Podocytes are new cellular targets of haemoglobin‐mediated renal damage

Recurrent and massive intravascular haemolysis induces proteinuria, glomerulosclerosis, and progressive impairment of renal function, suggesting podocyte injury. However, the effects of haemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin–cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway, and altered podocyte morphology, with decreased expression of the slit diaphragm proteins nephrin and synaptopodin. Hb uptake activated nuclear factor erythroid‐2‐related factor 2 (Nrf2) and induced expression of the Nrf2‐related antioxidant proteins haem oxygenase‐1 (HO‐1) and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular haemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression, and podocyte apoptosis. These pathological effects were enhanced in Nrf2‐deficient mice, whereas Nrf2 activation with sulphoraphane protected podocytes against Hb toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO‐1, ferritin and phosphorylated Nrf2 in renal sections and urinary sediments of patients with massive intravascular haemolysis, such as atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular haemolysis, promoting oxidative stress, podocyte dysfunction, and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular haemolysis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Fat-free mass at admission predicts 28-day mortality in intensive care unit patients: the international prospective observational study Phase Angle Project

Purpose

Phase angle as measured by bioelectrical impedance analysis reflects fat-free mass. Fat-free mass loss relates to worse prognosis in chronic diseases. Primary aim of this study was: to determine the association between fat-free mass at intensive care unit admission and 28-day mortality.

Methods

Ten centres in nine countries participated in this multicentre prospective observational study. The inclusion criteria were age >18 years; expected length of stay >48 h; absence of pacemaker, heart defibrillator implant, pregnancy and lactation. Fat-free mass was assessed by measurement of the 50-kHz phase angle at admission. The primary endpoint was 28-day mortality. The area under the receiver operating characteristic curve (AUC) was used to assess prediction of 28-day mortality by fat-free mass at ICU admission. The variables associated with 28-day mortality were analysed by means of multivariable logistic regression.

Results

Of the 3605 patients screened, 931 were analysed: age 61 ± 16 years, male 60 %, APACHE II 19 ± 9, body mass index 26 ± 6, day 1 phase angle 4.5° ± 1.9°. Day 1 phase angle was lower in patients who eventually died than in survivors (4.1° ± 2.0° vs. 4.6° ± 1.8°, P = 0.001). The day 1 phase angle AUC for 28-day mortality was 0.63 [0.58–0.67]. In multivariable analysis, the following were independently associated with 28-day mortality: age (adjusted odds ratio (aOR) 1.014 [95 % confidence interval 1.002–1.027], P = 0.03), day 1 phase angle (aOR 0.86 [0.78–0.96], P = 0.008), APACHE II (aOR 1.08 [1.06–1.11], P < 0.001), surgical patient (aOR 0.51 [0.33–0.79], P = 0.002), and admission for other diagnosis (aOR 0.39 [0.21–0.72], P = 0.003). A multivariable combined score improved the predictability of 28-day mortality: AUC = 0.79 [0.75–0.82].

Conclusion

Low fat-free mass at ICU admission is associated with 28-day mortality. A combined score improves mortality predictability. Trial registration: NCT01907347 (http://www.clinicaltrials.gov).

     

Determinants of violence against health workers in Portugal

The focus of this article is on the determinants of workplace violence against health workers identified in two cross-sectional analytical studies. The prevalence of victims of the several types and of any-type of workplace violence was estimated in each study, as well as the relative frequency of the associated characteristics. Each dependent variable was also analyzed, in relation to the dichotomized independent variables using a stepwise logistic regression strategy. The Ministry of Health has adopted strategies, which include guidelines on what to do to prevent and correct violence against health workers and a workplace violence observatory. Workplace violence has societal, organizational and individual determinants that can be prevented and monitored.     

Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides

OBJECTIVE: This study tests the usefulness of ceftriaxone combined with ampicillin as an alternative to ampicillin plus gentamicin for the treatment of experimental endocarditis due to Enterococcus faecalis without high-level resistance to aminoglycosides. It also determines whether adding ceftriaxone to ampicillin and gentamicin increases the effectiveness against experimental enterococcal endocarditis resulting from E. faecalis. METHODS: Animals with catheter-induced endocarditis were infected intravenously with 108 cfu of the EF91 strain of E. faecalis and were treated for 3 days with ampicillin 2 g every 4 h administered as 'human-like' (H-L) pharmacokinetics, plus gentamicin 1 mg/kg every 8 h H-L, or ceftriaxone 2 g every 12 h H-L alone or combined with gentamicin 6 mg/kg every 24 h administered subcutaneously. RESULTS: The results of therapy for experimental endocarditis resulting from EF91 showed that the combination of ampicillin plus ceftriaxone was as effective as ampicillin plus gentamicin. The triple combination did not improve on the overall efficacies of the two-drug combinations. CONCLUSIONS: Because of its lower nephrotoxicity, ampicillin plus ceftriaxone may be a useful alternative therapy for E. faecalis endocarditis in selected patients.     

