Mild heat treatments induce long-term changes in metabolites associated with energy metabolism in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Heat-induced hormesis, the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. Yet little is known about the mechanisms underlying this effect. We used nuclear magnetic resonance spectroscopy to investigate the long-term effects of repeated mild heat treatments on the metabolome of male Drosophila melanogaster. 10 days after the heat treatment, metabolic aging appears to be slowed down, and a treatment response with 40 % higher levels of alanine and lactate and lower levels of aspartate and glutamate were measured. All treatment effects had disappeared 16 days later. Metabolic reprogramming has been associated with the life extending effects of dietary restriction. The metabolite changes induced by the hormetic treatment suggest that the positive effects might not be limited to the repair pathways induced, but that there also is a change in energy metabolism. A possible direct link between changes in energy metabolism and heat induced increase in Hsp70 expression is discussed.     

Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging

OBJECTIVES: We aimed to test the diagnostic accuracy of cardiovascular magnetic resonance (CMR) imaging in distinguishing pathological left ventricular non-compaction (LVNC) from lesser degrees of trabecular layering seen in healthy volunteers and, in those with cardiomyopathies and concentric left ventricular hypertrophy, potential differential diagnoses. We hypothesized that pathological trabeculation could be distinguished by determining the ratio of non-compacted to compacted myocardium (NC/C ratio). BACKGROUND: Left ventricular non-compaction is characterized by a non-compacted myocardial layer in the left ventricle. Cardiovascular magnetic resonance images this layer with unprecedented quality, particularly in the ventricular apex, where echocardiography has inherent difficulties. METHODS: We analyzed magnetic resonance cine images, using the 17-segment model in 45 healthy volunteers, 25 athletes, 39 patients with hypertrophic cardiomyopathy and 14 with dilated cardiomyopathy, 17 with hypertensive heart disease, and 30 with aortic stenosis, as well as images from 7 patients previously diagnosed with LVNC whose diagnoses were supported by additional features. RESULTS: Areas of non-compaction were common and occurred more frequently in all groups studied in apical and lateral, rather than in basal or septal, segments. A NC/C ratio of >2.3 in diastole distinguished pathological non-compaction, with values for sensitivity, specificity, and positive and negative predictions of 86%, 99%, 75%, and 99%, respectively. CONCLUSIONS: Left ventricular non-compaction is diagnosed accurately with CMR using the NC/C ratio in diastole.     

Clinical features and serum antinuclear antibodies in 230 Danish patients with systemic sclerosis

The objective was to investigate the relationship between the presence of different types of antinuclear antibodies (ANA) in patients with systemic sclerosis (SSc) and the presence of clinical features. Sera from 230 patients with SSc were tested for the presence of ANA, including anticentromere antibodies (ab), antitopoisomerase I ab, anti- U1 RNP ab and antinucleolar ab, including anti-Th RNP, anti-U3 RNP and anti-U17 RNP. Clinical features were registered prospectively in a clinical database. Eighty-two per cent of the patients were women. The median age was 58 yr (45-67, quartiles) and median age at disease onset was 44 (30-55) yr. ANA were found in 86% of the patients (anticentromere: 34%; antitopoisomerase I: 14%; anti-U1 RNP: 6.5%; antinucleolar total: 16%; anti-Th RNP: 2.2%; anti-U3 RNP: 3.5%; anti- U17 RNP: 0%). Anticentromere ab were found to be related to a high prevalence of calcinosis, telangiectasia, digital ulcers, acrosclerosis, primary biliary cirrhosis, isolated reduction of pulmonary diffusing capacity, and a low prevalence of radiological evidence of pulmonary fibrosis. Antitopoisomerase I ab were associated with a high prevalence of digital joint deformity, distal osteolysis, radiological signs of pulmonary fibrosis, a low prevalence of calcinosis and late onset of disease. Anti-U1 RNP ab were related to a high prevalence of arthritis and myositis, a low prevalence of calcinosis, and early disease onset. The presence of antinucleolar ab, including anti-U3 RNP and anti-Th RNP, was not significantly related to any particular clinical features in this study; possibly due to the small number of patients with these ab. The presence of anticentromere, antitopoisomerase I and anti-U1 RNP ab in the serum was also found to have previously described clinical correlations in a group of Danish SSc patients.      

Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens

A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.     

The immunofluorescence antibody test (IFAT) for the diagnosis of schistosomiasis used in a non-endemic area

OBJECTIVE: To evaluate an immunofluorescence antibody test (IFAT) for diagnosis of schistosomiasis in nonimmune travellers and immigrants from endemic areas. METHODS: 65 patients (48 Danes and 17 immigrants) with schistosomiasis were included. The diagnosis of schistosomiasis was based on the presence of schistosome eggs in faeces, urine, sperm, rectal or bladder biopsies and/or the presence of specific antibodies determined by the serological immunofluorescence antibody test (IFAT). Egg excretion was detected using conventional methods and the IFAT performed on whole S. mansoni schistosomula worms, harvested after 8 weeks from mice. Two patterns of immunofluorescence were observed: Fluorescence in the gut of the schistosome called 'Gut Associated Antigen, GAA', and fluorescence of the surface of the schistosomula called 'Membrane Bound Antigen, MBA'. RESULTS: Eggs were found in 44% of the Danish patients and in 76% of immigrants. The diagnosis was based on a positive IFAT in 48% of the patients. In patients from nonendemic areas, the finding of antibodies against GAA was diagnostic while optimal sensitivity in the immigrants was reached by measuring antibodies against both GAA and MBA. CONCLUSION: In patients from nonendemic areas GAA is a sensitive marker of acute infection with schistosomiasis. In patients from endemic areas the demonstration of both GAA and MBA is necessary to properly identify long-lasting, nonacute infections. Egg-detection and/or measurement of CAA and CCA remain the methods of choice to monitor treatment as the immunofluorescence assay may remain positive for several years after treatment.     

