PubMed Health⌕ Search

Biomedical subjects

A M Klein

Publications and source records attributed to A M Klein.

At least 19 recordsLinked to original sources
PubMed2001

Transgenic ALS mice show increased vulnerability to the mitochondrial toxins MPTP and 3-nitropropionic acid.

The pathogenesis of neurodegenerative diseases may involve a genetic predisposition acting in concert with environmental toxins. To test this hypothesis we examined whether transgenic mice with the G93A mutation in Cu,Zn superoxide dismutase show increased vulnerability to either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 3-nitropropionic acid (3-NP). Compared to littermate controls G93A transgenic mice showed a greater loss of striatal dopamine, DOPAC, and HVA at 50, 70, and 120 days of age following administration of MPTP; however, cell loss in the substantia nigra was not greater. The G93A transgenic mice showed significantly increased vulnerability to striatal lesions produced by 3-NP compared with littermate controls at 120 days of age. The finding that G93A mice show increased vulnerability to mitochondrial toxins further implicates mitochondrial dysfunction in the pathogenesis of neuronal death in these mice. The findings support the hypothesis that a genetic defect can increase susceptibility to environmental toxins and that this may play a role in the pathogenesis of neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis.

EGb761 is a standardized extract of green Gingko biloba, which exerts protective effects against mitochondrial damage and oxidative stress. We examined whether oral administration of 0.022% or 0.045% EGb761 in the diet could impart neuroprotective effects in a transgenic mouse model (G93A) of amyotrophic lateral sclerosis (ALS). EGb761 significantly improved motor performance and survival, and protected against a loss of spinal-cord anterior motor horn neurons in male G93A mutant transgenic ALS mice, but not in littermate female mutant transgene mice. While EGb761 extended survival in littermate female G93A mice, significance was not reached. EGb761, however, significantly improved weight loss in both male and female transgenic ALS mice. These findings provide evidence for a gender-specific neuroprotective effect of EGb761 in a transgenic model of ALS and suggest that EGb761 may be a potential effective treatment in patients with ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Growth-related oncogene-alpha expression in human nasal polyps.

The cytokine growth-related oncogene-alpha (GRO-alpha) is a potent mediator of leukocyte recruitment and proliferation in inflammatory diseases. We hypothesized that GRO-alpha is produced in the inflammatory nasal polyp microenvironment. Evaluation of nasal polyps from 27 patients for distribution and content of GRO-alpha antigen, by use of immunohistochemical techniques and ELISA, revealed its presence in all 27 tissue samples. It was found predominantly within the eosinophils and neutrophils, with tissue levels ranging from 34 pg/mg total protein (TP) to 1746 pg/mg TP, with a mean value of 631 +/-98 pg/mg TP. Control tissues contained between 82 pg/mg TP and 316 pg/mg TP (mean 176+/-38 pg/mg TP). These results were statistically significant (P<0.03). Clinical correlations and statistical comparisons were calculated. These data suggest that GRO-alpha may be an important factor in the recruitment and activation of leukocytes in nasal polyposis, making it a potential target for therapeutic intervention.

Adult↗
PubMed2000

Partial deficiency of manganese superoxide dismutase exacerbates a transgenic mouse model of amyotrophic lateral sclerosis.

The pathogenesis of neuronal cell death as a consequence of mutations in copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis may involve oxidative damage and mitochondrial dysfunction. We examined whether crossing transgenic mice with the G93A SOD1 mutation with transgenic mice with a partial depletion of manganese superoxide dismutase (SOD2) would affect the disease phenotype. Compared with G93A mice alone, the mice with partial deficiency of SOD2 and the G93A SOD1 mutation showed a significant decrease in survival and an exacerbation of motor deficits detected by rotorod testing. There was a significant exacerbation of loss of motor neurons and substantia nigra dopaminergic neurons in the G93A mice with a partial deficiency of SOD2 compared with G93A mice at 110 days. Microvesiculation of large motor neurons was more prominent in the G93A mice with a partial deficiency of SOD2 compared with G93A mice at 90 days. These findings provide further evidence that both oxidative damage and mitochondrial dysfunction may play a role in the pathogenesis of motor neuron death associated with mutations in SOD1.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Creatine and cyclocreatine attenuate MPTP neurotoxicity.

Systemic administration of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) produces parkinsonism in experimental animals by a mechanism involving impaired energy production. MPTP is converted by monoamine oxidase B to 1-methyl-4-phenylpyridinium (MPP+), which blocks complex I of the electron transport chain. Oral supplementation with creatine or cyclocreatine, which are substrates for creatine kinase, may increase phosphocreatine (PCr) or cyclophosphocreatine (PCCr) and buffer against ATP depletion and thereby exert neuroprotective effects. In the present study we found that oral supplementation with either creatine or cyclocreatine produced significant protection against MPTP-induced dopamine depletions in mice. Creatine protected against MPTP-induced loss of Nissl and tyrosine hydroxylase immunostained neurons in the substantia nigra. Creatine and cyclocreatine had no effects on the conversion of MPTP to MPP+ in vivo. These results further implicate metabolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic approach, which may have applicability for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis.

Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.

Alanine↗
PubMed1999

Neurotoxicity and oxidative damage of beta amyloid 1-42 versus beta amyloid 1-40 in the mouse cerebral cortex.

Senile plaques (SP), a neuropathological hallmark of Alzheimer's disease (AD), are characterized by extracellular accumulations of beta amyloid (A beta). SP predominantly contain A beta 42 with a small amount of associated A beta 40. We determined the neurotoxic properties of A beta 42 as compared to A beta 40 by injections into the frontal cortex of three month old C57BL/6 mice. A beta 42 was associated with a significantly larger area of glial fibrillary acidic protein (GFAP) immunoreactivity and a greater density of reactive astrocytes than A beta 40. Immunohistochemical staining for markers of oxidative damage against 3-nitrotyrosine (3-NT) and 8-hydroxydeoxyguanosine (8-OHDG) were significantly more intense around the A beta 42 injection compared to the A beta 40 injection sites. These findings are consistent with previous in vitro studies and suggest that A beta 42 is more neurotoxic and may generate more free radical damage than A beta 40.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Huntington aggregates may not predict neuronal death in Huntington's disease.

The mechanism by which polyglutamine expansion in Huntington's disease (HD) results in selective neuronal degeneration remains unclear. We previously reported that the immunohistochemical distribution of N-terminal huntingtin in HD does not correspond to the severity of neuropathology, such that significantly greater numbers of huntingtin aggregates are present within the cortex than in the striatum. We now show a dissociation between huntingtin aggregation and the selective pattern of striatal neuron loss observed in HD. Aggregate formation was predominantly observed in spared interneurons, with few or no aggregates found within vulnerable spiny striatal neurons. Multiple perikaryal aggregates were present in almost all cortical NADPH-diaphorase neurons and in approximately 50% of the spared NADPH-diaphorase striatal neurons from early grade HD cases. In severe grade HD patients, aggregates were more prominent as nuclear inclusions in NADPH-diaphorase neurons, with less perikaryal and neuropil aggregation. In contrast, nuclear or perikaryal huntingtin aggregates were present in less than 4% of the vulnerable calbindin striatal neurons in all HD cases. These findings support the hypothesis that polyglutamine aggregation may not be a predictor of cell loss. Rather than a harbinger of neuronal death, mutant huntingtin aggregation may be a cytoprotective mechanism against polyglutamine-induced neurotoxicity.

Adolescent↗
PubMed1999

Enterocutaneous fistula as a postoperative complication of laparoscopic inguinal hernia repair.

Trocar injuries to the small bowel during laparoscopic hernia repair are a rare complication, the most common complications being postoperative neuralgias, scrotal swelling, scrotal ecchymosis, and hematoma. A 15-year-old boy was admitted 5 days status-post transabdominal laparoscopic inguinal hernia repair of a symptomatic right pantaloon hernia, with signs and symptoms of a retrocecal abscess. Despite laparotic intervention and appendectomy, the next 2 years passed with almost daily, purulent, right lower quadrant wound drainage, in an otherwise asymptomatic patient. Superficial wound exploration and sinogram in 1996 revealed a sinus tract in direct communication with the small bowel. Elective laparotomy in December 1997 involved a successful resection of a 2.5-cm fistula with involved mesh, and the communicating small bowel through a midline incision, followed by a primary closure of the small-bowel opening. The patient has recovered without complications.

Adolescent↗
PubMed1996

The natural history of nephrocalcinosis in premature infants treated with loop diuretics.

