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PubMedDate not supplied

Effect of starvation and insulin-induced hypoglycemia on oxidative stress scavenger system and electron transport chain complexes from rat brain, liver, and kidney.

Considerable evidence suggests that oxidative stress plays an important role in tissue damage associated with hypoglycemia and other metabolic disorders. The altered brain neurotransmitters metabolism, cerebral electrolyte contents, and impaired blood-brain barrier function may contribute to CNS dysfunction in hypoglycemia. The present study elucidates the effect of starvation and insulin-induced hypoglycemia on the free radical scavanger system--reduced glutathione (GSH) content, glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), gamma-glutamyl transpeptidase (gamma-GTP), gamma-glutamyl cystein synthetase (gamma-GCS), catalase and superoxide dismutase (SOD), and mitochondrial electron transport chain (ETC) complexes I-IV from three different regions of rat brain, namely cerebral hemispheres (CH), cerebellum (CB), and brainstem (BS). Peripheral organs, such as liver and kidney, were also studied. Significant changes in these enzymic activities were observed. The analysis of such alterations is important in ultimately determining the basis of neuronal dysfunction during metabolic stress conditions, such as hypoglycemia, and also defining the nature of these changes may help to develop therapeutic means to cure metabolically stressed tissues.

Animals↗

PubMed2006

Magnesium and the inflammatory response: potential physiopathological implications.

The purpose of this review is to summarize experimental findings showing that magnesium modulates cellular events involved in inflammation. Experimental magnesium deficiency in the rat induces after a few days a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines and acute phase proteins, excessive production of free radicals. Increase in extracellular magnesium concentration, decreases inflammatory response while reduction in the extracellular magnesium results in cell activation. Because magnesium acts as a natural calcium antagonist, the molecular basis for inflammatory response is probably the result of modulation of intracellular calcium concentration. The priming of phagocytic cells, the opening calcium channel and activation of N-methyl-d-aspartate (NMDA) receptors, the activation of nuclear factor-kappa B (NFkappaB) have been considered as potential mechanisms. Moreover, magnesium deficiency induces a systemic stress response by activation of neuro endocrinological pathways. As nervous and immune systems interact bidirectionally, the roles of neuromediators have also been considered. Magnesium deficiency contributes to an exaggerated response to immune stress and oxidative stress is the consequence of the inflammatory response. Inflammation contributes to the pro-atherogenic changes in lipoprotein metabolism, endothelial dysfunction, thrombosis, hypertension and explains the aggravating effect of magnesium deficiency on the development of metabolic syndrome. Further studies are still needed to assess more accurately the role of magnesium in immune response in humans, but these experimental findings in animal models suggest that inflammation is the missing link to explain the role of magnesium in many pathological conditions.

Animals↗

PubMed2026

The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. RESULTS: GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10- 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10- 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10- 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region. CONCLUSIONS: This study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.

Humans↗

PubMed1999

The effect of pravastatin on renal function and lipid metabolism in patients with renal dysfunction with hypertension and hyperlipidemia. Pravastatin and Renal Function Research Group.

The effect of pravastatin on renal function in hypertensive patients with mild renal dysfunction and hyperlipidemia was examined. A total of 57 subjects given dihydropyridine calcium blockers were randomly assigned to placebo (n = 25) and pravastatin groups (n = 32). The period of study was 6 months. In the placebo group, lipid metabolism did not change throughout the study period, but the serum creatinine concentration (Scr) increased from a baseline of 1.6+/-0.07 mg/dl to 2.1+/-0.2 mg/dl in the 6th month of study and blood urea nitrogen (BUN) increased from 26.2+/-1.1 mg/dl to 32.4+/-30.1 mg/dl. In the pravastatin group, the serum total cholesterol decreased from a baseline of 251.4+/-7.3 mg/dl to 218.2+/-6.5 mg/dl in the 6th month of study, while Scr (1.3+/-0.07 mg/dl vs. 1.3 +/-0.09 mg/dl) and BNU (20.5+/-1.2 mg/dl vs. 21.0+/-1.4 mg/dl) did not change. The change in Scr in the placebo group was significantly different from that in the pravastatin group (F = 3.75, p = 0.05). The slope of the change in 1/Scr was 0.02+/-0.07 dl x mg(-1) x month(-1) in placebo group and -0.01+/-0.03 dl x mg(-1) month(-1) in pravastatin group (P<0.05). The results indicate that pravastatin attenuates the deterioration of renal function in patients with mild renal dysfunction, together with an improvement of lipid metabolism.