Cancer: disease and nutrition are key determinants of patients’ quality of life

Goals of work The aims of this study were (1) to evaluate quality of life (QoL), nutritional status and dietary intake taking into account the stage of disease and therapeutic interventions, (2) to determine potential interrelationships, and (3) to quantify the relative contributions of the cancer, nutrition and treatments on QoL.Patients and methods In this prospective cross-sectional study conducted in 271 head and neck, oesophagus, stomach and colorectal cancer patients, the following aspects were evaluated: QoL (EORTC-QLQ C30), nutritional status (percent weight loss over the previous 6 months), usual diet (comprehensive diet history), current diet (24-h recall) and a range of clinical variables.Main results Usual and current intakes differed according to the site of the tumour (P=0.02). Patients with stage III/IV disease showed a significant reduction from their usual energy/protein intake (P=0.001), while their current intakes were lower than in patients with stage I/II disease (P=0.0002). Weight loss was greater in patients with stage III/IV disease than in those with stage I/II disease (P=0.001). Estimates of effect size revealed that QoL function scores were determined in 30% by cancer location, in 20% by nutritional intake, in 30% by weight loss, in 10% by chemotherapy, in 6% by surgery, in 3% by disease duration and in 1% by stage of disease. Likewise in the case of symptom scales, 41% were attributed to cancer location, 22% to stage, 7% to nutritional intake, 7% to disease duration, 4% to surgery, 1% to weight loss and 0.01% to chemotherapy. Finally for single items, 30% were determined by stage, 20% by cancer location, 9% by intake, 4% by surgery, 3% by weight loss, 3% by disease duration and 1% by chemotherapy.Conclusions Although cancer stage was the major determinant of patients QoL globally, there were some diagnoses for which the impact of nutritional deterioration combined with deficiencies in nutritional intake may be more important than the stage of the disease process.Conflict of interest statement: The authors assert that they have no financial or personal relationships with other people or organizations that could inappropriately influence their work.     

Tumor microenvironment and hemorheological abnormalities

This article reviews the various mechanisms in a malignant tumor that lead to hypoxia, production of tumor interstitial fluid, and rheological changes in its microenvironment. In addition, the associated procoagulant effects are described. The latter phenomenon is the result of complex and dynamic interplay among tumor cells, endothelial cells, circulating blood cells, and angiogenic, clotting, and hemorheological factors. The implications of these abnormalities on therapeutic approach are discussed.     

A cross-sectional study to assess the prevalence of DSM-5 specific learning disorders in representative school samples from the second to sixth grade in Brazil

Little is known about specific learning disorder (SLD) in low- and middle-income countries (LMICs), and even less from representative school samples in small size cities outside huge urban centers. Few studies addressed the new DSM-5 criteria for SLDs. We investigated the prevalence of DSM-5 SLDs, their comorbidities and correlates in school samples of students from the second to sixth grades living in median cities from four different geographic regions in Brazil. A national test for academic performance covering reading, writing and mathematical abilities was applied. Psychiatric diagnoses were assessed by the K-SADS-PL applied to the primary caregiver. A total of 1618 children and adolescents were included in the study. The following prevalence rates of SLDs were found: 7.6 % for global impairment, 5.4 % for writing, 6.0 % for arithmetic, and 7.5 % for reading impairment. Attention-deficit/hyperactivity disorder (ADHD) was the only comorbidity significantly associated with SLD with global impairment (p = 0.031). Anxiety disorders and ADHD were associated with SLD with arithmetic impairment. Significant differences were detected in prevalence rates among cities, and several socio-demographic correlates (age, gender, IQ, and socioeconomic status) were significantly associated with SLD with global impairment in our sample. Careful validation and normatization of instruments to assess academic performance is a major problem in LMICs. As expected, we found a significant heterogeneity in prevalence rates of SLD according to geographic regions considering that Brazil is a country with a robust diversity. SLD with global and arithmetic impairment was significantly associated with psychiatric comorbidities.