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PubMed1994

Cockayne syndrome: a case report.

A 4-year-old female with Cockayne syndrome presented for cataract extraction under general anesthesia. She was thin and frail; her neck, epiglottis and larynx were stiff; she was deaf and blind; and she could not speak, sit unaided, or perspire. At the time of her admission, she weighed 5.5 kg. Cockayne syndrome is a disease of childhood characterized by mental retardation and premature aging. Although the underlying abnormality appears to be autosomal recessive inheritance or metabolic (possibly thymic) dysfunction, there is no consensus on etiology. The multiple organ involvement carries significant implications for the anesthetist. Intubation can be technically difficult, and care of the skin can be problematic. Essential hypertension, hepatic deficiencies, osteoporosis, deafness, blindness, and other effects of premature aging may be encountered making perioperative management a challenge.

Anesthesia, General↗

PubMedDate not supplied

Epilepsy in congenital lipodystrophy. Case report.

A case of congenital lipodystrophy complicated by complex-partial epilepsy is reported in a nine-year-old girl. The peculiarity of this rare case is represented by partial complex epilepsy with diffuse electroencephalographic alterations represented by a continuous seizure-like pattern that persisted unmodified despite the successful antiepileptic treatment. Although the etiopathology of lipodystrophy is, at present, still elusive, we hypothesize that the primitive dysfunction of lipidic metabolism plays a critical role in both determining central nervous system (CNS) alterations and the findings that characterized this extremely rare disease.

Adipose Tissue↗

PubMed1993

Wellness testing. Design and experience of an established program.

Consumers have responded to available information and generated a large demand for self-initiated testing. Carefully planned testing can provide significant benefits to these self-selected subjects. Most notable examples include using sensitive and specific tests for iron metabolism and thyroid dysfunction. Cholesterol and lipid concerns are also motivators for testing. Nutrition and laboratory professionals must get involved with self-initiated testing to assure proper design, proper methods, proper reporting, and proper follow-up. It is hoped that this article and accompanying references will aid the implementation of effective wellness testing.

Adult↗

PubMed1998

Hypertension in east Africans and others of African descent: a review.

As the number of fatalities from cardiovascular diseases declines in western industrial nations, an opposite trend is observed in the East African region. Inter-regional variations in the prevalence of vascular disorders have been attributed to socioeconomic, psychosocial and heritable physiological parameters. Although faulty mineralocorticoid metabolism and the dysfunctional kidney are prominent features of circulatory problems, many current studies are focused on membrane receptors, transmembrane ion transport mechanisms, ion channels and the possible genetic polymorphisms that determine the characteristics of those molecular structures in the vascular system of normal or hypertensive persons. In this review, a composite of the data available on each of the above parameters and its significance in the pathogenesis of hypertension in the industrial West and transforming economies of East Africa is presented.

Africa, Eastern↗

PubMed2000

The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: A double-blind, placebo-controlled, positron-emission tomography study.

BACKGROUND: The mechanism for the beneficial effect of beta-blocker therapy in patients with left ventricular (LV) dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using positron-emission tomography (PET), are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MVO(2)). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency. METHODS AND RESULTS: The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work-metabolic index in patients with LV dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; LV ejection fraction <40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in analysis because of withdrawal from the study, incomplete follow-up, or nonanalyzable PET data. The rate of oxidative metabolism (k) was measured using C-11-acetate PET, and stoke volume index (SVI) was measured using echocardiography. The work-metabolic index was calculated as follows: (systolic blood pressure x SVI x heart rate)/k. No significant change in oxidative metabolism occurred with placebo (k=0.061+/-0.022 to 0.054+/-0.012 per minute). Metoprolol reduced oxidative metabolism (k=0.062+/-0. 024 to 0.045+/-0.015 per minute; P:=0.002). The work-metabolic index did not change with placebo (from 5.29+/-2.46 x 10(6) to 5.14+/-2. 06 x 10(6) mm Hg. mL/m(2)), but it increased with metoprolol (from 5. 31+/-2.15 x 10(6) to 7.08+/-2.36 x 10(6) mm Hg. mL/m(2); P:<0.001). CONCLUSIONS: Selective beta-blocker therapy with metoprolol leads to a reduction in oxidative metabolism and an improvement in cardiac efficiency in patients with LV dysfunction. It is likely that this energy-sparing effect contributes to the clinical benefits observed with beta-blocker therapy in this patient population.

Acetates↗

PubMed1998

Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism.

