HIV-related Legal Needs, Demographic Change, and Trends in Australia since 1992: A Review of Legal Administrative Data.

An enabling legal environment is essential for an effective HIV response. Using legal administrative data from the HIV/AIDS Legal Centre (HALC), Australia's specialist HIV community legal service, this article characterizes the nature and trends in the legal issues and needs of those with HIV-related legal issues in New South Wales, Australia since 1992. At present, approximately 40% of all PLHIV living in NSW receive a legal service from HALC during the most recent five-year period. Clients received legal services relating to immigration law at a greatly increased rate (2010: 36%; 2019: 53%), discrimination matters decreased (2010: 17%; 2019: 5.9%), wills and estates remained steady (2010: 9%; 2019: 8.3%). Most clients identify as male (76.9%), homosexual (55%) and are aged between 35 and 49 years of age (34.6%). This demographic profile of clients changed over time, becoming younger and more likely to have been born overseas, and increasingly identifying as heterosexual.

On the interdependence of ketone body oxidation, glycogen content, glycolysis and energy metabolism in the heart.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-ß-hydroxybutyrate (ßHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on ßHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]glucose and/or 4 mM [14 C]ßHB to measure glycolytic rates or ßHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reaction, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi ) concentrations were measured using 31 P-nuclear magnetic resonance spectroscopy. Rates of ßHB oxidation in LG hearts were half that in HG hearts, with ßHB oxidation directly proportional to glycogen content. ßHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with ßHB alone was twice that of hearts perfused with ßHB and glucose, which had significantly higher levels of the glycolytic intermediates fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. ßHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total NADP/H pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although ßHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. ßHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac ßHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (d-ß-hydroxybutyrate, acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Krebs cycle intermediates; therefore their utilisation requires anaplerotic supplementation, and intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. It is demonstrated here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate ß-hydroxybutyrate oxidation in isolated perfused rat heart, and this contribution was quantified using a novel pulse-chase metabolic approach. Further, using metabolomics and 31 P-MR, it was shown that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise ßHB, and ßHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis.

Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis.

OBJECTIVES: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation. METHODS: We stimulated purified monocytes and whole peripheral blood mononuclear cells (PBMCs) from patients with GPA, patients with MPA or healthy controls with PR3 or MPO and visualised MGC and granuloma-like structure formation using light, confocal and electron microscopy, as well as measuring the cell cytokine production. We investigated the expression of PR3 binding partners on monocytes and tested the impact of their inhibition. Finally, we injected zebrafish with PR3 and characterised granuloma formation in a novel animal model. RESULTS: In vitro, PR3 promoted monocyte-derived MGC formation using cells from patients with GPA but not from patients with MPA, and this was dependent on soluble interleukin 6 (IL-6), as well as monocyte MAC-1 and protease-activated receptor-2, found to be overexpressed in the cells of patients with GPA. PBMCs stimulated by PR3 formed granuloma-like structures with central MGC surrounded by T cells. This effect of PR3 was confirmed in vivo using zebrafish and was inhibited by niclosamide, a IL-6-STAT3 pathway inhibitor. CONCLUSIONS: These data provide a mechanistic basis for granuloma formation in GPA and a rationale for novel therapeutic approaches.

The Legal Needs of People Living with a Sexually Transmissible Infection or Blood-Borne Virus: Perspectives From a Sample of the Australian Sexual Health and Blood Borne Virus Workforce.

Law and the legal environment are important factors in the epidemiology and prevention of sexually transmissible infections (STIs) and blood-borne viruses (BBVs). However, there has been no sustained effort to monitor the legal environment surrounding STIs and BBVs. This article presents the first data on the incidence and impacts of unmet legal needs for those affected by an STI or BBV in Australia using a survey administered to a sample of the Australian sexual health and BBV workforce. Migration, Housing, Money/Debt, Health (including complaints about health services), and Crime (accused/offender) were reported as the five most common legal need areas, with 60% of respondents describing these legal problems as generating a "severe" impact on health. These results indicate that unmet legal needs generate significant negative impacts in terms of individual health, on public health, and the ability to provide sustainable services such as testing and treatment to those facing unmet legal needs.

