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Biomedical subjects

F Taroni

Publications and source records attributed to F Taroni.

At least 55 records · Page 3Linked to original sources
PubMed1999

The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis.

Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies.

Apoptosis↗
PubMed1998

Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies or brachial plexopathies, commonly associated with a chromosome 17p11.2-12 deletion encompassing the peripheral myelin protein-22 (PMP22) gene. We tried to identify criteria distinguishing HNPP among patients with acute painless mononeuropathy/plexopathy. We investigated by pulsed-field gel electrophoresis the presence of the deletion in 27 patients with isolated or recurrent acute painless mononeuropathy or brachial plexopathy, and no obvious cause of neuropathy. Eight patients carried the deletion, whereas 19 had neither the deletion nor mutations in the PMP22 gene. Age at onset, presenting modality, precipitating events, and rate of recovery did not significantly differ in the two groups. Family history was informative for HNPP diagnosis in 3 cases only. HNPP patients more often showed recurrent episodes, brachial plexopathy, and clinical or electrophysiologic involvement of other nerves. Non-HNPP patients more frequently had peroneal palsy, recent weight loss, and normal electrophysiologic examination in other nerves. Signs of generalized neuropathy and evidence of disease in other family member are often subtle in HNPP and must be thoroughly investigated in patients with acute painless mononeuropathy/plexopathy.

Action Potentials↗
PubMed1998

Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes.

Carnitine palmitoyltransferase II (CPT II) deficiency manifests as two different clinical phenotypes: a muscular form and a hepatic form. We have investigated three nonconsanguineous Japanese patients with CPT II deficiency. Molecular analysis revealed two missense mutations, a glutamate (174)-to-lysine substitution (E174K) and a phenylalanine (383)-to-tyrosine substitution (F383Y) in the CPT II cDNA. Transfection experiments in COS-1 cells demonstrated that the two mutations markedly decreased the catalytic activity of mutant CPT II. Case 1 (hepatic form) was homozygous for the F383Y mutation, whereas case 3 (muscular form) was homozygous for the E174K mutation. Case 2 and her brother, who were compound heterozygotes for E174K and F383Y, exhibited the hepatic phenotype. We also identified a novel polymorphism in the CPT2 gene, a phenylalanine (352)-to-cysteine substitution (F352C), which did not alter CPT II activity in transfected cells. It was present in 21 out of 100 normal alleles in the Japanese population, but absent in Caucasian populations. Genotyping with the F352C polymorphism and the two previously reported polymorphisms, V368I and M647V, allowed normal Japanese alleles to be classified into five haplotypes. In all three families with CPT II deficiency, the E174K mutation resided only on the F1V1M1 allele, whereas the F383Y mutation was observed on the F2V2M1 allele, suggesting a single origin for each mutation.

Adult↗
PubMed1998

Very-long-chain acyl-coenzyme A dehydrogenase deficiency in a child with recurrent myoglobinuria.

A 9-year-old boy had recurrent episodes of myoglobinuria and normal urinary organic acid profile. Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency was detected biochemically in cultured skin fibroblasts and confirmed by Western blot analysis. The patient had a distinctive plasma fatty-acid profile, which was present even between attacks. Early diagnosis of this disorder is important because of the apparently protective effect of an appropriate dietary regimen.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1998

The health care reform in Italy: transition or turmoil.

Health care reform in Italy is transforming its centrally planned, vertically integrated National Health Service into a market-oriented system in which public funders contract directly with individual providers. A model is envisaged in which a plurality of public and private care providers compete for contracts with capitated health agencies responsible for assuring uniform levels of services for geographically defined populations. The ultimate goal of the reform is to guarantee universal coverage and secure global spending limits while, at the same time, promoting efficiency in the delivery of care and enhancing responsiveness to consumers. The emphasis upon incentives for the individual provider which will be introduced should, however, be considered against the quest for equity in health care which was the central tenet of the 1978 reform and is yet to be attained. The fragmentation of the National Health Service into many separate, competing delivery units might well damage the ability to plan strategically for addressing the substantial inequities in health status, health care utilization, and health service availability which still exist across the country. Competition between a plurality of providers and fee-for-service payment schemes add additional concerns about unnecessary care and supplier-induced demand. It creates the need for developing rules to make competition manageable and providing sound clinical and financial information that make enforcement possible. The poor record scored in managing the contractual relationships between the LHUs and the strong private health sector suggests that massive investment in promoting managerial skills and developing appropriate clinical and financial information systems are required. Careful experimentation in implementing the reform and continuous monitoring of its impact on the health care system are, therefore, the imperatives of the next two years.

Capitation Fee↗
PubMed1997

Characterisation of carnitine palmitoyltransferases in patients with a carnitine palmitoyltransferase deficiency: implications for diagnosis and therapy.