PURPOSE: To unravel why intravesical oxybutynin is more effective and causes significantly fewer systemic side effects than oral oxybutynin in the treatment of neurogenic bladder dysfunction, we tested the hypothesis that the absorption and metabolism of oxybutynin are changed after intravesical instillation. MATERIALS AND METHODS: A high-performance liquid chromatography assay was developed for both oxybutynin and its active metabolite, N-desethyl-oxybutynin. Plasma concentrations were quantified after intravesical (n = 11) and oral (n = 5) administration of oxybutynin in children under steady-state conditions. Pharmacokinetic parameters were calculated. RESULTS: Oral administration of oxybutynin (0.2 mg./kg./dose) resulted in peak plasma concentrations for N-desethyl-oxybutynin which were 7.4 +/- 1.3 times higher than corresponding values for oxybutynin (n = 5). Also the AUC (area under the plasma concentration time curve) values were higher for N-desethyl-oxybutynin compared with those of oxybutynin, the ratio being 10.8 +/- 1.0 (n = 5). Intravesical instillation (0.2 mg./kg./dose), on the other hand, resulted in reduced metabolite generation and peak plasma concentrations for N-desethyl-oxybutynin which were in the same range as those for oxybutynin, the ratio being 1.2 +/- 0.1 (n = 11). The ratio for the AUC values for N-desethyl-oxybutynin and oxybutynin was 2.1 +/- 0.2 (n = 11). CONCLUSIONS: The significantly lower AUC ratio of the N-desethyl metabolite over the mother compound, due to a reduced first pass metabolism, may explain the clinically relevant reduction of side effects that characterizes intravesical compared with oral oxybutynin therapy.

Administration, Intravesical↗

PubMed1989

Hepatotoxicity and metabolism of isoflurane in rats with cirrhosis.

A rat model was used to determine whether isoflurane exacerbates liver dysfunction and whether its metabolism is changed in the presence of cirrhosis. Male Wistar rats were gavaged weekly with carbon tetrachloride until cirrhosis was well advanced. They and control rats without pretreatment with carbon tetrachloride and without cirrhosis were then exposed to 1.45% (1 MAC) isoflurane for 3 hours. Blood and urine samples were taken before, immediately, as well as 4, 24, 48, and 72 hours after anesthesia to measure liver function and isoflurane defluorination. After the last samples had been obtained, the rats were sacrificed and the liver removed for histologic examination and in vitro metabolic studies. Serum levels of SGOT and SGPT and inorganic fluoride production in rats with cirrhosis were similar to those in control rats without cirrhosis. Concentrations of cytochromes b5 and p-450 and specific activities of microsomal defluorinase and several cytosolic enzymes were significantly lower in cirrhotic than in noncirrhotic liver, but their total amounts in whole liver were the same. The results imply that cirrhosis does not increase the risk of acute hepatotoxicity of isoflurane. They also demonstrate that metabolism of isoflurane and perhaps other volatile anesthetics may be unaffected in rats with cirrhosis, even though liver architecture is severely disrupted.

Animals↗

PubMed2006

Role of trimetazidine in management of ischemic cardiomyopathy.

Despite treatment with conventional agents, a high proportion of patients with ischemic cardiomyopathy continue to have symptoms. Moreover, a substantial proportion shows progressive contractile dysfunction leading to left ventricular (LV) enlargement and heart failure. Therefore, a need exists for new treatments for ischemic cardiomyopathy that tackle mechanisms other than those already addressed by conventional agents. Emerging evidence suggests that in patients with ischemic cardiomyopathy, LV dysfunction develops as a result of alterations in substrate metabolism, which contribute to contractile dysfunction and the progression of LV remodeling. Trimetazidine, a novel pharmacologic agent that acts on myocardial metabolic pathways, appears to protect the heart from the deleterious effects of ischemia, and it has been shown to enhance LV contractility in patients with stunned or hibernating myocardium. This article reviews recent clinical trials that have assessed the therapeutic role of trimetazidine in patients with ischemic cardiomyopathy. Trimetazidine has been shown to improve symptoms and LV ejection fraction and to have a beneficial effect on the inflammatory profile and endothelial function in these patients. These results suggest that trimetazidine is a useful adjunct to our current armamentarium for the treatment of patients with ischemic cardiomyopathy.

Humans↗

PubMed1991

Abnormal vitamin B12 metabolism in human immunodeficiency virus infection. Association with neurological dysfunction.