Neutrophils are key mediators in crescentic glomerulonephritis and targets for new therapeutic approaches.

Crescentic glomerulonephritis (CGN) results from a diverse set of diseases associated with immune dysregulation and the breakdown of self-tolerance to a wide range of autoantigens, some known and some that remain unknown. Experimental data demonstrate that neutrophils have an important role in the pathogenesis of CGN. Upon activation, neutrophils generate reactive oxygen species, release serine proteases and form neutrophil extracellular traps (NETs), all of which can induce direct tissue damage. In addition, serine proteases such as myeloperoxidase and proteinase 3, presented on NETs, can be processed and recognized as autoantigens, leading to the generation and maintenance of autoimmune responses in susceptible individuals. The basis of the specificity of autoimmune responses in different patients to NET proteins is unclear, but relates at least in part to differences in human leucocyte antigen expression. Conditions associated with CGN are often characterized by aberrant neutrophil activation and NETosis and, in some, impaired NET degradation. Targeting neutrophil degranulation and NETosis is now possible using a variety of novel compounds and may provide a promising therapeutic alternative to glucocorticoid use, which has been a mainstay of management in CGN for decades and is associated with significant adverse effects. In this review, we discuss the evidence supporting the role of neutrophils in the development of CGN and the pathways identified in neutrophil degranulation and NETosis that may translate to novel therapeutic applications.

Identifying barriers for nature-based solutions in flood risk management: An interdisciplinary overview using expert community approach.

The major event that hit Europe in summer 2021 reminds society that floods are recurrent and among the costliest and deadliest natural hazards. The long-term flood risk management (FRM) efforts preferring sole technical measures to prevent and mitigate floods have shown to be not sufficiently effective and sensitive to the environment. Nature-Based Solutions (NBS) mark a recent paradigm shift of FRM towards solutions that use nature-derived features, processes and management options to improve water retention and mitigate floods. Yet, the empirical evidence on the effects of NBS across various settings remains fragmented and their implementation faces a series of institutional barriers. In this paper, we adopt a community expert perspective drawing upon LAND4FLOOD Natural flood retention on private land network (https://www.land4flood.eu) in order to identify a set of barriers and their cascading and compound interactions relevant to individual NBS. The experts identified a comprehensive set of 17 barriers affecting the implementation of 12 groups of NBS in both urban and rural settings in five European regional environmental domains (i.e., Boreal, Atlantic, Continental, Alpine-Carpathian, and Mediterranean). Based on the results, we define avenues for further research, connecting hydrology and soil science, on the one hand, and land use planning, social geography and economics, on the other. Our suggestions ultimately call for a transdisciplinary turn in the research of NBS in FRM.

Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN.

BACKGROUND: Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN. METHODS: We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis. RESULTS: All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses. CONCLUSIONS: Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.

Diagnosis of Acute Kidney Injury in Children Hospitalized in a Sub-Saharan African Unit by Saliva Urea Nitrogen Dipstick Test.

