The Evolving Spectrum of Kidney Histology in HIV-Positive Patients in South Africa.

Introduction: Sub-Saharan Africa remains challenged by the highest burden of human immunodeficiency virus (HIV), an epidemic of tuberculosis (TB), and increasing number of people with HIV (PWH) on antiretroviral therapy (ART), all of which may result in kidney injury. Methods: This observational cohort study describes the spectrum of kidney disease in PWH in South Africa, between 2005 and 2020. Kidney biopsies were analyzed in 4 time periods as follows: early ART rollout (2005-2009), tenofovir disoproxil (TDF) introduction (2010-2012), TDF-based fixed dose combination (2013-2015), and ART at HIV diagnosis (2016-2020). Logistic regression was used to identify factors associated with HIV-associated nephropathy or focal segmental glomerulosclerosis (HIVAN/FSGS) and tubulointerstitial disease (TID). Results: We included 671 participants (median age 36, interquartile range, 21-44 years; 49% female; median CD4 cell count 162 [interquartile range, 63-345] cells/mm3). Over time, ART (31%-65%, P < 0.001), rate of HIV suppression (20%-43%, P < 0.001), nonelective biopsies (53%-72%, P < 0.001), and creatinine at biopsy (242-449 µmol/l, P < 0.001) increased. A decrease in HIVAN (45%-29% P < 0.001) was accompanied by an increase in TID (13%-33%, P < 0.001). Granulomatous interstitial nephritis accounted for 48% of TID, mostly because of TB. Exposure to TDF was strongly associated with TID (adjusted odds ratio 2.99, 95% confidence interval 1.89-4.73 P < 0.001). Conclusion: As ART programs intensified and increasingly used TDF, the spectrum of kidney histology in PWH evolved from a predominance of HIVAN in the early ART era to TID in recent times. The increase in TID is likely due to multiple exposures that include TB, sepsis, and TDF as well as other insults.

Association of cognition with functional trajectories in patients admitted to geriatric wards: A retrospective observational study.

AIM: Impaired cognition is common among older patients admitted to acute hospitals, but its association with functional trajectories has not been well studied. METHODS: A retrospective observational study was carried out in an English tertiary university hospital. We analyzed all first episodes of county residents aged ≥75 years admitted to the Department of Medicine for the Elderly wards between December 2014 and May 2015. A history of dementia or a cognitive concern in the absence of a known diagnosis of dementia were recorded on admission. A cognitive concern included possible undiagnosed dementia or delirium. Function was retrospectively measured with the modified Rankin Scale at preadmission baseline, admission and discharge. RESULTS: There were 663 first hospital episodes over the period, of which 590 patients survived. Among the latter, 244 had no cognitive impairment, 134 a diagnosis of dementia, 66 a cognitive concern in the absence of a known dementia and 146 had missing cognitive data. When frailty, acuity, age and comorbidity were controlled for, people with known dementia had a similar functional recovery compared with those with no cognitive impairment. People with a cognitive concern, but no known dementia, had lesser functional recovery and greater disability at discharge than those with no cognitive impairment (mean discharge modified Rankin Scale 3.4 compared with 3.1, P = 0.011). CONCLUSIONS: Dementia per se might not be a marker of poor rehabilitation potential. Older people with acute cognitive concerns might be more vulnerable to poor functional recovery. Our cognitive variables are not gold standard, and further research is required to clarify this relationship. Geriatr Gerontol Int 2017; 17: 1438-1443.

Clinical frailty and functional trajectories in hospitalized older adults: A retrospective observational study.