An increased prevalence of vitamin B12 deficiency has been reported in patients infected by the human immunodeficiency virus (HIV). We report an unexpectedly high prevalence (20%) of such abnormal vitamin B12 metabolism in a population of HIV-infected patients referred for neurological evaluation. This abnormality was associated with both peripheral neuropathy and myelopathy. A majority of those treated with cyanocobalamin had a therapeutic response. Selected neuropathological results suggest a relationship between vitamin B12 deficiency and vacuolar myelopathy. Vitamin B12 deficiency may be a frequent and treatable cause of neurological dysfunction in patients with HIV infection.

HIV Infections↗

PubMed2006

Altered metabolism and mitochondrial genome in prostate cancer.

Mutations in mitochondrial DNA are frequent in cancer and the accompanying mitochondrial dysfunction and altered intermediary metabolism might contribute to, or signal, tumour pathogenesis. The metabolism of human prostate peripheral zone glandular epithelial cells is unique. Compared with many other soft tissues, these glandular epithelial cells accumulate high concentrations of zinc, which inhibits the activity of m-aconitase, an enzyme involved in citrate metabolism through Krebs cycle. This causes Krebs cycle truncation and accumulation of high concentrations of citrate to be secreted in prostatic fluid. The accumulation of zinc also inhibits terminal oxidation. Therefore, these cells exhibit inefficient energy production. In contrast, malignant transformation of the prostate is associated with an early metabolic switch, leading to decreased zinc accumulation and increased citrate oxidation. The efficient energy production in these transformed cells implies increased electron transport chain activity, increased oxygen consumption, and perhaps, excess reactive oxygen species (ROS) production compared with normal prostate epithelial cells. Because ROS have deleterious effects on DNA, proteins, and lipids, the altered intermediary metabolism may be linked with ROS production and accelerated mitochondrial DNA mutations in prostate cancer.

DNA, Mitochondrial↗

PubMed1989

[Clinical studies on lipid metabolism in hyperthyroidism and hypothyroidism--evaluation of serum apolipoprotein levels before and after treatment].

The present study was undertaken to assess lipid metabolism in patients with thyroid dysfunction with special reference to serum apolipoprotein levels. Serum lipid, lipoprotein and apolipoprotein levels were determined in 28 hyperthyroid and 16 hypothyroid female patients while untreated and euthyroid. Apolipoproteins were measured by the method of single radial immuno-diffusion (SRID). These results were compared with the values of 28 female controls. In the untreated hyperthyroid group, the serum levels of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were significantly decreased compared to the controls and increased after treatment. In hypothyroidism, these values before treatment were higher than those in the controls and decreased after treatment. Serum apo A-I, A-II, B and C-III levels were significantly decreased in the untreated hyperthyroid group compared to the control values. Apo C-II and E levels in hyperthyroidism were identical both before and after treatment compared with the control values, respectively. In the untreated hypothyroidism, apo B, C-II, C-III and E levels were significantly elevated compared to the controls, and these changes in apolipoproteins except apo C-II were restored after treatment. Apo A-I and A-II levels in the untreated hypothyroidism were not statistically different from the values after treatment or those in the control group. Serum thyroid hormone (T3, T4) levels inversely correlated apo B and C-III in all subjects. In hypothyroidism, serum TSH positively correlated with apo B, C-II and C-III. The increase in relative body weight (%RBW) in hyperthyroidism during treatment correlated with the changes of TC and LDL-C. In conclusion, these results indicate that thyroid hormones have a substantial influence on the serum apolipoprotein levels, and that measurement of apolipoproteins as well as lipids and lipoproteins in patients with thyroid dysfunction may be useful to evaluate the lipid metabolism and the effect of therapy.

Adolescent↗

PubMed2004

Astrocyte mitochondrial mechanisms of ischemic brain injury and neuroprotection.

Research on ischemic brain injury has established a central role of mitochondria in neuron death. Astrocytes are also damaged by ischemia, although the participation of mitochondria in their injury is ill defined. As astrocytes are responsible for neuronal metabolic and trophic support, astrocyte dysfunction will compromise postischemic neuronal survival. Ischemic alterations to astrocyte energy metabolism and the uptake and metabolism of the excitatory amino acid transmitter glutamate may be particularly important. Despite the significance of ischemic astrocyte injury, little is known of the mechanisms responsible for astrocyte death and dysfunction. This review focuses on differences between astrocyte and neuronal metabolism and mitochondrial function, and on neuronal-glial interactions. The potential for astrocyte mitochondria to serve as targets of neuroprotective interventions is also discussed.

Animals↗

PubMed1992

[The role of autonomic dysfunction in the pathogenesis of lipid and lipoprotein metabolic disorders in patients with metabolic-alimentary obesity].