INTRODUCTION: Acute kidney injury in pediatric patients (pAKI) is common in developing countries and leads to significant morbidity and mortality. Most nephrology services in developing countries are only in larger cities and for that reason many cases remain undiagnosed. We evaluated the performance of a saliva urea nitrogen (SUN) dipstick to diagnose pAKI in Sudan. METHODS: We collected demographic and clinical information, serum creatinine (SCr), blood urea nitrogen (BUN), SUN, and urine output (UO) in children with pAKI. pAKI was diagnosed based on different criteria (Risk, Injury, Failure, Loss of kidney function, and end-stage kidney disease, Acute Kidney Injury Network and Kidney Disease Improving Global Outcomes). We also recorded hospital and 3-months' mortality and progression to chronic kidney disease (CKD) as outcomes. RESULTS: We studied 81 patients (mean age 10.7 ± 7 years, 51.9% females) and divided them by age into (a) neonates (<120 days; n = 21; 25.9%); (b) -infants (120-365 days; n = 18; 25.9%); and (c) children (>365 days; n = 42; 53.1%). Diagnosis using different pAKI definitions resulted in differences in AKI staging. SUN reliably reflected BUN over the entire study period, regardless of treatment modality or pAKI severity. Neither pAKI staging, SUN, BUN, nor SCr were associated with mortality or progression to CKD. UO predicted all-cause mortality during the 3-months follow-up. CONCLUSION: Diagnosis of pAKI using different criteria differs in triage and staging. SUN reflects BUN particularly at higher BUN levels and allows monitoring of treatment responses. Despite the lack of predictive power of SUN to predict hard outcomes, measurement of SUN by dipstick can be used to identify, screen, and monitor pediatric patients with pAKI.

Using a Rotating 3D LiDAR on a Mobile Robot for Estimation of Person's Body Angle and Gender.

We studied the use of a rotating multi-layer 3D Light Detection And Ranging (LiDAR) sensor (specifically the Velodyne HDL-32E) mounted on a social robot for the estimation of features of people around the robot. While LiDARs are often used for robot self-localization and people tracking, we were interested in the possibility of using them to estimate the people's features (states or attributes), which are important in human-robot interaction. In particular, we tested the estimation of the person's body orientation and their gender. As collecting data in the real world and labeling them is laborious and time consuming, we also looked into other ways for obtaining data for training the estimators: using simulations, or using LiDAR data collected in the lab. We trained convolutional neural network-based estimators and tested their performance on actual LiDAR measurements of people in a public space. The results show that with a rotating 3D LiDAR a usable estimate of the body angle can indeed be achieved (mean absolute error 33.5 ° ), and that using simulated data for training the estimators is effective. For estimating gender, the results are satisfactory (accuracy above 80%) when the person is close enough; however, simulated data do not work well and training needs to be done on actual people measurements.

Emerging evidence of an effect of salt on innate and adaptive immunity.

Salt intake as part of a western diet currently exceeds recommended limits, and the small amount found in the natural diet enjoyed by our Paleolithic ancestors. Excess salt is associated with the development of hypertension and cardiovascular disease, but other adverse effects of excess salt intake are beginning to be recognized, including the development of autoimmune and inflammatory disease. Over the last decade there has been an increasing body of evidence demonstrating that salt affects multiple components of both the innate and adaptive immune systems. In this review we outline the recent laboratory, animal and human data, highlighting the effect of salt on immunity, with a particular focus on the relevance to inflammatory kidney disease.

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults.

Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-ß-hydroxybutyrate (ßHB) to similar concentrations within minutes, with ßHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18-70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, three times a day for 28 days (a total of 2.1 L). Anthropomorphic measurements, plus fasting blood and urine analyses were made weekly. It was found that elevating blood ßHB concentrations from 0.1 to 4.1 (±1.1) mM three times a day for 28 days had no effect on body weights or composition, fasting blood glucose, cholesterol, triglyceride or electrolyte concentrations, nor blood gases or kidney function, which were invariably normal. Mild nausea was reported following 6 of the 2,016 drinks consumed. We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.

Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose.

