α-Gal A missense variants associated with Fabry disease can lead to ER stress and induction of the unfolded protein response

Anderson-Fabry Disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA, the gene encoding the lysosomal hydrolase α-galactosidase A (α-Gal A), leading to accumulation of glycosphingolipids in the lysosomes. FD is a multisystemic disorder leading to progressive cardiovascular, cerebrovascular and kidney dysfunction. Phenotypes are divided in two main classes, classic or non-classic, depending on substrate accumulation, age at onset, disease manifestation, severity and progression. The more severe classical phenotype is generally associated with mutations leading to absent or strongly reduced α-Gal A activity, while mutations with higher residual activity generally lead to the non-classical one. Approximately 70% of the over 1,000 Fabry disease-associated mutations are missense mutations, some leading to endoplasmic reticulum (ER) retention of mutant protein. We hypothesized that such mutations could be associated, besides the well-known absence of α-Gal A function/activity, to a possible gain of function effect due to production of a misfolded protein. We hence expressed α-Gal A missense mutations in HEK293 GLA -/- cells and investigated the localization of mutant protein and induction of ER stress and of the unfolded protein response (UPR). We selected a panel of 7 missense mutations, including mutants shown to have residual or no activity in vitro. Immunofluorescence analysis showed that mutants with residual activity have decreased lysosomal localization compared with wild type, and partial retention in the ER, while missense mutants with no residual activity are fully retained in the ER. UPR (ATF6 branch) was significantly induced by all but two mutants, with clear correlation with the extent of ER retention and the predicted mutation structural effect. These data identify a new molecular pathway, associated with gain of function effect, possibly involved in pathogenesis of FD

Analysis of obese patients' medical conditions in the pre and postoperative periods of bariatric surgery

ABSTRACT Objective: to compare the clinical conditions of obese patients in the pre and postoperative period of bariatric surgery. Methods: we carried out a descriptive, retrospective, quantitative study by consulting the charts of 134 patients who underwent bariatric surgery in the period from 2009 to 2014. We collected the data between September and November 2015. We performed a descriptive statistical analysis and comparative analysis of anthropometric, metabolic, biochemical and clinical variables, considering six months before and after surgery. Results: the majority of the patients were female (91.8%), with a higher prevalence (35%) in the age group 18-29 years old, complete high-school education (65.6%) and grade III obesity (60.4%). Six months after surgery, weight and lipid profile reduction were significant in both genders, but the impact on biochemical, anthropometric, metabolic and clinical parameters was significant only in female subjects, with a reduction in morbidities associated with obesity, such as arterial hypertension, diabetes mellitus, dyslipidemia and metabolic syndrome and in the use of drugs to control them. Conclusion: bariatric surgery was effective in weight loss, with improvements in anthropometric, metabolic and biochemical parameters and in the reduction of morbidities associated with obesity

Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial

Introduction: Primary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease may have different long-term outcomes. After 10 years of follow-up, 35%-50% of the untreated patients with persistent nephrotic syndrome may die or progress to end stage renal disease. The 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend that initial therapy should consist of alternating steroids and an alkylating agent for 6 months. Recent observational studies showed that the anti-CD20 antibody rituximab may be effective in inducing remission. We designed a pilot multicentre randomised trial to inform the design of a larger trial testing the efficacy and safety of treatment with steroids and cyclophosphamide versus rituximab in patients with primary MN and heavy proteinuria (>3.5 g/24 hours). Methods and analysis: This pilot, open-label, two-parallel-arm, randomised clinical trial will enrol 70 patients with primary MN and heavy proteinuria. Patients will be randomised in a 1:1 ratio to either the intervention arm (rituximab) or the active comparator arm (corticosteroid/alkylating-agent therapy). The study will provide estimates of the probability of complete remission of proteinuria and risk of serious side effects at 12 months to inform the design of a larger trial. We will also assess the recruitment potential of each participating centre to address study feasibility. Ethics and dissemination: The trial received ethics approval from the local ethics boards. We will publish pilot data to inform the design of a larger clinical trial. Trial registration numbers: NCT03018535; 2011-006115-59

Analysis of obese patients' medical conditions in the pre and postoperative periods of bariatric surgery