OBJECTIVES: Carnitine palmitoyltransferase (CPT) deficiency is one of the most common defects of mitochondrial fatty acid oxidation. Two different enzymes (CPT-I and CPT-II) are involved. Due to problems in measuring enzyme activity, relatively little is known about the substrate specificity of each of the human enzymes. This is of considerable importance in the treatment of patients. The objectives were to establish a reliable method for the measurement of CPT activity in whole cells, to use this to characterise the substrate specificity of each enzyme, and finally, to determine if medium chain triglycerides would be of benefit in the treatment of deficient patients. METHODS: A simple permeabilisation technique was used which allows the measurement of CPT activity in a small amount of cultured skin fibroblasts or peripheral blood cells. Using this technique three patients were identified with CPT deficiency. In two of these patients, one with CPT-I deficiency and one with CPT-II deficiency, a complete substrate specificity profile of the mitochondrial carnitine acyltransferases was established for all saturated even chain acyl-CoA esters. RESULTS: For both enzymes the highest CPT activity was with C12-CoA. About 70% of total cellular carnitine octanoyltransferase activity was due to mitochondrial CPT. As CPT is involved in the transport of medium chain fatty acids the metabolic response of a patient with CPT-II deficiency to dietary medium chain triglycerides was assessed. Despite the normal production of ketone bodies there was a significant medium chain dicarboxylic aciduria in the patient, indicating a limited capacity of the CPT independent mitochondrial uptake of medium chain fatty acids. CONCLUSIONS: CPT deficiency can easily be diagnosed in permeabilised cultured skin fibroblasts. Both CPT-I and CPT-II are more active with medium chain length substrates than previously assumed. Care should therefore be taken in the treatment of these patients with medium chain triglycerides.

Adult↗
PubMed1997

Variation in hospital use and avoidable patient morbidity.

OBJECTIVES: To determine whether geographical areas with relatively low overall hospitalization rates have higher population-based rates of admission of patients with advanced stages of disease. METHODS: Age- and sex-standardized hospital admission rate were calculated for the residents of the 80 Local Health Units in Lombardia, Italy. Using the Disease Staging classification, advanced stage admissions were identified for six common medical and surgical conditions, which it was presumed would reflect untimely hospital admission. Standardized rates of advanced stage admissions were compared in areas with overall high hospitalization rates (high-use areas). RESULTS: Hospitalization at advanced stages of disease in the low-use areas were significantly higher for the six conditions combined (55.9 vs 43.0 per 100,000; P = 0.005), and for external hernia, appendicitis and uterine fibroma, but not for bacterial pneumonia, diverticular disease and peptic ulcer. For the six study conditions combined, residents of overall low-use area were 30% more likely to be admitted with advanced stages of disease. CONCLUSION: Low overall hospitalization rates were found to be associated with greater severity of illness at hospitalization and potentially avoidable morbidity for some conditions. Policies aimed at curbing unnecessary hospital admission should consider preserving access for appropriate treatment.

Acute Disease↗
PubMed1997

Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies.

A duplication of a 1.5-Megabase genomic region encompassing the gene for the peripheral myelin protein 22 (PMP22) is found on chromosome 17p11.2-12 in Charcot-Marie-Tooth disease type 1A (CMT1A), whereas the reciprocal deletion is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Since most CMT1A patients harbor three copies of the PMP22 gene, and most HNPP patients carry only a single copy, a gene dosage effect has been proposed as a mechanism for both diseases. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from three CMT1A and four HNPP patients. Quantitative immunohistochemical determination showed that PMP22 protein expression relative to that of myelin protein zero and myelin basic protein was increased in all CMT1A patients and reduced in all HNPP patients, as compared with biopsy samples of patients with normal PMP22 gene expression. These data demonstrate that both neuropathies result from an imbalance of PMP22 protein expression.

Adolescent↗
PubMed1996

Inheritance of the S113L mutation within an inbred family with carnitine palmitoyltransferase enzyme deficiency.

Deficiency of carnitine palmitoyltransferase type II (CPT II) is a clinically heterogeneous autosomal recessive disorder of lipid metabolism. The most common mutation in the CPT II gene is the S113L mutation, which substitutes leucine for serine at amino acid position 113. We studied an inbred family with three affected cousins with CPT II deficiency and found the S113L mutation to be present in a homozygous state in all three patients. Pedigree analysis traced the S113L mutation back to one common ancestor. Although the patients in this family have an identical genotype at the CPT II locus, their clinical picture ranges from asymptomatic to lethal.

Base Sequence↗
PubMed1996

Recurrent myoglobinuria due to carnitine palmitoyltransferase II deficiency: expression of the molecular phenotype in cultured muscle cells.