Exogenous ketone drinks may improve athletic performance and recovery, but information on their gastrointestinal tolerability is limited. Studies to date have used a simplistic reporting methodology that inadequately represents symptom type, frequency, and severity. Herein, gastrointestinal symptoms were recorded during three studies of exogenous ketone monoester (KME) and salt (KS) drinks. Study 1 compared low- and high-dose KME and KS drinks consumed at rest. Study 2 compared KME with isocaloric carbohydrate (CHO) consumed at rest either when fasted or after a standard meal. Study 3 compared KME+CHO with isocaloric CHO consumed before and during 3.25 hr of bicycle exercise. Participants reported symptom type and rated severity between 0 and 8 using a Likert scale at regular intervals. The number of visits with no symptoms reported after ketone drinks was n = 32/60 in Study 1, n = 9/32 in Study 2, and n = 20/42 in Study 3. Following KME and KS drinks, symptoms were acute but mild and were fully resolved by the end of the study. High-dose KS drinks caused greater total-visit symptom load than low-dose KS drinks (13.8 ± 4.3 vs. 2.0 ± 1.0; p < .05) and significantly greater time-point symptom load than KME drinks 1-2 hr postdrink. At rest, KME drinks caused greater total-visit symptom load than CHO drinks (5.0 ± 1.6 vs. 0.6 ± 0.4; p < .05). However, during exercise, there was no significant difference in total-visit symptom load between KME+CHO (4.2 ± 1.0) and CHO (7.2 ± 1.9) drinks. In summary, exogenous ketone drinks cause mild gastrointestinal symptoms that depend on time, the type and amount of compound consumed, and exercise.

Diagnostic performance of salivary urea nitrogen dipstick to detect and monitor acute kidney disease in patients with malaria.

BACKGROUND: Acute kidney injury (AKI) is a common complication of malaria. In low resource settings, a lack of diagnostic tools and delayed treatment of malaria associated AKI lead to significant morbidity and mortality. The aim of this study was to assess the diagnostic performance of salivary urea nitrogen (SUN) dipstick to detect and monitor kidney disease [KD = AKI or acute kidney disease (AKD) without AKI] in malaria patients in Angola. METHODS: Patients 11-50 years old admitted with malaria at the Josina Machel (Maria-Pia) Hospital, Luanda, Angola, between 2nd March and 10th May 2016 were enrolled in this study. All participants had serum creatinine (sCr), blood urea nitrogen (BUN) and SUN dipstick tested at the time of recruitment and daily for up to 4 days. AKD without AKI refers to acute renal impairment which do not fulfilled the main criteria for AKI (increases in the baseline serum creatinine and/or decreases in urine output) according defined by the kidney disease improving global outcomes (KDIGO) guideline. RESULTS: Eight-six patients were admitted with malaria diagnosis (mean age 21.5 ± 9.4 years, 71% male) and 27 (32%) were diagnosed with KD. The mean (± SD) sCr and BUN of the KD group at admission (day 0) were 5.38 (± 5.42) and 99.4 (± 61.9) mg/dL, respectively. Three (3.5%) patients underwent haemodialysis and eight (9.3%) died within the first 4 days of hospital admission [5 (62.5%) with KD; 3 (37.5%) without kidney disease; p = 0.047]. The SUN threshold for KD diagnosis was tested pad #5 (SUN > 54 mg/dL). At this threshold, the SUN dipstick had a sensitivity of 67% and specificity of 98% to diagnose KD. The area under the receiver operating characteristics curve (ROC) for KD diagnosis on admission was 0.88 (95% CI 0.79-0.96). The SUN dipstick was most accurate at higher levels of BUN. CONCLUSION: The SUN dipstick had reasonable sensitivity and excellent specificity when used to diagnose KD in a cohort of patients with malaria in a resource-limited setting. Given the severity of presenting illness and kidney injury, the SUN dipstick diagnostic threshold was high (test pad #5). SUN may be used to detect AKI in patients with malaria in low resources settings, thus facilitating earlier access to adequate treatment, which may improve survival.

Incidence, aetiology and outcomes of obstetric-related acute kidney injury in Malawi: a prospective observational study.