AIM: Frailty predicts inpatient mortality and length of stay, but its link to functional trajectories is under-researched. Addenbrooke's Hospital, Cambridge, UK, collects the Clinical Frailty Scale (CFS) within 72 h of admission for those aged ≥75 years. We studied whether the CFS links to functional trajectories in hospitalized older adults. METHODS: This was a retrospective observational study in an English university hospital. We analyzed all first episodes of county residents aged ≥75 years admitted to the Department of Medicine for the Elderly wards between December 2014 and May 2015. Data were extracted from the hospital's information systems. Patients were classified as non-frail (CFS 1-4), moderately frail (CFS 5-6) and severely frail (CFS 7-8). Function was retrospectively measured with the modified Rankin Scale (mRS) at preadmission, admission and discharge. RESULTS: Of 539 eligible patients, 46 died during admission (mortality rates: 2% in CFS 1-4, 5% in CFS 5-6, 19% in CFS 7-8). Among the 493 survivors, 121 were non-frail, 235 moderately and 137 severely frail. The mean mRS of the non-frail was 1.8 (95% CI 1.7-2.0) at baseline, 3.3 (95% CI 3.1-3.5) on admission and 2.2 (95% CI 2.0-2.3) on discharge (mean length of stay 9 days). The moderately frail had a mean mRS of 2.9 (95% CI 2.8-3.0) at baseline, 4.0 (95% CI 3.8-4.1) on admission and 3.2 (95% CI 3.1-3.3) on discharge (mean length of stay 15 days). The severely frail had mean mRS of 3.5 (95% CI 3.3-3.6) at baseline, 4.3 (95% CI 4.1-4.4) on admission and 3.7 (95% CI 3.6-3.9) on discharge, respectively (mean length of stay 17 days). CONCLUSIONS: In older inpatients, frailty might be linked to lower and slower functional recovery. Prospective work is required to confirm these trajectories and understand how to influence them. Geriatr Gerontol Int 2017; 17: 1063-1068.

The core content of emergency medical services medicine.

On September 23, 2010, the American Board of Medical Specialties (ABMS) approved emergency medical services (EMS) as a subspecialty of emergency medicine. As a result, the American Board of Emergency Medicine (ABEM) is planning to award the first certificates in EMS medicine in the fall of 2013. The purpose of subspecialty certification in EMS, as defined by ABEM, is to standardize physician training and qualifications for EMS practice, to improve patient safety and enhance the quality of emergency medical care provided to patients in the prehospital environment, and to facilitate integration of prehospital patient treatment into the continuum of patient care. In February 2011, ABEM established the EMS Examination Task Force to develop the Core Content of EMS Medicine (Core Content) that would be used to define the subspecialty and from which questions would be written for the examinations, to develop a blueprint for the examinations, and to develop a bank of test questions for use on the examinations. The Core Content defines the training parameters, resources, and knowledge of the treatment of prehospital patients necessary to practice EMS medicine. Additionally, it is intended to inform fellowship directors and candidates for certification of the full range of content that might appear on the examinations. This article describes the development of the Core Content and presents the Core Content in its entirety.

The role of state medical direction in the comprehensive emergency medical services system: a resource document.

Medical oversight is a fundamental component of every emergency medical services (EMS) system. The quality of physician medical direction has a significant impact upon the system and patient outcome. The lead agency for the state EMS system is a principal facet of our emergency care system, and the state EMS medical director is a vital component within this comprehensive network. The selection of an experienced, qualified physician for the provision of state EMS medical direction is a critical decision. This resource document provides a snapshot of the status of state EMS medical direction in our nation in 2007 and a projection of the achievable benchmarks for the role of the state EMS medical director in the future. As an informational resource, this tool will assist state EMS officials, legislators, laypersons, and partners within the emergency care system to comprehend, create or improve, and support the state EMS medical director position within their jurisdictions.

Chronic binge-like moderate ethanol drinking in rats results in widespread decreases in brain serotonin, dopamine, and norepinephrine turnover rates reversed by ethanol intake.