Carnitine palmitoyltransferase II deficiency (CPT II) is an autosomal recessive disorder and the most frequent cause of hereditary myoglobinuria. We report the case of a young man who presented a severe fever-induced episode of rhabdomyolysis and myoglobinuria resulting in acute renal failure. Cultured skeletal muscle cells have been used for the biochemical and molecular characterization of the defect in this patient. Immunoblot analysis revealed reduced steady-state level of CPT II protein. A PCR-based method detected the common Ser113Leu substitution only in one allele, suggesting that the patient is a compound heterozygote for this common mutation and a different as yet unidentified mutation.

Adult↗
PubMed1996

Estimation of survival after AIDS diagnosis: CD4 T lymphocyte count versus clinical severity.

We compared the relative contribution to estimating survival after AIDS diagnosis of a clinical severity measure, the Severity Index for Adults with AIDS (SIAA), and laboratory values at AIDS diagnosis that are often used prognostically. Three SIAA categories were defined from the first AIDS-defining condition and the most severe complication within 3 months. We studied 421 Italian patients surviving > or = 3 months after AIDS diagnosis. Survival curves for laboratory measures grouped by quartile showed poorest survival for CD4 count <100/microliter, hemoglobin <8 g/dl, total lymphocyte count <400/microliter, and albumin <3 g/dl. Adjusting for demographics and zidovudine therapy, the estimated hazard of death was 2.4 (95% CI, 1.6-3.5) for CD4 counts <100/microliter versus higher counts and 4.9 (95% CI, 3.0- 7.8) for the most versus the least severe SIAA category. SIAA offered greater prognostic discrimination than CD4 count at AIDS diagnosis.

AIDS Serodiagnosis↗
PubMed1996

Hypoparathyroidism in mitochondrial trifunctional protein deficiency.

Mitochondrial trifunctional protein deficiency, a recently identified disorder of fatty-acid oxidation, may show characteristic features such as peripheral neuropathy, pigmentary retinopathy, and acute fatty liver degeneration in pregnant women with an affected fetus. We describe a patient with trifunctional protein deficiency whose clinical picture consisted of severe calcium and phosphate abnormalities caused by hypoparathyroidism.

Female↗
PubMed1996

Deletion of the PMP22 gene and hereditary neuropathy with liability to pressure palsies.

Deletion of the 1.5 Mb tract on chromosome 17p11.2-12 that is duplicated in Charcot-Marie-Tooth disease type 1A is commonly associated with hereditary neuropathy with liability to pressure palsies. The deletion, which originates from an unequal meiotic crossover involving two homologous repeats, causes underexpression of the peripheral myelin protein gene PMP22. PMP22 frameshift and non-sense mutations can be found in the rare nondeleted cases. Targeted disruption of the PMP22 gene in mice has provided an animal model for the disease. Current studies are aimed at characterising the genetics of this chromosomal rearrangement and the pathogenic role of altered PMP22 expression.

Animals↗
PubMed1996

Fatty acid mitochondrial beta-oxidation and hypoglycaemia in children.

Mitochondrial fatty acid beta-oxidation is a major source for energy production, particularly at times of stress or fasting. Inborn errors of fatty acid oxidation have emerged during the past decade as important inherited causes of severe metabolic disturbances, including hypoketotic hypoglycaemia, cardiomyopathy, skeletal muscle myopathy, and childhood sudden death. Since the first description in 1973, at least 14 different genetic defects of mitochondrial fatty acid metabolism have been recognized. Our current understanding of the basic biochemistry, clinical presentations, and molecular bases of fatty acid oxidation disorders is reviewed.

Child↗
PubMed1996

Patterns of hospital care and physician perspectives from an Italian, Japanese, and USA hospital.

Many studies have compared different countries' health care systems at the macro level. Less has been done to analyze care provided for patients with specific diseases and to compare physician attitudes concerning factors that influence patient care. This study compares severity of illness and length of hospital stay for patients admitted for diabetes mellitus, cholecystitis, or appendicitis at three teaching hospitals in Italy, Japan, and the United States. Physicians caring for patients with these diseases were surveyed to assess their opinions of the adequacy of resources available at their hospital, perceived administrative pressures concerning resource use, and interactions with patients and their families that relate to admission and discharge decisions. The severity of the patient mix was consistently higher in the U.S. hospital than in the Italian or Japanese hospitals. Controlling for diagnosis, severity of illness, surgery, age, and presence of co-morbid conditions, the U.S. hospital consistently had the shortest stays and the Japanese hospital the longest. Japanese physicians were more likely than U.S. or Italian physicians to report insufficient resources, such as nurses, to provide quality care, but less likely to report administrative pressures interfering with patient care. Differences in hospital utilization may reflect variation in clinical practices, availability of resources, barriers to access to care, organizational differences at the national and hospital level, and patient and family preferences.

Adult↗