PURPOSE: We investigated the natural history of nephrocalcinosis in premature infants treated with furosemide and attempted to identify factors to predict infants most at risk. MATERIALS AND METHODS: We evaluated 13 preterm infants in this longitudinal pilot study. During hospitalization and while receiving a loop diuretic nephrocalcinosis developed in each patient. Patients were divided into groups based on resolution (6) and nonresolution (7) according to spontaneous resolution of nephrocalcinosis at any point during followup. The 2 groups were compared to each other and to a control group. RESULTS: Mean followup after discontinuation of furosemide in the resolution versus nonresolution groups was 10.3 and 7.7 months, respectively. Between the 2 groups there was no significant difference in average gestational age, birth weight, number of days hospitalized or on furosemide, or total furosemide dose. Mean calcium-to-creatinine ratio while receiving furosemide at the time nephrocalcinosis developed was 0.38 in the resolution group but 2.23 in the nonresolution group (p < 0.005). Initial calcium-to-creatinine ratio in age matched infants who did not have nephrocalcinosis was 0.4. Frank renal stones developed in 2 of the 7 patients without resolution and 0 of the 6 with resolution. When nephrocalcinosis resolved, it was at a mean of 5.2 months following discontinuation of the diuretic. CONCLUSIONS: Early data indicate that nephrocalcinosis resolves in approximately 50% of premature infants 5 to 6 months after discontinuation of furosemide. The only factor that appears to be predictive of the infants who will have resolution is the calcium-to-creatinine ratio when nephrocalcinosis is diagnosed. In patients without resolution this ratio is much higher than in age adjusted normal controls, while in those with resolution it appears normal for age.

Diuretics↗
PubMed1995

Intestinal perforations in infants with a very low birth weight: a disease of increasing survival?

Seventeen infants with a very low birth weight (VLBW) and spontaneous, non-necrotizing enterocolitis (NEC), intestinal perforations are presented; 14 of them were seen in the past 3 years. A comparison with 16 surgically treated NEC infants (< 1,000 g) is provided. At our institution, the yearly survival of VLBW infants increased from 54% to 90% over the past 6 years. All 17 non-NEC patients were operated on, and 15 (88.2%) survived. Ileal perforations were observed frequently. Initial enterostomies were followed by reanastomosis at an average age of 3 months. A 22.6-month follow-up was attained for all survivors. Non-NEC intestinal perforations in tiny neonates are increasing and constitute a challenging but treatable group. The improving survival rate of VLBW infants will probably be accompanied by a variety of complications.

Enterocolitis↗
PubMed1990

Sensorineural hearing loss associated with Kawasaki disease.

In five children who met the diagnostic criteria for Kawasaki Disease, sensorineural hearing loss developed in association with the acute illness. The children, aged 7 months to 13 years, had deficits ranging from mild to profound bilateral sensorineural hearing loss. There were no associated neurologic abnormalities, and immunologic investigations and magnetic resonance imaging failed to reveal a cause. Treatment regimens differed among the children, but none had high salicylate levels (greater than 20 mg/dl) or received other ototoxic medications. Antiinflammatory therapy was not obviously beneficial in any case, and four of the children have persistent hearing deficits. We conclude that auditory involvement may be a complication of Kawasaki disease; screening of clinically affected children should be considered.

Adolescent↗
PubMed1989

Rectal pH in children.

In an attempt to establish normal values for rectal pH in children, we have measured pH in 100 paediatric patients. Measurement of rectal pH was performed in 25 infants and 75 children (27 girls and 73 boys) using a monocrystalline antimony electrode. Rectal pH was 9.6 +/- 0.9 (mean +/- SD, range 7.2 to 12.1) and was independent of sex, age and nutrition. This wide range of rectal pH values offers a possible explanation for the widely scattered bioavailability of drugs administered by the rectal route. Mean rectal pH was considerably higher than that reported for adults; this unexpected alkalinity should be taken into account, when drug formulations are considered for rectal administration in children.

Adolescent↗
PubMed1988

Prolonged anaesthesia with isoflurane and halothane. Effects on hepatic function.

Hepatic function was assessed pre-operatively and on the first and sixth postoperative days in 40 healthy patients who underwent prolonged maxillofacial surgery with isoflurane or halothane anaesthesia. No major changes were observed in hepatic enzymes or bilirubin. One-stage prothrombin time and Factor VII concentrations decreased on the first postoperative day and this change was more pronounced in the halothane group. The results support the use of isoflurane rather than halothane for prolonged anaesthesia in respect of the synthesising function of the liver.

Anesthesia, Inhalation↗
PubMed1986

[The effect of rectal pH values on the absorption of methohexital].

The factors underlying the unpredictability of the pharmacokinetics of rectally administered methohexitone remain unclear. The "pH partition hypothesis" offers an explanation. We investigated six children with rectal pH values ranging from 7.5 to 9.8, who were given 25 mg/kg methohexitone 10% via the rectal route under general anaesthesia. Blood samples were taken at zero, 3, 5, 7, 10, 15, 20, 30, 40, 60, 90 and 120 min; rectal pH was measured at zero and 1 min. The methohexitone plasma levels reached a maximum (Cmax) of 2.63 micrograms/ml (median) after 17.5 min (median). The elimination half-life ranged from 37 to 218 min. No positive correlation between lower pH and better resorption (AUC and Cmax) was found. The resorption kinetics of rectally administered methohexitone cannot be explained by its electrochemical properties alone.

Anesthesia, Rectal↗