Obesity is a "disease of civilization" that leads to the formation of vascular pathology. Vegetodystonia, a heterogeneous syndrome both as regards the type and clinical course, is a pronounced clinical manifestation of obesity. The role of vegetodystonia in the formation of atherogenic potential of obesity has not been studied yet. 77 patients with metabolic alimentary obesity were examined for blood lipidograms as compared to the vegetative status and anthropometric data. Based on a correlation analysis performed, a relationship was discovered between the changes in the parameters indicated. The character of the correlation was determined by the type of vegetodystonia. The leading part in the formation of atherogenic potential is played by sympathoadrenal influences which are most manifest is permanent vegetovascular dystonia of the vagoinsular type. The treatment of obesity should be carried out with regard to the concrete variety of vegetative dysfunction.

Adolescent↗

PubMed1999

Changes of cerebral energy metabolism and lipid peroxidation in rats leading to mitochondrial dysfunction after diffuse brain injury.

The effect of mild closed head trauma, induced by the weight-drop method (450 g from a 1-m height), on lipid peroxidation and energy metabolism of brain tissue was determined at various times after cerebral injury in spontaneously breathing rats (1, 10, 30 minutes and 2, 6, 15, 24, 48, and 120 hours). Animals were continuously monitored for the evaluation of blood pressure, blood gases, heart rate, and intracranial pressure. Analysis of malondialdehyde (MDA) as an index of lipid peroxidation, ascorbic acid, high-energy phosphates, nicotinic coenzymes, oxypurines, and nucleosides was performed by high-performance liquid chromatography (HPLC) on neutralized perchloric acid extract of the whole brain. Data showed that MDA, undetectable in control, sham-operated rats, was already present within 1 minute of trauma (1.77 nmol/g wet weight; SD = 0.29) and reached maximal values by 2 hours (72.26 nmol/g w.w.; SD = 11.26), showing a progressive slow decrease thereafter. In contrast, ATP, GTP, and nicotinic coenzyme (NAD and NADP) concentrations showed significant reduction only by the second hour postinjury. Maximal decrease of the ATP and GTP concentrations were seen at 6 hours postinjury, whereas NAD and NADP concentrations showed maximum decline by 15 hours. Values recorded in mechanically ventilated rats did not differ significantly from those obtained in spontaneously breathing animals. These findings, supported by the absence of blood gas and blood pressure changes in the spontaneously breathing rats, strongly support the premise that biochemical changes (primarily lipid peroxidation) are not caused by secondary ischemic-hypoxic phenomena but rather are triggered by these forces acting on the brain at the time of impact. In addition, these results suggest that depression of energy metabolism might be caused by peroxidation of the mitochondrial membrane with a consequent alteration of the main mitochondrial function-that is, the energy supply.

Adenine Nucleotides↗

PubMed2001

Nerve conduction defects are retarded by tight metabolic control in type I diabetes.

This follow-up study examines whether the development of nerve dysfunction is retarded by tight metabolic control in patients with type I diabetes mellitus. Seventy-one patients and 115 age-matched healthy control subjects underwent studies of nerve conduction in peroneal and sural nerves. The presence of diabetes was associated with a reduction in peroneal motor nerve conduction velocity (MCV) by 5.9 m/s, sural sensory nerve conduction velocity (SCV) by 3.4 m/s, and sural sensory nerve action potential (SNAP) amplitude by 22%. Dysfunction in peroneal MCV, sural SCV, and sural SNAP were related to long-term poor metabolic control. Eleven of 12 patients with HbA1c <6.5% had normal nerve conduction or abnormality in only one nerve as compared to 2 of 15 patients with HbA1c >8.0%. It is concluded that tight long-term metabolic control (HbA1c <6.5%) can retard nerve dysfunction in patients with type I diabetes mellitus and a mean disease duration of 12 years.

Action Potentials↗

PubMed2004

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia.

OBJECTIVE: The purpose of this study was (a) to study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel-III criteria and (b) to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance. DESIGN AND METHODS: A double-blind, parallel, identical placebo-drug, randomized study was performed for 2 months in 50 patients. Patients were randomly allocated to two groups. In group 1, patients were treated with diet plus placebo for 2 months. In group 2, patients were treated with diet plus placebo for 1 month, followed by diet plus folic acid (5 mg/day) plus vitamin B12 (500 microg/day) for another month. RESULTS: In group 2, folate treatment significantly decreased homocysteine levels by 27.8% (12.2+/-1.2 vs 8.8+/-0.7 micromol/l; P<0.01). A significant decrement was observed for insulin levels (19.9+/-1.7 vs 14.8+/-1.6 microU/ml; P<0.01) accompanied by a 27% reduction in the homeostasis model assessment levels. A positive relationship was found between the decrement of homocysteine and insulin levels (r=0.60; P<0.002). In parallel, endothelial dysfunction significantly improved in the treated group, since post-ischemic maximal hyperemic vasodilation increased by 29.8% and cGMP by 13.6% while asymmetrical dimethylarginine levels decreased by 21.7%. On the contrary, in group 1 patients, treated with placebo, no changes were shown in any of the variables. CONCLUSIONS: Folate and vitamin B12 treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine levels, in patients with metabolic syndrome, suggesting that folic acid has several beneficial effects on cardiovascular disease risk factors.

