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Biomedical subjects

J Panetta

Publications and source records attributed to J Panetta.

11 recordsLinked to original sources
PubMed2005

The importance of liver biopsy in the investigation of possible mitochondrial respiratory chain disease.

The diagnosis of mitochondrial respiratory chain deficiency is usually made by analysis of mitochondrial respiratory chain activity in muscle biopsy. We describe 4 patients in whom the diagnosis was based on mitochondrial respiratory chain deficiency in liver alone. In 3 patients, liver complex IV activity was deficient, and the 4th patient had liver complex I deficiency (relative to citrate synthase and complex II activity). The enzyme activities in skeletal muscle biopsies from these patients were normal or equivocal. The age at presentation and the neurological symptoms differed from one patient to another. All 3 patients with complex IV deficiency had non-specific white matter changes on brain MRI. None of the patients had clinical or biochemical evidence of liver disease. These findings illustrate the wide variety of presentations associated with liver mitochondrial respiratory chain deficiency. They also demonstrate the importance of mitochondrial respiratory chain enzyme analysis in liver, in addition to muscle, even in cases where the primary clinical deficit is neurological and there is no liver disease.

Biopsy↗
PubMed2004

Effect of high-dose vitamins, coenzyme Q and high-fat diet in paediatric patients with mitochondrial diseases.

We reviewed the medical records of all patients with confirmed mitochondrial diseases treated with any or all of thiamin, riboflavin, coenzyme Q, vitamin C (approximately 10 mg/kg per day) and a high-fat diet (50-60% of caloric intake) between 1997 and 2003. There were 15 patients (9 male): 10 had enzymatic deficiency and 10 had a molecular diagnosis. Age at diagnosis was 11 months to 17 years 10 months. Treatment was commenced at time of clinical diagnosis in 12 patients. Follow-up period was 3 days to 7 years (median 22 months). Improvement was reported in 9 patients, of whom 4 attained further developmental skills, but this was only temporary in 6 patients. Five patients died during the follow-up period (3 days to 7 years). Patients with the 3243A > G mutation showed no significant change in the course of their disease, except for fewer migraine attacks. Of the six patients who had seizures, one has had a significant reduction in the severity of the seizures and one has had no further seizures. Plasma lactate levels were noncontributory. We conclude that high-dose vitamin and cofactor treatment and, where applicable, high-fat diet, are well tolerated and possibly effective in the short term, but ineffective in the longer term.

Adolescent↗
PubMed2000

Transcription factor nuclear factor-kappa B is activated in neurons after focal cerebral ischemia.

Nuclear factor-kappa B (NF-kappaB) is a multisubunit transcription factor that when activated induces the expression of genes encoding acute-phase proteins, cell adhesion molecules, cell surface receptors, and cytokines. NF-kappaB is composed of a variety of protein subunits of which p50-and p65-kDa (RelA) are the most widely studied. Under resting conditions, these subunits reside in the cytoplasm as an inactive complex bound by inhibitor proteins, IkappaB alpha and IkappaB beta. On activation, IkappaB is phosphorylated by IkappaB kinase and ubiquitinated and degraded by the proteasome; simultaneously, the active heterodimer translocates to the nucleus where it can initiate gene transcription. In the periphery, NF-kappaB is involved in inflammation through stimulation of the production of inflammatory mediators. The role of NF-kappaB in the brain is unclear. In vitro, NF-kappaB activation can be either protective or deleterious. The role of NF-kappaB in ischemic neuronal cell death in vivo was investigated. Adult male rats were subjected to 2 hours of focal ischemia induced by middle cerebral artery occlusion (MCAO). At 2, 6, and 12 hours after reperfusion, the expression and transactivation of NF-kappaB in ischemic versus nonischemic cortex and striatum were determined by immunocytochemistry and by electrophoretic mobility gel-shift analysis. At all time points studied, p50 and p65 immunoreactivity was found exclusively in the nuclei of cortical and striatal neurons in the ischemic hemisphere. The contralateral nonischemic hemisphere showed no evidence of nuclear NF-kappaB immunoreactivity. Double immunofluorescence confirmed expression of p50 in nuclei of neurons. Increased NF-kappaB DNA-binding activity in nuclear extracts prepared from the ischemic hemisphere was further substantiated by electrophoretic mobility gel-shift analysis. Because the activation of NF-kappaB by many stimuli can be blocked by antioxidants in vitro, the effect of the antioxidant, LY341122, previously shown to be neuroprotective, on NF-kappaB activation in the MCAO model was evaluated. No significant activation of NF-kappaB was found by electrophoretic mobility gel-shift analysis in animals treated with LY341122. These results demonstrate that transient focal cerebral ischemia results in activation of NF-kappaB in neurons and supports previous observations that neuroprotective antioxidants may inhibit neuronal death by preventing the activation of NF-kappaB.