ABSTRACT Objective: to compare the clinical conditions of obese patients in the pre and postoperative period of bariatric surgery. Methods: we carried out a descriptive, retrospective, quantitative study by consulting the charts of 134 patients who underwent bariatric surgery in the period from 2009 to 2014. We collected the data between September and November 2015. We performed a descriptive statistical analysis and comparative analysis of anthropometric, metabolic, biochemical and clinical variables, considering six months before and after surgery. Results: the majority of the patients were female (91.8%), with a higher prevalence (35%) in the age group 18-29 years old, complete high-school education (65.6%) and grade III obesity (60.4%). Six months after surgery, weight and lipid profile reduction were significant in both genders, but the impact on biochemical, anthropometric, metabolic and clinical parameters was significant only in female subjects, with a reduction in morbidities associated with obesity, such as arterial hypertension, diabetes mellitus, dyslipidemia and metabolic syndrome and in the use of drugs to control them. Conclusion: bariatric surgery was effective in weight loss, with improvements in anthropometric, metabolic and biochemical parameters and in the reduction of morbidities associated with obesity.</div

Effect of sleeve gastrectomy on lipid parameters and cardiometabolic risk in young women

ABSTRACT Objective: to analyze the effect of vertical gastrectomy on lipid profile and cardiometabolic risk in young women, preoperatively and 6 months after the operation. Methods: retrospective study, encompassing medical record reviews of women’s charts, preoperatively and in six months after the operation. Data collection was performed in the second half of 2015, using a review protocol with questions on the clinical-laboratory profile, anthropometric and laboratory classification of dyslipidemias. Descriptive and inferential analysis were used to treat the variables, using measures of variance, association and linear regression. Results: we analyzed medical records of 114 women undergoing vertical gastrectomy, with a mean age of 33.82±10.92, and with complete high school education. There was a significant reduction of anthropometric data, as well as serum lipid values, six months after the surgical procedure. The coefficients of determination and the results of linear regression, showed that the reduction in serum triglyceride values and increase in high-density lipoprotein have a direct impact on the reduction of the cardiometabolic risk. Regarding the laboratory classification of dyslipidemias, it was observed that the majority presented a significant reduction at the six-month follow-up. Mixed hyperlipidemia showed no significant reduction. The categorized cardiometabolic risk showed a significant reduction in women at risk before vertical gastrectomy. Conclusion: at the six-month follow-up, vertical gastrectomy was effective in reducing the serum lipid profile and the cardiometabolic risk of young women when compared to the preoperative data. There was also a different improvement in the laboratory classification of dyslipidemias at the six-month follow-up after the surgical procedure.</jats:p

Racial and social disparities in the access to automated peritoneal dialysis - Results of a national PD cohort

The prevalence of patients on automated peritoneal dialysis (APD) is increasing worldwide and may be guided by clinical characteristics, financial issues and patient option. Whether socioeconomic factors at the patient level may influence the decision for the initial peritoneal dialysis (PD) modality is unknown. This is a prospective cohort study. The primary outcome of interest was the probability to start PD on APD. The inclusion criteria were adult patients incident in PD. Exclusion criteria were missing data for either race or initial PD modality. We used a mixed-model analysis clustering patients according to their PD center and region of the country. We included 3,901 patients of which 1,819 (46.6%) had APD as their first modality. We found a significant disparity for race and educational level with African American patients less likely to start on APD (Odds ratio 0.74 CI95% 0.58-0.94) compared to Whites whilst those with greater educational levels were more likely to start on APD (Odds ratio 3.70, CI95% 2.25-6.09) compared to illiterate patients. Limiting the use of APD in disadvantaged population may be unethical. Demographics and socioeconomic status should not be necessarily part of the decision-making process of PD modality choice.Pontifícia Universidade Católica Do Paraná (PUCPR)Wessex Renal and Transplant Service Queen Alexandra HospitalPrograma de Pós-Graduação em Medicina e Ciências da Saúde Pontifícia Universidade Católica Do Rio Grande Do sul (PUCRS)Universidade Estadual Paulista (UNESP)Universidade Estadual Paulista (UNESP