Aged↗

PubMed2000

Troglitazone improves endothelial dysfunction in patients with insulin resistance.

Insulin resistance is a possible major metabolic cause of atherosclerosis. Endothelial dysfunction is commonly found in patients with insulin resistance, and primary treatment of insulin resistance with troglitazone should improve such endothelial dysfunction. Thus, the effects of troglitazone on endothelial function were investigated. Thirteen non-diabetic male subjects with hyperinsulinemic response to oral glucose load (n = 7) and normal (n = 6) subjects were investigated. Flow-mediated dilatation (FMD) of the brachial artery was examined by high resolution ultrasonography before and after the administration of troglitazone of 400 mg for 4 weeks. In insulin resistant subjects, fasting glucose (4.9+/-0.3 to 4.7+/-0.3 mmol/L, p<0.05), insulin (45+/-30 to 25+/-15 pmol/L, p<0.05) and response to oral glucose load (AUC glucose: 15.0+/-3.5 to 13.0+/-2.2 mmol x h/L, p<0.05; AUC insulin: 965+/-560 to 475+/-275 pmol x h/L, p<0.05) were significantly reduced. FMD was significantly improved in insulin resistant subjects. A significant negative correlation was observed between FMD and AUC insulin (r=-0.64, p<0.05). The present study demonstrates that FMD is impaired in insulin resistant subjects, and troglitazone improves the blunted vascular response and impaired insulin response. This finding suggests that primary treatment of insulin resistance could prevent the development of atherosclerosis by improving endothelial dysfunction.

Adult↗

PubMed2001

Energy stores and metabolites in chronic reversibly and irreversibly dysfunctional myocardium in humans.

OBJECTIVES: Our goal was to study metabolic energy stores and lactate content in chronic reversibly and irreversibly dysfunctional myocardium. BACKGROUND: It is unknown whether metabolism is deranged in chronic reversibly and irreversibly dysfunctional myocardium in humans. Semiquantitative histological examinations have shown altered mitochondrial morphology and glycogen accumulation in dysfunctional regions. METHODS: We studied 25 patients with a mean ejection fraction of 38 +/- 9% scheduled for coronary artery bypass surgery. Regional perfusion and metabolism were assessed by positron emission tomography, and regional function was assessed by echocardiography. Perioperative myocardial biopsies were obtained from a control region and from a dysfunctional region. We analyzed biopsies for contents of noncollagen protein (NCP), ATP, ADP, AMP, glycogen and lactate. Six months after surgery we assessed wall motion by echocardiography to group patients in those with (n = 11) and without (n = 14) functional improvement. RESULTS: Reversibly dysfunctional myocardium had reduced perfusion (0.59 +/- 0.16 vs. 0.69 +/- 0.20 ml/g/min, p < 0.05), similar glucose-tracer uptake (92 +/- 12 and 95 +/- 14%), ATP/ADP ratio (2.4 +/- 1.1 and 2.4 +/- 0.7), glycogen content (631 +/- 174 and 632 +/- 148 nmol/microg NCP) and lactate levels (59 +/- 27 and 52 +/- 29 nmol/microg NCP) compared with control regions. Irreversibly dysfunctional regions (n = 14) had severely reduced perfusion (0.48 +/- 0.15 vs. 0.72 +/- 0.12 ml/g/min, p < 0.001) and glucose-tracer uptake (52 +/- 16 vs. 94 +/- 15%, p < 0.001), reduced ATP/ADP ratio (1.5 +/- 0.9 vs. 2.3 +/- 0.9, p < 0.05), similar glycogen content (579 +/- 265 vs. 593 +/- 127 nmol/microg NCP) and increased lactate levels (114 +/- 52 vs. 89 +/- 24 nmol/microg NCP, p < 0.01) compared with control regions. CONCLUSIONS: Contents of metabolic energy stores and lactate in chronic reversibly dysfunctional myocardium were preserved. In contrast, energy stores were depleted in myocardium without functional recovery after revascularization.

Adenosine Diphosphate↗