Animals↗
PubMed1999

Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration.

Many recent studies have emphasized the deleterious role of inflammation in CNS injury. Increases in free fatty acids, eicosanoids, and products of lipid peroxidation are known to occur in various conditions of acute and chronic CNS injury, including cerebral ischemia, traumatic brain injury, and Alzheimer's disease. Although an inflammatory response can be induced by many different means, phospholipases, such as cytosolic phospholipase A(2) (cPLA(2)), may play an important role in the production of inflammatory mediators and in the production of other potential second messengers. cPLA(2) hydrolyzes membrane phospholipids and its activity liberates free fatty acids leading directly to the production of eicosanoids. We investigated the cellular localization of cytosolic phospholipase A(2) in the CNS following: (1) focal and global cerebral ischemia, (2) facial nerve axotomy, (3) human cases of Alzheimer's disease, (4) transgenic mice overexpressing mutant superoxide dismutase, a mouse model of amyotrophic lateral sclerosis, and (5) transgenic mice overexpressing mutant amyloid precursor protein, which exhibits age-related amyloid deposition characteristic of Alzheimer's disease. We show that in every condition evaluated, cytosolic phospholipase A(2) is present in reactive glial cells within the precise region of neuron loss. In conditions where neurons did not degenerate or are protected from death, cytosolic phospholipase A(2) is not observed. Both astrocytes and microglial cells are immunoreactive for cytosolic phospholipase A(2) following injury, with astrocytes being the most consistent cell type expressing cytosolic phospholipase A(2). The presence of cytosolic phospholipase A(2) does not merely overlap with reactive astroglia, as reactive astrocytes were observed that did not exhibit cytosolic phospholipase A(2) immunoreactivity. In most conditions evaluated, inflammatory processes have been postulated to play a pivotal role and may even participate in neuronal cell death. These results suggest that cytosolic phospholipase A(2) may prove an attractive therapeutic target for neurodegeneration.

Alzheimer Disease↗
PubMed1999

Early treatment with a novel inhibitor of lipid peroxidation (LY341122) improves histopathological outcome after moderate fluid percussion brain injury in rats.

OBJECTIVE: Reactive oxygen species are thought to participate in the pathobiology of traumatic brain injury (TBI). This study determined whether treatment with LY341122, a potent inhibitor of lipid peroxidation and an antioxidant, would provide neuroprotection in a rat model of TBI. METHODS: To investigate the efficacy of LY341122 in this parasagittal fluid percussion model (1.8-2.1 atm), the rats received oral administration of LY341122 (100 mg/kg) or vehicle 2 hours before and 4 hours after TBI (each group, n = 7). To investigate the therapeutic window for treatment, rats were treated with LY341122 or vehicle for 20 hours by femoral vein infusion starting at 5 minutes, 30 minutes, or 3 hours after TBI (each group, n = 5). Three days after injury, analysis of contusion volumes and the frequency of damaged cortical neurons was conducted. RESULTS: Oral administration of LY341122 before and after TBI led to a significant reduction in overall contusion volume (3.28 mm3+/-0.75 mm3 [mean +/- standard error of the mean] versus 1.32 mm3 +/- 0.33 mm3; P < 0.05) and also reduced the frequency of damaged cortical neurons (1191.7 +/- 267.1 versus 474.6 +/- 80.2; P < 0.05). In the second experiment, rats treated with LY341122 at 5 minutes or 30 minutes after TBI also demonstrated a significant reduction (P < 0.05) in contusion volume (1.92 mm3 +/- 0.64 mm3 or 1.59 mm3 +/- 0.50 mm3, respectively) compared with vehicle-treated rats (4.32 mm3 +/- 1.15 mm3). A significant reduction in total cortical necrotic neuron counts was also demonstrated in the 5-minute group (2243.8 +/- 265.3 versus 1457.8 +/- 265.3; P < 0.05). In contrast, histopathological outcome was not significantly improved when treatment was delayed until 3 hours after TBI. CONCLUSION: These data reinforce the hypothesis that lipid peroxidation and reactive oxygen species participate in the acute pathogenesis of TBI. Treatment delayed until 3 hours after TBI did not provide significant histopathological protection.

Administration, Oral↗
PubMed1996

Hepatitis C virus antibody (anti-HCV): prevalence in psoriasis.