Admission Bedside Lung Ultrasound Reclassifies Mortality Prediction in Patients With ST-Segment–Elevation Myocardial Infarction

Background: Early risk stratification is essential for in-hospital management of ST-segment–elevation myocardial infarction. Acute heart failure confers a worse prognosis, and although lung ultrasound (LUS) is recommended as a first-line test to assess pulmonary congestion, it has never been tested in this setting. Our aim was to evaluate the prognostic ability of admission LUS in patients with ST-segment–elevation myocardial infarction. Methods: LUS protocol consisted of 8 scanning zones and was performed before primary percutaneous coronary intervention by an operator blinded to Killip classification. A LUS combined with Killip (LUCK) classification was developed. Receiver operating characteristic and net reclassification improvement analyses were performed to compare LUCK and Killip classifications. Results: We prospectively investigated 215 patients admitted with ST-segment–elevation myocardial infarction between April 2018 and June 2019. Absence of pulmonary congestion detected by LUS implied a negative predictive value for in-hospital mortality of 98.1% (93.1–99.5%). The area under the receiver operating characteristic curve of the LUCK classification for in-hospital mortality was 0.89 ( P =0.001), and of the Killip classification was 0.86 ( P &lt;0.001; P =0.05 for the difference between curves). LUCK classification improved Killip ability to predict in-hospital mortality with a net reclassification improvement of 0.18. Conclusions: In a cohort of patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, admission LUS added to Killip classification was more sensitive than physical examination to identify patients at risk for in-hospital mortality. LUCK classification had a greater area under the receiver operating characteristic curve and reclassified Killip classification in 18% of cases. Moreover, absence of pulmonary congestion on LUS provided an excellent negative predictive value for in-hospital mortality. </jats:sec

Comparison of Admission Lung Ultrasound and Left Ventricular End-Diastolic Pressure in Patients Undergoing Primary Percutaneous Coronary Intervention

Background: Left ventricular end-diastolic pressure (LVEDP) is related to ventricular dysfunction and increased retrograde pulmonary capillary pressure. Lung ultrasound (LUS) is a sensitive and easy-to-use method for assessment of pulmonary congestion. Both methods have shown prognostic value in patients with ST-segment–elevation myocardial infarction. Our aim was to evaluate the correlation between LVEDP and bedside LUS and to compare their prognostic value in patients undergoing primary percutaneous coronary intervention. Methods: Prospective cohort study of ST-segment–elevation myocardial infarction patients treated in a tertiary care hospital in Brazil. LUS was performed immediately before coronary angiography. LVEDP was recorded before primary percutaneous coronary intervention, blinded to LUS results. Primary outcome was any in-hospital major adverse cardiovascular event, defined as in-hospital mortality, new myocardial infarction, stroke, and new cardiogenic shock. Results: In total, 218 patients were included; their mean age was 60 (±12) years, and 64% were men. Cardiogenic shock was present in 16.5% of patients on admission. Overall in-hospital mortality was 15%. Median LVEDP was 19 mm Hg (interquartile range, 13–28); median LUS zones positive for pulmonary congestion were 1/patient (interquartile range, 0–5); Spearman correlation between them was 0.33 ( P &lt;0.001). LVEDP and LUS C statistic for in-hospital major adverse cardiovascular event was 0.63 ([95% CI, 0.55–0.70] P =0.002) and 0.71 ([95% CI, 0.64–0.77] P &lt;0.001), respectively. In multivariable analysis, LUS remained associated with in-hospital major adverse cardiovascular event (odds ratio, 1.14 [95% CI, 1.06–1.23]; P =0.01) for every positive LUS zone; LVEDP, however, did not (odds ratio, 1.01 [95% CI, 0.99–1.03]; P =0.23). Conclusions: We found a weak correlation between LVEDP and LUS in our cohort of ST-segment–elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. Pulmonary congestion in acute heart failure is a complex pathophysiological process and goes beyond fluid overload and hemodynamics. Unlike LVEDP, LUS was significantly associated with in-hospital major adverse cardiovascular event, new cardiogenic shock, and in-hospital mortality in multivariable analysis. Graphic Abstract: A graphic abstract is available for this article. </jats:sec