Spontaneous and induced immunoglobulin synthesis and anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis: relation to leukocyte subpopulations in blood and active lesions

Summary Using a reverse plaque forming cell (PFC) assay the production of immunoglobulin (Ig) by peripheral blood mononuclear cells (MNCs) in vitro was studied in 12 patients with Wegener's granulomatosis (WG). Spontaneous IgG production was increased in two of six untreated patients. The IgG response of MNCs from eight untreated patients to pokeweed mitogen (PWM) and Epstein-Barr virus (EBV) stimulation was significantly depressed. The IgM and IgA production followed the individual pattern of IgG. Blood B-cell and T-cell subset concentrations were normal before therapy, whereas the monocyte concentration was increased in four of six patients. Titers of anti-neutrophil cytoplasm autoantibodies (ANCAs) did not correlate with spontaneous or induced Ig production nor with blood leukocyte subset concentrations. Biopsy specimens from upper respiratory tract lesions in seven untreated patients showed numerous macrophages, activated T lymphocytes, and plasma cells, suggesting a pathogenetic role of these cells in the development of lesions and local production of ANCAs.     

Purified murine hematopoietic stem cells function longer on nonirradiated W41/Wv than on +/+ irradiated stroma

Mouse bone marrow (BM) was separated into low-density, lineage- negative, wheat germ agglutinin-positive (WGA+), Rhodamine-123 bright (Rhbright) or dim (Rhdim) cells to obtain populations that were highly enriched for committed progenitors (Rhbright cells) or for more primitive stem cells (Rhdim). When 2,500 Rhbright or Rhdim cells were seeded onto 6-week-old irradiated (20 Gy) long-term BM cultures (LTBMC), the nonadherent cell production from Rhbright cells was transient and ended after 5 weeks. Production from Rhdim cells did not begin until week 3, peaked at week 5, and ended at week 8, when the irradiated stroma seemed to fail. Termination of cell production from Rhdim cells did not occur in nonirradiated LTBMC from W41/Wv mice. During peak nonadherent cell production, 25% to 30% of the cells in the nonirradiated LTBMC from W41/Wv mice had donor cell markers. Two approaches were tested to try to enhance the proportion or number of donor cells. Addition of Origen-HGF at the time of seeding Rhdim cells caused a nonspecific increase in both host and donor cell production, but a specific increase in production of donor cells was obtained by seeding the cultures at 2 weeks rather than 6 weeks. Limiting dilution of Rhdim cells gave the same frequency of wells producing cells on both irradiated +/+ and nonirradiated W41/Wv or W/Wv cultures.     

Sobrevida de Pacientes com Insuficiência Cardíaca Aguda e Fração de Ejeção Intermediária em um País em Desenvolvimento – Estudo de Coorte no Sul do Brasil

BackgroundHeart Failure with mid-range Ejection Fraction (HFmEF) was recently described by European and Brazilian guidelines on Heart Failure (HF). The ejection fraction (EF) is an important parameter to guide therapy and prognosis. Studies have shown conflicting results without representative data from developing countries.ObjectiveTo analyze and compare survival rate in patients with HFmEF, HF patients with reduced EF (HFrEF), and HF patients with preserved EF (HFpEF), and to evaluate the clinical characteristics of these patients.MethodsA cohort study that included adult patients with acute HF admitted through the emergency department to a tertiary hospital, reference in cardiology, in south Brazil from 2009 to 2011. The sample was divided into three groups according to EF: reduced, mid-range and preserved. A Kaplan-Meier curve was analyzed according to the EF, and a logistic regression analysis was done. Statistical significance was established as p < 0.05.ResultsA total of 380 patients were analyzed. Most patients had HFpEF (51%), followed by patients with HFrEF (32%) and HFmEF (17%). Patients with HFmEF showed intermediate characteristics related to age, blood pressure and ventricular diameters, and most patients were of ischemic etiology. Median follow-up time was 4.0 years. There was no statistical difference in overall survival or cardiovascular mortality (p=.0031) between the EF groups (reduced EF: 40.5% mortality; mid-range EF 39.7% and preserved EF 26%). Hospital mortality was 7.6%.ConclusionThere was no difference in overall survival rate between the EF groups. Patients with HFmEF showed higher mortality from cardiovascular diseases in comparison with HFpEF patients. (Arq Bras Cardiol. 2021; 116(1):14-23)     

High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study

Background

As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described.

Methods

Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report.

Results

Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report.

Conclusions

Adherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.