Effective critical micellar concentration of a zwitterionic detergent: A fluorimetric study on n-dodecyl phosphocholine

We have investigated the effect of ionic strength on the aggregation behavior of n-dodecyl phosphocholine. On the basis of the classical Corrin-Harkins relation, the critical micellar concentration of this detergent decreases with a biphasic trend on lithium chloride addition. It is nearly constant below 150 mM salt, with a mean value of 0.91 mM, whereas it undergoes a dramatic 80-fold decrease in 7 M LiCl. Such a drop in the critical micellar concentration could be explained by the effect of salting out and the implication of phosphocholine head groups on the organization of surrounding water. Knowledge of the effective critical micellar concentration of n-dodecyl phosphocholine could be useful in the purification of membrane proteins in non-denaturing conditions

Assessment of the management and clinical outcomes of patients with non-diabetic hyperglycaemia and newly diagnosed type 2 diabetes in primary care in England

Background It is unknown whether the detection of non-diabetic hyperglycaemia before the diagnosis of Type 2 diabetes is associated with vascular disease at time or following the diagnosis of Type 2 diabetes. Aim I assessed the association between glycaemic testing and detection of non-diabetic hyperglycaemia before the diagnosis of Type 2 diabetes is associated and vascular disease at time or following the diagnosis of Type 2 diabetes. Methods I identified 159,736 individuals with newly diagnosed Type 2 diabetes from the CPRD database in England between 2004 and 2017. I used logistic regression models to compare presence of vascular disease at the time of Type 2 diabetes diagnosis by prior glycaemic status. I employed time-partitioned Cox regression models to model differences in rates of vascular disease and mortality following the diagnosis of Type 2 diabetes. Results Half of the study population (49.9%) had at least one vascular disease, over one-third (37.4%) had microvascular disease, and almost a quarter (23.5%) had a diagnosed macrovascular disease at the time of Type 2 diabetes diagnosis. Individuals with prior non-diabetic hyperglycaemia were more likely to have microvascular disease and coronary heart disease at time of diagnosis of Type 2 diabetes. As compared with individuals with glycaemic values within the normal range in the three years before the diagnosis of Type 2 diabetes, those detected with non-diabetic hyperglycaemia had increased risk of microvascular disease that persisted up to 7.5 years. Conclusions Non-diabetic hyperglycaemia before diagnosis of Type 2 diabetes is associated with increased odds of microvascular disease and coronary heart disease in newly diagnosed Type 2 diabetes. It is also associated with increased rates of microvascular disease following the diagnosis of Type 2 diabetes. Detection of non-diabetic hyperglycaemia might represent an opportunity for a timely identification of NDH and specific clustering of NDH with other risk factors for T2D, which might prompt earlier assessment for risk factors and tailored cardiovascular risk reduction strategies during the NDH phase to reduce the burden of vascular disease.Open Acces

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities

Management of vascular risk in people with multiple sclerosis at the time of diagnosis in England: A population-based study

Background: Vascular management in People with Multiple Sclerosis (PwMS) is important given the higher vascular burden than the general population, associated with increased disability and mortality. Objectives: We assessed differences in the prevalence of type 2 diabetes and hypertension; and the use of antidiabetic, antihypertensive and lipid-lowering medications at the time of the MS diagnosis. Methods: This is a population-based study including PwMS and matched controls between 1987 and 2018 in England. Results: We identified 12,251 PwMS and 72,572 matched controls. PwMS had a 30% increased prevalence of type 2 diabetes (95% confidence interval (CI) = 1.19, 1.42). Among those with type 2 diabetes, PwMS had a 56% lower prevalence of antidiabetic usage (95% CI = 0.33, 0.58). Prevalence of hypertension was 6% greater in PwMS (95% CI = 1.05, 1.06), but in those with hypertension, usage of antihypertensive was 66% lower in PwMS (95% CI = 0.28, 0.42) than controls. Treatment with lipid-lowering medications was 63% lower in PwMS (95% CI = 0.54, 0.74). PwMS had a 0.4-mm Hg lower systolic blood pressure (95% CI = −0.60, −0.13). 3.8% of PwMS were frail. Conclusion: At the time of diagnosis, PwMS have an increased prevalence of vascular risk factors, including hypertension and diabetes though paradoxically, there is poorer treatment. Clinical guidelines supporting appropriate vascular assessment and management in PwMS should be developed

The association between voluntary health insurance and health outcomes in older adults in Europe: A survival analysis

Objectives: Voluntary health insurance (VHI) often serves a supplementary role in Europe. The ageing population and adoption of cost-sharing models in response to economic pressures raise concerns that VHI could contribute to health inequalities among older people. This study investigates the association of VHI with health outcomes among older people across 16 European countries and Israel. Study design: Prospective cohort study. Methods: Data on participants aged ≥50 years across 16 European countries and Israel were obtained from four waves (2013–2020) of the Survey of Health, Ageing, and Retirement in Europe (SHARE). Gompertz proportional hazards models assessed the association of VHI with mortality and multimorbidity. Hazard ratios (HR) and 95 % confidence intervals (CI) are reported. Results: VHI prevalence was 38.2 % in 2013 and 34.9 % in 2015, with a higher prevalence among higher-income groups. VHI was associated with a 13 % lower risk of mortality (HR: 0.87, 95% CI: 0.81–0.94) after accounting for demographic, socioeconomic, lifestyle, and health-related factors. VHI was also associated with a lower risk of multimorbidity (HR: 0.92, 95 % CI: 0.87–0.97). Conclusions: VHI was associated with a reduced risk of mortality and multimorbidity, after adjusting for demographic, socioeconomic, lifestyle, and health-related factors. VHI might facilitate the access to timely and high-quality healthcare services, which may exacerbate health inequalities among older individuals