This research was initiated to assess the turnover rates (TORs) of dopamine (DA), norepinephrine (NA), serotonin (5-HT), aspartate, glutamate, and GABA in brain regions during rodent ethanol/sucrose (EtOH) and sucrose (SUC) drinking and in animals with a history of EtOH or SUC drinking to further characterize the neuronal systems that underlie compulsive consumption. Groups of five male rats were used, with two trained to drink EtOH solutions, two to drink SUC and one to serve as a non-drinking control. When stable drinking patterns were obtained, rats were pulse labeled intravenously and killed 60 or 90 min later and the TORs of DA, norepinephrine, 5-HT, aspartate, glutamate, and GABA determined in brain regions. Changes in the TOR of 5-HT, DA, and NA were detected specific to EtOH drinking, SUC drinking or a history of EtOH or SUC drinking. An acute EtOH deprivation effect was detected that was mostly reversed with EtOH drinking. These results suggest that binge-like drinking of moderate amounts of EtOH produces a deficit in neuronal function that could set the stage for the alleviation of anhedonic stimuli with further EtOH intake that strengthen EtOH seeking behaviors which may contribute to increased EtOH use in at risk individuals.

Effects of 4-hydroxynonenal on mitochondrial 3-hydroxy-3-methylglutaryl (HMG-CoA) synthase.

Chronic ethanol consumption causes increased production of reactive oxygen species in hepatic mitochondria accompanied by elevations in products of lipid peroxidation such as 4-hydroxynonenal (4-HNE). In the current study we investigated the effects of chronic ethanol consumption on a prominent protein-4-HNE adduct in liver mitochondria. Male Sprague-Dawley rats were fed a liquid diet for 31 days in which ethanol constituted 36% of total calories. Immunoblot analyses of liver mitochondria from ethanol-fed and control animals, using an antibody to a 4-HNE-protein adduct, demonstrated elevated 4-HNE binding (+50%) to a mitochondrial protein of approximately 55 kDa due to chronic ethanol consumption. Analysis of this protein using AspN digestion and tandem mass spectrometry identified it as the mitochondrial form of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase. Activity of the activated form of this enzyme was unchanged in livers from ethanol-fed animals, but the protein level was elevated by 36%, which suggests a compensatory mechanism to maintain constant levels of synthase activity in the mitochondrion in the face of continuous inactivation by 4-HNE. Treatment of isolated mitochondria with 4-HNE demonstrated that the enzyme activity decreased as a function of 4-HNE concentration and with time of exposure. This study demonstrates that ethanol consumption increases the formation of a 4-HNE adduct with mitochondrial HMG-CoA synthase, which has the potential to inactivate the enzyme in situ.

Patient delay in responding to symptoms of possible heart attack: can we reduce time to care?

In Australia, many deaths and significant cardiac disability result from delayed response to symptoms of heart attack. Although delays due to transport and initiation of reperfusion therapy in hospital may contribute to late treatment, the major component of delay is the time patients take in deciding to seek help. A critical examination of campaigns to shorten patient delay concludes that they were based on a factual, short-term, non-targeted approach that included education and mass media strategies. They achieved equivocal results. One randomised controlled trial has been conducted. Although this showed an improved understanding of heart attack symptoms, it did not shorten pre-hospital delays. The implications of these findings are that future campaigns to shorten patient delay are likely to be more effective if they address the psychosocial and behavioural blocks to action, are ongoing rather than short term, and focus on people at highest risk, including those with known or high risk of coronary heart disease, those in rural locations, and Indigenous Australians. The National Heart Foundation of Australia proposes a comprehensive strategy to incorporate this approach into its future campaigns to reduce patient delay for suspected heart attack.

Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis.