Blood Urea Nitrogen↗

PubMed2005

Metabolite profile of cerebrospinal fluid in patients with spina bifida: a proton magnetic resonance spectroscopy study.

STUDY DESIGN: The present study was carried out to assess the metabolic differences between cerebrospinal fluid samples of patients with spina bifida and age-matched control individuals. OBJECTIVES: To study the metabolite profile of cerebrospinal fluid of patients with spina bifida using proton magnetic resonance spectroscopy, compare the levels of metabolites with controls, establish correlation of underlying neuronal dysfunction with metabolic changes in patients with spina bifida, and evaluate the potential use of this technique as an additional tool for diagnostic assessment. SUMMARY OF BACKGROUND DATA: Combination of embryopathy, stretching, ischemia, compression, and trauma is responsible for cord dysfunction in spina bifida. Changes in neuronal metabolism leads to changes in the local milieu of cerebrospinal fluid in the cord. Change in metabolite profile of cerebrospinal fluid in spina bifida in terms of increase in products of anaerobic metabolism, nerve membrane integrity, and nerve ischemia has not yet been studied. METHODS: Cerebrospinal fluid obtained from patients and control individuals were characterized using various one- and two-dimensional proton magnetic resonance spectroscopy techniques. Concentration of various metabolites was calculated using the area under the nuclear magnetic resonance peak. RESULTS: Statistically significantly higher levels of lactate, choline, glycerophosphocholine, acetate, and alanine in the cerebrospinal fluid of patients with spina bifida was observed compared with control individuals. CONCLUSIONS: Significantly higher levels of metabolites were observed in patients with spina bifida, representing a state of nerve ischemia, anaerobic metabolism, and disruption of neuronal membrane.

Acetates↗

PubMed2000

Ranolazine attenuates palmitoyl-L-carnitine-induced mechanical and metabolic derangement in the isolated, perfused rat heart.

The effect of ranolazine, a novel anti-ischaemic drug that stimulates the activity of pyruvate dehydrogenase, on palmitoyl-L-carnitine-induced mechanical dysfunction and metabolic derangement in isolated perfused rat hearts has been studied and compared with the effect of dichloroacetate, an activator of pyruvate dehydrogenase. Rat hearts paced electrically were perfused aerobically at constant flow by the Langendorff technique. Palmitoyl-L-carnitine (4 microM) increased left ventricular end-diastolic pressure and reduced left ventricular developed pressure (i.e. induced mechanical dysfunction); it also reduced tissue levels of adenosine triphosphate and increased tissue levels of adenosine monophosphate (i.e. induced metabolic derangement). These functional and metabolic alterations induced by palmitoyl-L-carnitine were attenuated by ranolazine (5, 10, and 20 microM) in a concentration-dependent manner. In contrast, dichloroacetate (1 and 10 mM) did not attenuate palmitoyl-L-carnitine-induced mechanical and metabolic derangement. In the normal (palmitoyl-L-carnitine-untreated) heart, however, ranolazine did not modify mechanical function and energy metabolism. These results suggest that ranolazine attenuates palmitoyl-L-carnitine-induced mechanical and metabolic derangement in the rat heart, and that the beneficial action of ranolazine is not because of the energy-sparing effect or activation of pyruvate dehydrogenase.