BACKGROUND: In cases of psoriasis (PS), the etiology of the underlying liver disease is occasionally unknown. To investigate antibodies to hepatitis C virus (anti-HCV), their prevalence and clinical significance, 118 unselected outpatients with PS were studied prospectively. METHODS: Anti-HCV was assayed in serum by second-generation enzyme-linked immunosorbent assay (ELISA), considering a serum anti-HCV (+), when the optical density ratio was equal to or greater than three times the cut-off value, in duplicate determinations, whereas anti-HBc, anti-HBs, HBsAg, anti-HBe, and HBeAg were also evaluated by ELISA, as were the transaminases. As controls we took the 1.2% anti-HCV prevalence found in 60,000 blood donors from Buenos Aires city. RESULTS: Nine of 118 serum samples (7.6%) proved to be anti-HCV (+) (P < 0.001). There were no differences between positive and negative cases as regards gender, age, history of hepatitis, transfusions, or parenteral exposure, disease duration, or psoriasis type, and prior treatment with methotrexate and etretinate. Fifteen percent (17/113) were anti-HBc (+), 64.7% anti-HBs (+) (11/17) and 2.5% HBsAg (+) (3/17), whereas 3/17 (2.5%) showed isolated anti-HBc positivity. Liver biopsies in six anti-HCV patients disclosed four with chronic active hepatitis, one with cirrhosis, and one with steatosis. CONCLUSIONS: In the presence of liver disease in PS patients, an HCV infection should be considered as an alternative diagnosis. The high anti-HCV prevalence in this series is attributable to infection by inapparent parenteral routes, through minute skin abrasions, as reported for hepatitis B virus in PS.

Adolescent↗
PubMed1996

Evaluating the antioxidant potential of new treatments for inflammatory bowel disease using a rat model of colitis.

BACKGROUND: Reactive oxygen species may mediate tissue injury in inflammatory bowel disease. Aminosalicylates have antioxidant activity and the antioxidants, superoxide dismutase and allopurinol, are of reported benefit in inflammatory bowel disease. AIM: To develop a convenient technique for testing the antioxidant potential of standard and novel therapeutic agents for use in inflammatory bowel disease. METHODS: Amplified chemiluminescence was used to measure reactive oxygen species production by colonic biopsy specimens from rats with acetic acid induced colitis and to assess the in vitro effect of conventional antioxidants, standard therapies and proposed novel therapies for inflammatory bowel disease. RESULTS: The model was validated by demonstrating that the profile of effects on chemiluminescence of acetic acid induced colitis biopsy specimens given by conventional antioxidants (sodium azide, catalase, copper-zinc superoxide dismutase, dimethyl sulphoxide, N-acetylcysteine and ascorbate) and standard therapies (5-aminosalicylate and hydrocortisone) resembled that previously reported using biopsy specimens from ulcerative colitis. Human recombinant manganese superoxide dismutase did not alter chemiluminescence. Two novel compounds, LY231617 (10 mM) and amflutizole (20 mM), reduced chemiluminescence by 98% (n = 5, p = 0.009) and 88% (n = 5, p = 0.03), respectively. CONCLUSIONS: The similarity of the chemiluminescence responses of colonic biopsy specimens from acetic acid induced colitis and ulcerative colitis to a range of conventional antioxidants and standard treatments suggests that this model is a useful method for testing the antioxidant potential of new therapies for inflammatory bowel disease. The antioxidant actions of dimethyl sulphoxide, ascorbate, and the novel compounds, amflutizole and LY231617 in this model suggest that these agents merit further assessment in the treatment of inflammatory bowel disease.

Acetic Acid↗
PubMed1996

Accelerating the culture change!

Exide Electronics, a major supplier of uninterruptible power system equipment, embarked on a journey of changing a culture to improve quality, enhance customer responsiveness, and reduce costs. This case study examines the evolution of change over a period of seven years, with particular emphasis on the most recent years, 1992 through 1995. The article focuses on the Raleigh plant operations and describes how each succeeding year built on the successes and fixed the shortcomings of the prior years to accelerate the culture change, including corrective action and continuous improvement processes, organizational structures, expectations, goals, achievements, and pitfalls. The real challenge to changing the culture was structuring a dynamic approach to accelerate change! The presentation also examines how the evolutionary process itself can be created and accelerated through ongoing communication, regular feedback of progress and goals, constant evaluation and direction of the process, and measuring and paying for performance.

Communication↗
PubMed1995

Accelerating momentum for change!

As we develop strategies to compete globally, we are challenged with integrating our resources to execute these strategies effectively. Many companies are in the midst of dramatic shifts in corporate cultures, giving more responsibility to employees while raising expectations for their performance. The extent of these changes is far reaching and brings significant challenges to both employees and corporations. This article is a continuation of the evolution (over five years) of a corrective action/continuous improvement process implemented at Exide Electronics. It discusses organizational structures, including steering committees, corrective action teams, task teams, and work cells. Specific expectations, goals, and results of the teams are presented, along with ground rules for functioning within the organization. After structuring the organization and coordinating the resources effectively, the next challenge is accelerating momentum for change. The presentation also discusses the evolutionary process required to make a culture focused on change, including ongoing communication and feedback, constant evaluation and direction of the process, and measuring and paying for performance.

Communication↗