BACKGROUND: Most of the studies of alcoholic liver disease use models in which animals undergo involuntary administration of high amounts of ethanol and consume diets that are often high in polyunsaturated fatty acids. The objectives of this study were (1) to evaluate whether cynomolgus monkeys (Macaca fascicularis) drinking ethanol voluntarily and consuming a diet with moderate amounts of lipid would demonstrate any indices of alcoholic liver disease past the fatty liver stage and (2) to determine whether these alterations were accompanied by oxidative stress. METHODS: Six adult male and 6 adult female cynomolgus monkeys were allowed to consume ethanol voluntarily for 18 to 19 months. Additional monkeys were maintained on the same consumption protocol, but were not provided with ethanol. During the course of the study, liver biopsy samples were monitored for lipid deposition and inflammation, serum for levels of liver enzymes, and urine for concentrations of the isoprostane (IsoP) metabolite, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP, a biomarker for oxidative stress. Liver mitochondria were monitored for respiratory control and liver for concentrations of neutral lipids, adenine nucleotides, esterified F(2) isoprostanes, oxidized proteins, 4-hydroxynonenal (HNE)-protein adducts, and protein levels of cytochrome P-450 2E1 and 3A4. RESULTS: Ethanol consumption ranged from 0.9 to 4.05 g/kg/d over the period of the study. Serum levels of aspartate amino transferase were elevated in heavy-consuming animals compared with those in ethanol-naïve or moderate drinkers. Many of the ethanol consumers developed fatty liver and most showed loci of inflammation. Both hepatic energy charge and phosphorylation potential were decreased and NADH-linked respiration was slightly, but significantly depressed in coupled mitochondria as a result of heavy ethanol consumption. The urinary concentrations of 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP increased as high as 33-fold over that observed in ethanol-abstinent animals. Liver cytochrome P-450 2E1 concentrations increased in ethanol consumers, but there were no ethanol-elicited increases in hepatic concentrations of the esterified F(2) isoprostanes, oxidized proteins, or HNE-protein adducts. CONCLUSION: Our studies show that cynomolgus monkeys undergoing voluntary ethanol consumption for 1.5 years exhibit many of the features observed in the early stages of human alcoholic liver disease. Ethanol-elicited fatty liver, inflammation, and elevated serum aspartate amino transferase were evident with a diet that contained modest amounts of polyunsaturated lipids. The dramatic increases in urinary IsoP demonstrated that the animals were being subjected to significant oxidative stress that correlated with their level of ethanol consumption.

Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy.

BACKGROUND: Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT1) blockade on the development of alcoholic cardiomyopathy. METHODS AND RESULTS: We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg.kg(-1).d(-1) PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT(1) receptor expression. The RAS activation was followed by a progressive fall in LV contractility (E(ES), alcohol-fed dogs 3.9+/-0.8 versus control dogs 8.1+/-1.0 mm Hg/mL); reductions in the peak velocity of myocyte shortening (78.9+/-5.1 versus 153.9+/-6.2 microm/s) and relengthening; and decreased peak systolic Ca2+ transient ([Ca2+]iT) and L-type Ca2+ current (I(Ca,L); P<0.05). Irbesartan prevented the alcohol-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and I(Ca,L). With alcohol plus irbesartan, plasma Ang II, cardiac angiotensin-converting enzyme activity, and AT1 remained close to control values. CONCLUSIONS: Chronic alcohol consumption produces RAS activation followed by progressive cardiac dysfunction. The cardiac dysfunction is prevented by AT1 receptor blockade.

Role for GLUT1 in diabetic glomerulosclerosis.

Numerous studies have investigated specific pathways that link diabetes and high extracellular glucose exposure to glomerulosclerosis and mesangial cell extracellular matrix production. However, only in the past ten years has a role for glucose transporters in this process been addressed. Many different glucose transporters are expressed in glomeruli; of these, the GLUT1 facilitative glucose transporter is upregulated in the diabetic renal cortex and in response to glomerular hypertension, as well as in cultured mesangial cells exposed to high glucose. Transgenic mouse and cell models have recently been developed to test the role of GLUT1 in the pathogenesis of glomerulosclerosis with and without diabetes. Clinical studies of GLUT1 alleles performed in humans have identified GLUT1 susceptibility alleles for diabetic nephropathy. Studies are also currently under way to assess the potential role of GLUT1 in nondiabetic renal disorders.