Trajectories and management of vascular risk following the diagnosis of multiple sclerosis: A population-based matched cohort study between 1987 and 2018 in England

Background: People with multiple sclerosis (PwMS) have an increased cardiovascular and cerebrovascular disease burden, but this could be mitigated by vascular risk factor management. Objectives: We compared the trajectories of vascular risk factors, vascular comorbidities and clinical management in PwMS against the general population post-MS diagnosis while controlling for frailty. Methods: Retrospective longitudinal analysis using English data from the Clinical Practice Research Datalink between 1987 and 2018 comprising PwMS matched with up to six controls without MS by age, sex and general practice. Results: We compared 12,251 PwMS with 72,572 matched controls; 3.8% of PwMS had mild–moderate frailty, 1.2% more than matched controls. Compared to controls, PwMS had an elevated incidence of Type 2 diabetes (HR 1.18, 95% CI (1.04, 1.34)), and starting antihypertensive medications (HR 1.40, 95% CI (1.33, 1.47)). Among those with hypertension at baseline, blood pressure trajectories did not differ between PwMS and controls. PwMS had increased rates of meeting targets for hypertension management (HR 1.25, 95% CI (1.12, 1.41)). Conclusion: The observation that PwMS with hypertension are more likely to meet treatment targets than matched controls is encouraging, but the elevated rates of vascular comorbidities suggest that tighter vascular management may be needed in this population

Trajectories and management of vascular risk following the diagnosis of multiple sclerosis: A population-based matched cohort study between 1987 and 2018 in England

Background: People with multiple sclerosis (PwMS) have an increased cardiovascular and cerebrovascular disease burden, but this could be mitigated by vascular risk factor management. // Objectives: We compared the trajectories of vascular risk factors, vascular comorbidities and clinical management in PwMS against the general population post-MS diagnosis while controlling for frailty. // Methods: Retrospective longitudinal analysis using English data from the Clinical Practice Research Datalink between 1987 and 2018 comprising PwMS matched with up to six controls without MS by age, sex and general practice. // Results: We compared 12,251 PwMS with 72,572 matched controls; 3.8% of PwMS had mild–moderate frailty, 1.2% more than matched controls. Compared to controls, PwMS had an elevated incidence of Type 2 diabetes (HR 1.18, 95% CI (1.04, 1.34)), and starting antihypertensive medications (HR 1.40, 95% CI (1.33, 1.47)). Among those with hypertension at baseline, blood pressure trajectories did not differ between PwMS and controls. PwMS had increased rates of meeting targets for hypertension management (HR 1.25, 95% CI (1.12, 1.41)). // Conclusion: The observation that PwMS with hypertension are more likely to meet treatment targets than matched controls is encouraging, but the elevated rates of vascular comorbidities suggest that tighter vascular management may be needed in this population

A Cardiovascular Risk Score for Use in Occupational Medicine

Cardiovascular disease is one of the most frequent causes of long-term sickness absence from work. The study aims to develop and validate a score to assess the 10-year risk of unsuitability for work accounting for the cardiovascular risk. The score can be considered as a prevention tool that would improve the cardiovascular risk assessment during health surveillance visits under the assumption that a high cardiovascular risk might also translate into high risk of unsuitability for work. A total of 11,079 Italian workers were examined, as part of their scheduled occupational health surveillance. Cox proportional hazards regression models were employed to derive risk equations for assessing the 10-year risk of a diagnosis of unsuitability for work. Two scores were developed: the CROMA score (Cardiovascular Risk in Occupational Medicine) included age, sex, smoking status, blood pressure (systolic and diastolic), body mass index, height, diagnosis of hypertension, diabetes, ischemic heart disease, mental disorders and prescription of antidiabetic and antihypertensive medications. The CROMB score was the same as CROMA score except for the inclusion of only variables statistically significant at the 0.05 level. For both scores, the expected risk of unsuitability for work was higher for workers in the highest risk class, as compared with the lowest. Moreover results showed a positive association between most of cardiovascular risk factors and the risk of unsuitability for work. The CROMA score demonstrated better calibration than the CROMB score (11.624 (p-value: 0.235)). Moreover, the CROMA score, in comparison with existing CVD risk scores, showed the best goodness of fit and discrimination

NMR Structure and CD Titration with Metal Cations of Human Prion α2-Helix-Related Peptides

The 173–195 segment corresponding to the helix 2 of the C-globular prion protein domain could be one of several “spots” of intrinsic conformational flexibility. In fact, it possesses chameleon conformational behaviour and gathers several disease-associated point mutations. We have performed spectroscopic studies on the wild-type fragment 173–195 and on its D178N mutant dissolved in trifluoroethanol to mimic the in vivo system, both in the presence and in the absence of metal cations. NMR data showed that the structure of the D178N mutant is characterized by two short helices separated by a kink, whereas the wild-type peptide is fully helical. Both peptides retained these structural organizations, as monitored by CD, in the presence of metal cations. NMR spectra were however not in favour of the formation of definite ion-peptide complexes. This agrees with previous evidence that other regions of the prion protein are likely the natural target of metal cation binding

Comorbidity in the multiple sclerosis clinic

Comorbid conditions are common in people with multiple sclerosis (MS) and can lead to diagnostic delay and poorer outcomes. Neurologists have an opportunity to identify and address comorbidities within routine care, without major time or resource burden. This review discusses modifiable comorbidities in MS – focusing on hypertension, dyslipidaemia, diabetes, and osteoporosis—highlighting their impact and potential intervention