BACKGROUND: A report by the Institute of Medicine suggests that changing the culture of health care organizations may improve patient safety. Research in this area, however, is modest and inconclusive. Because culture powerfully affects providers, and providers are a key determinant of care quality, the MEMO study (Minimizing Error, Maximizing Outcome) introduces a new model explaining how physician work attitudes may mediate the relationship between culture and patient safety. RESEARCH QUESTIONS: (1) Which cultural conditions affect physician stress, dissatisfaction, and burnout? and (2) Do stressed, dissatisfied, and burned out physicians deliver poorer quality care? METHODS: A conceptual model incorporating the research questions was analyzed via structural equation modeling using a sample of 426 primary care physicians participating in MEMO. FINDINGS: Culture, overall, played a lesser role than hypothesized. However, a cultural emphasis on quality played a key role in both quality outcomes. Further, we found that stressed, burned out, and dissatisfied physicians do report a greater likelihood of making errors and more frequent instance of suboptimal patient care. PRACTICE IMPLICATIONS: Creating and sustaining a cultural emphasis on quality is not an easy task, but is worthwhile for patients, physicians, and health care organizations. Further, having clinicians who are satisfied and not burned out or stressed contributes substantially to the delivery of quality care.     

Ethnicity as a correlate of the uptake of the first dose of mumps, measles and rubella vaccine

The aim of this study was to investigate whether a relationship exists between ethnicity and uptake of the first dose of mumps, measles and rubella (MMR1) vaccination, and to study important factors influencing the parental decision about vaccination. Examination of routine data on uptake of MMR1 vaccine among children living in the London borough of Brent, North West London, for associations with ethnicity was carried out. Six focus group interviews were held and a questionnaire on factors related to immunisation by convenience samples of mothers from Asian, Afro-Caribbean and White backgrounds was completed. The routine data reported MMR1 vaccine status for 6444 children living in Brent who were aged between 18 months and 3 years on 1 December 2003. A total of 37 mothers took part in the 6 focus group sessions. Significantly higher coverage by MMR1 vaccine in the Asian population (87.1%) compared with Afro-Caribbeans (74.7%) and the White group (57.5%) was noticed. The qualitative data revealed clear differences between the ethnic groups with respect to awareness of the controversy surrounding MMR vaccination (related to use of English-language media) and influence of grandparents and health professionals in decisions about immunisation. A multiple logistic regression model showed that although coverage of MMR vaccination increased with increasing socioeconomic status, there was no evidence of a statistically significant interaction between socioeconomic status and ethnicity. An important association between ethnicity and uptake of MMR1 vaccine is observed. This has implications for efforts to improve the currently inadequate levels of MMR vaccination across the population as a whole.     

The association of elevated body mass index (BMI) with complications and outcomes following anatomic total shoulder arthroplasty: a systematic review

PurposeObesity has been associated with increased perioperative complications following shoulder arthroplasty, though this finding has not been consistently reported. The purpose of this systematic review is to summarize the correlation between elevated body mass index (BMI) and the prevalence of perioperative complications and clinical outcomes following anatomic total shoulder arthroplasty (aTSA).MethodsAn extensive literature search of PubMed, Embase, ScienceDirect, and Google Scholar was conducted up until October 2020. Clinical studies that specifically examined the association between BMI and/or various categories of obesity with perioperative complications and functional outcomes following aTSA were included. Public databases (NIS, ACS-NSQIP, PearlDiver, and statewide databases) were largely excluded from the analysis unless procedural codes allowed for differentiation between reverse total shoulder arthroplasty (rTSA) and aTSA.ResultsEleven studies were included in this systematic review - 9 studies reported solely on perioperative complications, 1 study solely on functional outcomes, and 1 study on both complications and outcomes following aTSA. Seven papers had a MINORS (Methodological Index for Non-Randomized Studies) score of <16, indicating low methodological quality. There was no association found between elevated BMI and overall perioperative medical and surgical complications, surgical site infection (SSI), re-operation without revision, aseptic revision, periprosthetic fracture, intraoperative blood loss, need for blood transfusion, 90-day re-admission, absolute hospital LOS or short-term mortality. There is an increased risk for overall revision following aTSA and need for extended hospital LOS in patients with elevated BMI. Range of motion of the operative shoulder, pain, and patient reported outcome measures (PROMs) have generally demonstrated significant improvement following unconstrained arthroplasty.DiscussionIncreasing BMI was not found to be associated with an elevated risk for the majority of perioperative complications following aTSA. Range of motion and patient reported functional outcomes can be expected to improve, even amongst morbidly obese patients.Level of EvidenceLevel IV; Review Article     

Personalisierte Medizin in der Behandlung von periokulären Tumoren

Die Ophthalmologie - Ziel dieser Arbeit ist es, eine Übersicht über den aktuellen Stand der personalisierten Medizin bei der Therapie ausgewählter periokulärer Tumoren wie...