Acetanilides↗

PubMed1996

Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points.

The small changes in luminal narrowing observed with lowering total cholesterol are unlikely to be the principal mechanism by which lipid-lowering achieves a reduction in clinical events and revascularization rates. Endothelium dependent vasomotor function, and the cellular characteristics of plaques that seem to be intimately related to rupture and thrombosis, are factors that may explain the clinical success from correcting the dyslipidemias. Dyslipidemias cause endothelial dysfunction that predisposes to vasoconstriction of the epicardial coronary arteries and the resistance vessels relative to metabolic demand. Dysfunctional endothelium also promotes the recruitment of inflammatory cells into the vessel wall which contributes to the activation of vascular smooth muscle cells and sets up an environment within the plaque that predisposes to rupture and a prothrombotic state. Aggressive lowering of total cholesterol, and especially LDL and oxidized LDL, improves coronary endothelial function both of the epicardial and resistance vessels, and leads to a reduction in myocardial ischemia. Lipid-lowering may promote plaque stability in part by reducing the recruitment of inflammatory cells, and possibly by changing the size or consistency of the lipid-rich core of plaques. A thicker fibrous cap and stiffer plaque that is less likely to rupture may result, and in the event that rupture does occur, cholesterol lowering may reduce the formation of overlying thrombus. Testing coronary or peripheral artery endothelial vasomotor dysfunction may be a surrogate measure for assessing the effectiveness of interventions to prevent coronary heart disease. These tests are likely to be used increasingly to identify interventions that deserve greater attention in larger clinical trials, as well as providing mechanisms for any observed clinical benefits.

Animals↗

PubMedDate not supplied

[New information on the pathophysiology of atherosclerosis].

The past decade has witnessed enormous progress in our understanding of the nature of this process. The development of an atherosclerotic plaque is a complex process which begins with endothelial dysfunction, the trigger for which are factors such as hypercholesterolemia, smoking, hypertension, hyperhomocysteinemia and impaired glucose metabolism. This dysfunction includes increased endothelial permeability to lipoproteins and other plasma constituents, which is mediated by NO, PDGF, prostacyclin, angiotensin II and endothelin; up-regulation of endothelial adhesion molecules including VCAM-1, ICAM-1, and selectins and migration of leukocytes and monocytes-macrophages in the subendothelial space mediated by oxidized LDL, MCP-1, PDGF and MCSF. The next step includes smooth-muscle cells migration (stimulated by PDGF and TGF-beta), T-cell activation (mediated by TNF-alpha and IL-2), formation of foam-cells from macrophages (mediated by oxidized LDL, MCSF, TNF-alpha and IL-1) and platelet adherence and aggregation (stimulated by thromboxane A2, tissue factor etc). The smooth muscle cells form a fibrous cap which confers mechanical stability of the plaque and separates the lipid rich thrombogenic core from the lumen and circulating blood. Whether a plaque will remain intact and therefore stable or rupture and lead to thrombosis causing an acute coronary syndrome (MI, unstable angina pectoris) depends upon a number of factors, the most important of which is its composition. Plaque size plays only a minor role in determining risk of an acute coronary syndrome. Rupture of the fibrous cap occurs due to thinning of the cap caused by an influx and activation of macrophages which release metalloproteinases and other proteolytic enzymes (stimulated by inflammatory cells, particularly T-lymphocytes). These enzymes cause degradation of the fibrous tissue of the cap which can result in thrombous formation and occlusion of the artery. Stable plaques have a thick fibrous cap, a small lipid core, and few inflammatory cells. In contrast, vulnerable plaques have a high lipid content, numerous inflammatory cells, and a thin fibrous cap with reduced collagen and vascular smooth muscle cells in it. Although vulnerable plaques are believed to account for only a small number of all coronary atheromas, they are responsible for most acute coronary events.