BACKGROUND: Obstetric-related acute kidney injury (AKI) is thought to be a key contributor to the overall burden of AKI in low resource settings, causing significant and preventable morbidity and mortality. However, epidemiological data to corroborate these hypotheses is sparse. This prospective observational study aims to determine the incidence, aetiology and maternal-fetal outcomes of obstetric-related AKI in Malawi. METHODS: Women greater than 20 weeks gestation or less than 6 weeks postpartum admitted to obstetric wards at a tertiary hospital in Blantyre, Malawi, and at high-risk of AKI were recruited between 21st September and 11th December 2015. All participants had serum creatinine tested at enrolment; those with creatinine above normal range (> 82 µmol/L) underwent serial measurement, investigations to determine cause of kidney injury, and were managed by obstetric and nephrology teams. AKI was diagnosed and staged by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Primary outcomes were the incidence proportion and aetiology of AKI. Secondary outcomes were in-hospital maternal mortality, need for dialysis, renal recovery and length of stay; in-hospital perinatal mortality, gestational age at delivery, birthweight and Apgar score. RESULTS: 354 patients were identified at risk of AKI from the approximate 2300 deliveries that occurred during the study period. Three hundred twenty-two were enrolled and 26 (8.1%) had AKI (median age 27 years; HIV 3.9%). The most common primary causes of AKI were preeclampsia/eclampsia (n = 19, 73.1%), antepartum haemorrhage (n = 3, 11.5%), and sepsis (n = 3, 11.5%). There was an association between preeclampsia spectrum and AKI (12.2% AKI incidence in preeclampsia spectrum vs. 4.3% in other patients, p = 0.015). No women with AKI died or required dialysis and complete renal recovery occurred in 22 (84.6%) cases. The perinatal mortality rate across all high-risk admissions was 13.8%. AKI did not impact on maternal or fetal outcomes. CONCLUSIONS: The incidence of AKI in high-risk obstetric admissions in Malawi is 8.1% and preeclampsia was the commonest cause. With tertiary nephrology and obstetric care the majority of AKI resolved with no effect on maternal-fetal outcomes. Maternal-fetal outcomes in Sub-Saharan Africa may be improved with earlier detection of hypertensive disease in pregnancy.

The role of triacylglycerol in cardiac energy provision.

Triacylglycerols (TAGs) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity. Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through blood-borne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FAs) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives. Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.

The role of peroxisome proliferator-activated receptor α (PPARα)-mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using (31)P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [(3)H] labeling. Compared with a normoxic, chow-fed control mouse heart, hypoxia decreased PPARα expression, fatty acid oxidation, and mitochondrial uncoupling protein 3 (UCP3) levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations ([ATP]) and thereby, ejection fractions. A high-fat diet increased cardiac PPARα expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis. Hypoxia was unable to alter the high PPARα expression or reverse the metabolic changes caused by the high-fat diet, with the result that [ATP] and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have occurred already in PPARα-deficient (PPARα(-/-)) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPARα expression is essential for adaptive metabolic remodeling in hypoxia, but is prevented by dietary fat.-Cole, M. A., Abd Jamil, A. H., Heather, L. C., Murray, A. J., Sutton, E. R., Slingo, M., Sebag-Montefiore, L., Tan, S. C., Aksentijevic, D., Gildea, O. S., Stuckey, D. J., Yeoh, K. K., Carr, C. A., Evans, R. D., Aasum, E., Schofield, C. J., Ratcliffe, P. J., Neubauer, S., Robbins, P. A., Clarke, K. On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.

Incidence, aetiology and outcome of community-acquired acute kidney injury in medical admissions in Malawi.