Chronic ethanol consumption decreases mitochondrial and glycolytic production of ATP in liver.

AIMS: The synthesis of ATP in the liver of the chronic ethanol consumer is suppressed, particularly if the tissue becomes hypoxic. Moreover, the perivenous region of the liver lobule becomes even more oxygen deficient as a result of ethanol consumption. Synthesis of ATP in the perivenous region of the lobule may be depressed in the chronic ethanol consumer due to decreases in both mitochondrial and glycolytic activities. In this study the effects of hypoxia on hepatic ATP levels derived from synthesis by both oxidative phosphorylation and the glycolytic mechanisms were investigated. METHODS: Rats were pair-fed liquid diets containing 36% of calories as ethanol or an isocaloric control diet. The contributions of glycolysis and mitochondria to ATP production were assessed employing oligomycin, an inhibitor of oxidative phosphorylation. In order to localize the ethanol-elicited lesion in the glycolytic pathway, the metabolism of [3-(3)H] D-glucose was followed in hepatocytes from ethanol-fed and control animals. RESULTS: Under both hypoxic and normoxic conditions ATP losses were due to decreases in both glycolytic and mitochondrial ATP production. The rate of production of tritiated water from [3-(3)H] D-glucose was significantly decreased in hepatocytes from ethanol-fed animals, which indicates there is an ethanol-elicited lesion in glycolysis between glucose and glyceraldehyde-3-phosphate.

Quantification of dinor, dihydro metabolites of F2-isoprostanes in urine by liquid chromatography/tandem mass spectrometry.

The F2-isoprostanes (F2-IsoP) are a series of prostaglandin (PG)-F2-like compounds that are produced by free-radical-mediated oxidation of arachidonic acid. One F2-IsoP with potent biological activity is 15-F2t-IsoP and increased levels of 15-F(2t)-IsoP have been measured in several diseases. The major urinary metabolite of 15-F2t-IsoP (8-iso-PGF(2alpha)) is 2,3-dinor-5,6-dihydro-15-F2t-IsoP (15-F2t-IsoP-M). Previously, we developed a stable isotope dilution gas chromatography/negative chemical ionization/mass spectrometry (MS) assay for 15-F2t-IsoP-M, which, while highly sensitive, required time-consuming derivatization and thin-layer chromatography purification. We now report the development of a more rapid high-performance liquid chromatography method coupled to electrospray ionization-tandem mass spectrometry (LC/MS/MS) to analyze all of the dinor,dihydro metabolites of the F2-IsoP isomers (F2-IsoP-M). The precision of this assay was +/-5.0% and the accuracy 80%. The assay remained linear over a range of 1-100 ng injected onto the LC column. Levels of F2-IsoP-M determined by the LC/MS/MS assay method significantly correlated with levels of 15-F2t-IsoP-M determined by the GC/MS assay (R = 0.77y = 67.2x-0.5). The levels of F2-IsoP-M detected in spot urines from 40 normal subjects were 38.1+/-19.1 ng/mg creatinine (mean+/-SD). This method provides an accurate and rapid assay to assess oxidative status in vivo.

The effects of moderate ethanol consumption on the liver of the monkey, Macaca fascicularis.