Arteriosclerosis↗

PubMed2001

Troglitazone corrects metabolic changes but not vascular dysfunction in dietary-obese rats.

Insulin resistance has been attributed to the defect in vascular function associated with obesity, type 2 diabetes and dyslipidaemia. We have investigated vascular effects of chronic (3-week) administration of troglitazone on female Wistar rats with moderate dietary obesity. Compared with lean controls, untreated obese rats had significantly higher body weights, fat pad masses, plasma triglycerides, free fatty acids and leptin levels (for all P < 0.01). These metabolic changes were corrected by troglitazone treatment. In mesenteric arteries, responses to noradrenaline or KCl were similar in all groups. However, in noradrenaline-preconstricted arteries, vasorelaxations to acetylcholine and insulin were significantly (50-60% less than in lean, P < 0.001) attenuated in both untreated and troglitazone-treated obese rats. Relaxations to sodium nitroprusside showed similar but lesser impairment in both untreated and troglitazone-treated obese animals. Our data show that although troglitazone markedly improved obesity-induced metabolic changes, it failed to correct vascular dysfunction associated with obesity in female Wistar rats.

Acetylcholine↗

PubMed2001

How understanding the control of energy metabolism can help investigation of mitochondrial dysfunction, regulation and pharmacology.

Understanding the control of mitochondrial energy metabolism is central to knowing how mitochondria function within cells. Metabolic control analysis is the best approach available for studying the control of mitochondrial energy metabolism. Here I outline how metabolic control analysis has been used to help understand mitochondrial regulation, damage and pharmacology.

Adenosine Triphosphate↗

PubMed2004

[Cognitive function in patients with endometrial and colorectal cancer: connection with hormonal and metabolic status].

Cognitive dysfunction may be associated with the presence of an array of hormono-metabolic factors of risk for certain basic noninfectious diseases, supposedly, including cancer. The investigation was concerned with an appraisal of such cognitive functions as verbal and eye memory and ability to concentrate in endometrial and colorectal cancer patients versus hormonometabolic status and relevant parameters in menopausal women. The indices of short-term memory and concentration in endometrial carcinoma were significantly higher than both in colorectal cancer and osteoporotic patients. However, they were not among healthy women of the same age. A whole range of relationships between said indices and glucose- and estradiol levels in blood serum of patients was studied. No link was established between blood-serum cholesterol, b-lipoproteide and insulin concentration in patients, on the one hand, and cognitive function, on the other. Further research is expected to disclose the ties of the latter with other hormono-metabolic factors as well as tumor-related stress.

Aged↗

PubMed2001

2-Hydroxyestradiol attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats.

A pandemic of obesity is contributing importantly to the prevalence of the metabolic syndrome characterized by hypertension, insulin resistance, and hyperlipidemia. In turn, the metabolic syndrome is contributing to vascular disease and the accelerating epidemic of chronic renal failure. Currently, pharmacological approaches to attenuate obesity and its cardiovascular/renal sequelae are limited. The purpose of this study was to determine the effects of 2-hydroxyestradiol, a metabolite of 17beta-estradiol with minimal estrogenic activity, on the development of obesity, the metabolic syndrome, and heart, vascular, and renal dysfunction in obese ZSF1 rats, a well-characterized genetic model of obesity and the metabolic syndrome with concomitant heart, vascular, and kidney disease. ZSF1 rats were treated, beginning at 12 weeks of age, for 26 weeks with vehicle or 2-hydroxyestradiol (10 microg/kg/h). At baseline and after 24 weeks of treatment, animals were placed in metabolic cages, and food intake, water intake, urine output, and urinary excretion of proteins and glucose were determined. Next, in fasting animals, plasma cholesterol was measured, an oral glucose tolerance test was conducted, and total glycated hemoglobin levels were determined. At the end of the study, animals were anesthetized and instrumented for assessment of heart performance, renal hemodynamics, and mesenteric vascular reactivity. 2-Hydroxyestradiol attenuated the development of obesity and improved endothelial function, decreased nephropathy, decreased the severity of diabetes, lowered arterial blood pressure, and reduced plasma cholesterol. 2-Hydroxyestradiol may be an important lead for the development of safe and effect drugs to attenuate obesity and its metabolic, vascular, and renal sequelae.