BACKGROUND: Epidemiological data on Acute Kidney Injury (AKI) from low-income countries is sparse. The aim of this study was to establish the incidence, severity, aetiology, and outcomes of community-acquired AKI in Malawi. METHODS: We conducted a prospective observational study of general medical admissions to a tertiary hospital in Blantyre between 27th April and 17th July 2015. All patients were screened on admission with a serum creatinine; those with creatinine above laboratory reference range were managed by the nephrology team. Hospital outcome was recorded in all patients. RESULTS: Eight hundred ninety-two patients were included; 188 (21 · 1%) had kidney disease on admission, including 153 (17 · 2%) with AKI (median age 41 years; 58 · 8% HIV seropositive). 60 · 8% of AKI was stage 3. The primary causes of AKI were sepsis and hypovolaemia in 133 (86 · 9%) cases, most commonly gastroenteritis (n = 29; 19 · 0%) and tuberculosis (n = 18; 11 · 8%). AKI was multifactorial in 117 (76 · 5%) patients; nephrotoxins were implicated in 110 (71 · 9%). Inpatient mortality was 44 · 4% in patients with AKI and 13 · 9% if no kidney disease (p <0.0001). 63 · 2% of patients who recovered kidney function left hospital with persistent kidney injury. CONCLUSION: AKI incidence is 17 · 2% in medical admissions in Malawi, the majority is severe, and AKI leads to significantly increased in-hospital mortality. The predominant causes are infection and toxin related, both potentially avoidable and treatable relatively simply. Effective interventions are urgently required to reduce preventable young deaths from AKI in this part of the world.

Changes to both cardiac metabolism and performance accompany acute reductions in functional capillary supply.

BACKGROUND: The relative importance of arteriole supply or ability to switch between substrates to preserve cardiac performance is currently unclear, but may be critically important in conditions such as diabetes. METHODS: Metabolism of substrates was measured before and after infusion of polystyrene microspheres in the perfused working heart to mimic random capillary loss due to microvascular disease. The effect of acute loss of functional capillary supply on palmitate and glucose metabolism together with function was quantified, and theoretical tissue oxygen distribution calculated from histological samples and ventricular VO(2) estimated. RESULTS: Microsphere infusion led to a dose-dependent decrease in rate-pressure product (RPP) and oxygen consumption (P<0.001). Microsphere infusion also increased work/unit oxygen consumption of hearts ('efficiency') by 25% (P<0.01). When corrected for cardiac work palmitate oxidation remained tightly coupled to very low workloads (RPP<2500 mmHg/min), illustrating a high degree of metabolic control. Arteriole occlusion by microspheres decreased the density of patent capillaries (P<0.001) and correspondingly increased the average capillary supply area by 40% (P<0.01). Calculated rates of oxygen consumption declined from 16.6±7.2 ml/100 ml/min to 12.4±9 ml/100 ml/min following arteriole occlusion, coupled with increases in size of regions of myocardial hypoxia (Control=22.0% vs. Microspheres=42.2%). CONCLUSIONS: Cardiac mechanical performance is very sensitive to arteriolar blockade, but metabolite switching from fatty acid to glucose utilisation may also support cardiac function in regions of declining PO(2). GENERAL SIGNIFICANCE: Preserving functional capillary supply may be critical for maintenance of cardiac function when metabolic flexibility is lost, as in diabetes.

Saliva Urea Nitrogen Continuously Reflects Blood Urea Nitrogen after Acute Kidney Injury Diagnosis and Management: Longitudinal Observational Data from a Collaborative, International, Prospective, Multicenter Study.

BACKGROUND: Acute kidney injury (AKI) is a growing global concern and often reversible. Saliva urea nitrogen (SUN) measured by a dipstick may allow rapid diagnosis. We studied longitudinal agreement between SUN and blood urea nitrogen (BUN) and the diagnostic performance of both. METHODS: Agreement between SUN and BUN and diagnostic performance to diagnose AKI severity in AKI patients in the United States and Brazil were studied. Bland-Altman analysis and linear mixed effects models were employed to test the agreement between SUN and BUN. Receiver operating characteristics statistics were used to test the diagnostic performance to diagnose AKI severity. RESULTS: We found an underestimation of BUN by SUN, decreasing with increasing BUN levels in 37 studied patients, consistent on all observation days. The diagnostic performance of SUN (AUC 0.81, 95% CI 0.63-0.98) was comparable to BUN (AUC 0.85, 95% CI 0.71-0.98). CONCLUSION: SUN reflects BUN especially in severe AKI. It also allows monitoring treatment responses. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=445041.