BACKGROUND: Although evidence has accumulated for the cardioprotective effects of moderate ethanol consumption, little is known about the effects on the liver of consuming the equivalent of two drinks per day. The objective of this study was to determine the effects of moderate ethanol administration on the hepatic content of enzymes involved in ethanol oxidation, on hepatic lipid accumulation, and on serum markers of liver function/damage in the monkey, Macaca fascicularis. METHODS: Ovariectomized, adult monkeys were maintained for 34 months on an atherogenic diet containing cholesterol 1.21 mg/kJ. They were trained to drink ethanol plus vehicle at a dose of 0.5 g/kg body weight, which was administered 5 days a week for 2 years. Blood was collected for ethanol concentrations (1 hr after ethanol administration) and was also assayed for gamma-glutamyltransferase, alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities. Liver obtained at necropsy was analyzed for triglyceride and cholesterol contents and for alcohol dehydrogenase, cytochrome P450 2E1, and cytochrome P450 3A4 by Western blots. RESULTS: The blood ethanol concentrations measured 1 hr after ethanol administration were relatively constant over the 2-year dosing period. Hepatic levels of alcohol dehydrogenase and the cytochrome P450s were not significantly different between ethanol-consuming animals and control animals. Ethanol-associated increases in liver triglyceride were not significant due to high variability in hepatic lipid content in both the controls and ethanol consumers. However, covariance analyses using pretreatment concentrations of plasma cholesterol and apolipoprotein A-I suggested that the ethanol-related increase in hepatic free cholesterol was significant. Relative to controls, alcohol consumers had higher levels of serum ALT and a transient increase in ALP at 5 months. CONCLUSIONS: The observations made in this study on primates administered an atherogenic diet suggest that moderate ethanol ingestion has modest effects on the liver, including slightly increased ALT and ALP values. However, additional studies will be required to verify that this level of consumption is hepatotoxic when ingested over extended periods. This is still a concern because some human studies suggest that levels of ethanol considered to be cardioprotective cause liver injury when consumed over a lifetime.

Energy availability and alcohol-related liver pathology.

Alcohol consumption alters the metabolism of the most common type of cell found in the liver, the hepatocyte. The presence of alcohol in the body causes the liver to use more oxygen-for example, when breaking down the alcohol. Increased oxygen use, in turn, causes oxygen deficits in several key cells, particularly in hepatocytes located near the small hepatic veins. These veins return blood to the heart for re-oxygenation after it has passed through the liver. Hepatocytes surrounding these veins are the first to show signs of liver disease. The damage induced by oxygen deficits may be exacerbated by alcohol-induced deficits in other components that are essential for cell survival. For example, adenosine triphosphate (ATP), the cell's main source of energy, is generated primarily during the course of two sets of metabolic reactions: glycolysis and the mitochondrial oxidative phosphorylation process. Alcohol consumption may interfere with both of these pathways of ATP production through several mechanisms. An inadequate supply of ATP impairs the cell's ability to perform critical functions, including the repair of alcohol-induced cell damage, and may therefore contribute to cell death and alcoholic liver disease.

Reactive oxygen species production by the mitochondrial respiratory chain in isolated rat hepatocytes and liver mitochondria: studies using myxothiazol.

Increased production of reactive oxygen species (ROS) by the mitochondrion has been implicated in the pathogenesis of numerous liver diseases. However, the exact sites of ROS production within liver mitochondria and the electron transport chain are still uncertain. To determine the sites of ROS generation in liver mitochondria we evaluated the ability of a variety of mitochondrial respiratory inhibitors to alter the steady state levels of ROS generated within the intact hepatocyte and in isolated mitochondria. Treatment with myxothiazol alone at concentrations that significantly inhibit respiration dramatically increased the steady-state levels of ROS in hepatocytes. Similar results were also observed in isolated mitochondria oxidizing succinate. Coincubation with antimycin or rotenone had no effect on myxothiazol-induced ROS levels. Myxothiazol stimulation of ROS was mitochondrial in origin as demonstrated by the colocalization of MitoTracker Red and dichlorofluorescein staining using confocal microscopy. Furthermore, diphenyliodonium, an inhibitor that blocks electron flow through the flavin mononucleotide of mitochondrial complex I and other flavoenzymes, significantly attenuated the myxothiazol-induced increase in hepatocyte ROS levels. Together, these data suggest that in addition to the ubiquinone-cytochrome bc(1) complex of complex III, several of the flavin-containing enzymes or iron-sulfur centers within the mitochondrial electron transport chain should also be considered sites of superoxide generation in liver mitochondria.