Animals↗

PubMed2026

A refined MASH-HCC model identifies macrophage Gadd45b as a key orchestrator of inflammation-driven neoplastic progression.

Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading driver of hepatocellular carcinoma (HCC), yet the molecular mechanisms linking metabolic stress, chronic inflammation and tumorigenesis remain poorly understood. Here we established a metabolically relevant, time-efficient MASH-to-HCC model in C57BL/6N mice by combining a MASH diet with controlled CCl4 administration, enabling stepwise recapitulation of MASH-associated neoplastic progression. Using this model, we identified growth arrest and DNA damage 45b (Gadd45b) as a novel MASH-derived protumorigenic regulator selectively activated under metabolic stress. Integrated analyses of human bulk and single-cell transcriptomic datasets and mouse transcriptomic deconvolution revealed concordant macrophage remodeling and GADD45B/Gadd45b expression dynamics during MASH-to-HCC progression. Mechanistically, fatty acids and TNFα preferentially induced Gadd45b in macrophages, where it amplified TNFα-NF-κB signaling. Macrophage-derived inflammatory signals subsequently induced Gadd45b and NF-κB activation in hepatocytes, establishing a feed-forward inflammatory loop that promoted fibrogenic and partial EMT-like programs and tumor spheroid formation. Importantly, temporal profiling during spheroid formation and progression revealed transient induction of Gadd45b during early spheroid establishment, but not during later progression, indicating that Gadd45b-mediated inflammatory signaling primarily promotes tumor initiation rather than subsequent growth. Consistent with human data, Gadd45b expression increased with disease severity and positively correlated with inflammatory factors in the MASH-HCC model, whereas pharmacological inhibition attenuated the Gadd45b-inflammation signaling axis. Collectively, our findings establish macrophage Gadd45b as a key orchestrator linking metabolic stress, chronic inflammation, and neoplastic transformation during MASH-to-HCC progression. Our refined MASH-HCC model provides a robust platform for mechanistic studies and preclinical evaluation of inflammation-targeted therapies.

Journal Article↗

PubMed2026

High-fat diet-responsive DNM1 promotes hepatocellular carcinoma progression and predicts poor prognosis in viral-associated patients.

Hepatocellular carcinoma (HCC) arises from diverse etiologies, among which metabolic dysfunction-associated liver disease and chronic viral hepatitis are the two major drivers worldwide. However, the molecular mechanisms linking metabolic stress to HCC progression remain incompletely understood. Dynamin-1 (DNM1), primarily known for its role in vesicular trafficking, has emerged as a potential oncogene, yet its prognostic and functional significance in HCC remains largely unexplored. Here, we investigated the role of DNM1 in high-fat diet (HFD)-associated hepatocarcinogenesis. Transcriptomic profiling was conducted to identify differentially expressed genes between normal and high-fat diet murine models, with human orthologs mapped. Clinical relevance was validated using The Cancer Genome Atlas (TCGA-LIHC) dataset. Survival analysis, GSEA (Gene Set Enrichment Analysis), and subgroup stratifications based on viral hepatitis status were performed. In vitro, loss-of-function assays (shRNA knockdown) were executed in HepG2 and SK-Hep1 cell lines to assess cell viability and migration. DNM1 was significantly upregulated in high-fat diet models. In the TCGA-LIHC cohort, high DNM1 expression was an independent risk factor for poor overall survival (HR=1.44, P=0.039) and correlated with advanced tumor stages (Stage III+IV, P=0.010). In vitro knockdown of DNM1 profoundly impaired cell proliferation and migration in HCC cell lines. Strikingly, DNM1 expression was further elevated in patients with concurrent viral hepatitis (P=0.009). GSEA revealed that high DNM1 expression was positively associated with viral infection pathways and negatively correlated with critical immune responses, including interferon-alpha/gamma responses and host immune cytolysis. Survival analysis stratified by four subgroups demonstrated that patients with both viral infection and high DNM1 expression exhibited the worst prognosis (Overall Log-rank P < 0.001). Our findings identify DNM1 as a high-fat diet-responsive regulator that links metabolic stress to hepatocellular carcinoma progression. Elevated DNM1 expression promotes malignant phenotypes in HCC and identifies a subgroup of viral-associated patients with particularly poor prognosis, highlighting DNM1 as a potential prognostic biomarker and therapeutic target.

Hepatocellular carcinoma (HCC)↗

PubMed2004

Abnormal capillary permeability and endothelial dysfunction in hypertension with comorbid Metabolic Syndrome.

PURPOSE: Metabolic Syndrome as defined by ATP III criteria, a constellation of risk factors associated with insulin resistance, predisposes to premature atherosclerosis and early coronary events. Whether that negative risk profile is associated with endothelial dysfunction remains to be established. MATERIALS AND METHODS: Transcapillary escape rate of albumin (TERalb), a measure of capillary permeability and integrity of systemic capillary endothelium, and forearm vasodilation to intra-arterial acetylcholine (ACH), an index of nitric oxide (NO)-mediated vasomotor dysfunction, were assessed in 24 non-diabetic, uncomplicated hypertensive men with Metabolic Syndrome according to ATP III criteria (hypertension with at least two additional traits such as high triglycerides, low HDL, abdominal obesity, impaired fasting or post-load plasma glucose). Twelve age-matched lean normal hypertensive patients with normal lipid and glucose profile and nine normotensive subjects were the controls. All patients underwent lipids determination and fasting and post-OGTT insulin assessment; HOMA-IR was the index of insulin resistance. RESULTS: TERalb was higher in hypertensive patients with Metabolic Syndrome, without differences between hypertensive and normotensive controls. Blood pressure (BP), lipids, plasma glucose, insulin levels and HOMA-IR were unrelated to TERalb. Responses to acetylcholine were selectively attenuated in metabolic patients and, on an individual basis, related only to HDL cholesterol levels, independent of LDL cholesterol, BP, body size, triglycerides, and HOMA-IR values. No relationship existed between responses to acetylcholine and TERalb. CONCLUSIONS: Altered systemic capillary permeability characterizes insulin-resistant hypertensive patients with Metabolic Syndrome. That defect, which may promote early atherosclerosis development, coexists with blunted endothelial-mediated vasodilation, indicating a pervasive abnormality of endothelial function.

Acetylcholine↗

PubMed1994

A rat model manifesting methanol-induced visual dysfunction suitable for both acute and long-term exposure studies.

A toxic dose of methanol can induce visual dysfunction and metabolic acidosis in humans. However, the methanol dose range capable of inducing such toxicities and the mechanism(s) of visual dysfunction are not clearly understood. Nonprimate laboratory animals do not develop the characteristic human methanol toxicities even after a lethal dose. In the present study, we investigated whether visual dysfunction can be induced by methanol in a folate-reduced (FR) rat model which accumulates formate. Methanol was administered to rats by either the oral or inhalation route. The latencies of P1 and N1 peaks of flash-evoked potentials were significantly increased in methanol-challenged FR rats (3.5 g/kg, po), indicating that methanol administration caused an adverse effect in the retinogeniculocortical visual pathway. Effects on retinal function were then assessed by evaluating the electroretinogram (ERG). A dose-related reduction in b-wave amplitude of the ERG was manifested following oral methanol administration (1.5 to 2.5 g/kg). The b-wave amplitude reduction was also manifested in FR rats exposed to methanol vapors (2000 ppm, a concentration which was nontoxic in monkeys). These observations were consistent with reported human methanol toxicity cases. Thus, our data suggest that the FR rat model could serve as a valuable human surrogate for studying mechanisms of methanol-induced visual dysfunction and providing reliable toxicity data on the visual system under various exposure scenarios.

Administration, Inhalation↗

PubMed1992

Correlation of contractile dysfunction and abnormal tissue energy metabolism during hypoperfusion with norepinephrine in isolated rat hearts: differences between normal and diabetic hearts.

The relationship of myocardial high-energy phosphate depletion and lactate accumulation with contractile dysfunctions was investigated in streptozotocin-diabetic (DM) and normal rat hearts. The isolated hearts were perfused with 10(-6) M norepinephrine (NE) at various low-flow rates (0.4-6 ml/min/g heart wt) for 1 h. Left ventricular pressure (LVP) and contractile force (CF) were monitored, through a water-filled balloon in LV and through a hook attached to the apex, respectively. In DM hearts resting CF (diastolic tension) increased, when the perfusion flow rate was reduced below 6 ml and reached a maximum at a flow rate of less than 3 ml. The large increase in LV stiffness correlated with an elevation in diastolic LVP. In normal hearts these parameters were elevated at a flow rate below 1 ml. A flow-dependent decrease in developed CF was more prominent in DM than in normal hearts, while developed LVP and perfusion pressure were slightly higher in DM hearts with a marked increase in the LV stiffness. A flow-dependent decrease in high-energy phosphates and increases in inorganic phosphate and lactate were more prominent in the inner than in the outer layer of LV free wall in both groups. The change of ATP in the inner layer was greater, while increases of lactate in both layers were smaller in DM hearts. Changes in mechanical parameters correlated well with the ATP decrease and lactate increase in the inner layer in both groups. The correlation curves, however, were not coincidental: at the same low ATP and high lactate level, the LV stiffness was higher in DM hearts. Results indicate that DM hearts are more susceptible to flow-reduction with NE and depletion of total ATP in their tissue, and easily suffer from increased LV stiffness. This cannot be explained by the rate of decrease in total ATP and lactate accumulation alone.

Adenosine Triphosphate↗

PubMed2005

Mortality trends of HIV-infected patients after the introduction of highly active antiretroviral therapy: analysis of a cohort of 3,322 HIV-infected persons.

INTRODUCTION: The implementation of highly active antiretroviral therapies (HAART) has reduced the mortality attributed to the human immunodeficiency virus (HIV) infection. Variation in the specific causes of death has also changed since the implementation of these therapies. METHODS: A prospective study was performed in 3322 HIV-infected persons enrolled in Puerto Rico between 1992 and 2003. We measured the mortality rates and the causes of death as listed in the death certificate and analyzed the variation as a function of the antiretroviral therapy (ART) use. Statistical analyses were performed to evaluate differences. RESULTS: The study found that persons treated with HAART had significantly lower mortality risk than ART-naïve persons, regardless of gender and the use of injecting drugs. AIDS-defining conditions as a cause of demise were less frequently reported in patients with HAART. Gastrointestinal dysfunction, sepsis, metabolic abnormalities, and non-Kaposi neoplasms were more frequently reported as causes of death in patients treated with HAART. Hepatic failure as cause of death was also more frequent in these patients. The variation in the mortality trends was similar in both genders and according to the presence or absence of intravenous drug use. CONCLUSIONS: Highly active antiretroviral therapies (HAART) is associated with significant reduction in mortality and an increment in gastrointestinal dysfunction, sepsis, non-Kaposi neoplasms, and metabolic disorders as listed causes of death. Adverse and toxic profile of ART, along with the potential synergy of concomitant conditions, may accelerate these trends. Continued mortality surveillance of HIV/AIDS is imperative to follow the epidemic changes.

Adult↗