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Biomedical subjects

A H Rajput

Publications and source records attributed to A H Rajput.

At least 19 recordsLinked to original sources
PubMed2002

Brain aconitase activity is not decreased in progressive supranuclear palsy.

The novel finding of decreased activity of aconitase, a key Krebs cycle enzyme highly sensitive to oxidative damage, in cybrid cell lines using mitochondrial DNA from patients with progressive supranuclear palsy (PSP) implies an enzyme abnormality in brain. However, the authors found that postmortem brain aconitase activity is normal in PSP. This suggests that patients with PSP do not have systemic aconitase deficiency and that data derived from cybrid cell models of neurodegenerative disorders might not always predict similar changes in human brain.

Aconitate Hydratase↗
PubMed2001

Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson's disease.

INTRODUCTION: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson's disease. METHODS: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson's disease and from control subjects. Levels of several markers of dopaminergic function were also assayed. RESULTS: Levels of the transcription factor DeltaFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson's disease. Levels of several other proteins were not affected. Interestingly, levels of both DeltaFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter. CONCLUSIONS: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of DeltaFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in DeltaFosB and RGS9 occur in humans with Parkinson's disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson's disease and assist in the development of novel treatments.

Blotting, Western↗
PubMed2001

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Aged↗
PubMed2001

Elevated activity of phospholipid biosynthetic enzymes in substantia nigra of patients with Parkinson's disease.

We reported that the activities of phospholipase A2, phosphocholine cytidylyltransferase and phosphoethanolamine cytidylyltransferase, key phospholipid metabolic enzymes, are low in substantia nigra of normal human brain and that this might reduce the ability of nigral neurons to repair damage to cell membranes. To determine whether adaptive changes in nigral phospholipid metabolism can occur in idiopathic Parkinson's disease we compared activities of 11 catabolic and anabolic enzymes in autopsied brain of 10 patients with Parkinson's disease to those in control subjects. Nigral activity of the catabolic enzyme phospholipase A2 was normal in the Parkinson's disease group, whereas that of the biosynthetic enzymes phosphoethanolamine cytidylyltransferase, phosphocholine cytidylyltransferase, and phosphatidylserine synthase were elevated 193, 48 and 38%, respectively, possibly representing a compensatory response to repair membrane phospholipids. Enzyme activities were normal in all other brain areas with the exception of increased (+26%) activity of calcium-stimulated phospholipase A2 in putamen, a change which could be consequent to either decreased dopaminergic striatal input or to a dopamine nerve terminal degenerative process. Our data indicate that the normally low rate of membrane phospholipid synthesis in the substantia nigra, the primary area of neurodegeneration in Parkinson's disease, is increased during the course of the disorder. We suggest that pharmacotherapies which augment this compensatory response might have utility as a treatment for Parkinson's disease.

Aged↗
PubMed2001

Levodopa prolongs life expectancy and is non-toxic to substantia nigra.

The primary objective of the study was to determine the effect of levodopa (LD) on human substantia nigra. The study included patients seen at the Movement Disorder Clinic, Saskatoon over a 32 year period. The evidence provided is based on epidemiological observations of 934 consecutive Parkinson syndrome (PS) patients assessed during 22 years and detailed studies of six patients including two autopsies. Life expectancy increased significantly with LD therapy. The prolonged survival was evident when the patients were treated during early stage of the illness. One parkinsonian patient with substantia nigra (SN) pathology who was extensively studied for 30 years, revealed significant slowing of the disease progression while on LD. Three essential tremor patients who received 24 kg (26 years), 22 kg (21.5 years), and 8.5 kg (12.5 years) LD respectively, had no evidence of PS and one autopsy revealed normal SN. Two dopa-responsive dystonia patients who received LD 3 kg (11 years) and 17 kg (29 years) each had no evidence of PS and one autopsy revealed normal number of SN neurons. These observations indicate that LD is not toxic to human SN and are consistent with salutary effect of the drug on the SN in Parkinson's disease.

Adolescent↗
PubMed2001

Progressive supranuclear palsy: clinical features, pathophysiology and management.

Progressive supranuclear palsy (PSP) is a degenerative condition of unknown aetiology that produces an akinetic-rigid form of parkinsonism characterised by early falls and abnormalities of extraocular movements. Mean age of onset is approximately 63 years, and mean survival from symptom onset is 9 years. Men are much more frequently affected than women. The classic clinical finding is supranuclear ophthalmoplegia, which may not present until late in the illness, if at all. The clinical diagnosis of PSP can be difficult to make, as the sites of pathology are heterogeneous. Structural and functional neuroimaging studies, although not specific for PSP, may be of some assistance in making the diagnosis. The definitive diagnosis of PSP requires the presence of both clinical and neuropathological evidence. Multiple anatomical sites are affected in PSP. The most consistently involved are the subthalamic nucleus, globus pallidus interna and externa, pontine nuclei, periaqueductal grey matter and the substantia nigra. The location of the pathology accounts for the clinical features. The histological hallmark of PSP is the presence of globose neurofibrillary tangles in the affected subcortical nuclei. Neurofibrillary tangles are composed of abnormally phosphorylated tau, a microtubule-associated protein that is involved in maintenance of the cytoskeleton. Abnormalities near or in the gene coding for tau are implicated in the pathogenesis of PSP. The multiple neurotransmitter abnormalities, including those affecting dopamine, acetylcholine, gamma-aminobutyric acid and norepinephrine (noradrenaline) systems and pathways, as well as both pre- and post-synaptic pathology, make pharmacological therapy of PSP a challenge. Although an individual patient may respond to a drug, in general patients with PSP have a minimal response and a short duration of sustained benefit.

Animals↗
PubMed2001

The protective role of levodopa in the human substantia nigra.

Laboratory studies and studies of animal models of parkinsonism have produced contradictory evidence, but there is no evidence that LD is toxic to normal substantia nigra in animals. We have studied human subjects longitudinally to address that issue. A cumulative LD dose up to 24 kg was not toxic in one autopsied essential tremor (ET) case. Two other ET patients did not develop parkinsonism on 8.5 kg and 21 kg cumulative LD dose, respectively. One DOPA-responsive dystonia (DRD) case has no evidence of parkinsonism after 29 years and more than 17 kg of LD. A DRD patient who received 3 kg over 11 years had normal SN neuronal complement at autopsy. One patient who has clinical and laboratory evidence of nigral pathology as the basis of parkinsonism when untreated for 18 years had progressive disability. While on LD he has excellent symptomatic benefit and virtual cessation of progression of the disease. Epidemiologic studies indicate that those prescribed LD at an early stage of illness and hence given larger cumulative lifetime doses have longer survival than those in whom LD is started late and who receive smaller total doses. Our observations and the available literature support that levodopa is not toxic to normal or diseased substantia nigra in human beings. Evidence presented here indicates that levodopa has a protective effect on the human substantia nigra neurons.

Adult↗
PubMed2000

The evolution of diagnosis in early Parkinson disease. Parkinson Study Group.

CONTEXT: Since there is no diagnostic biological marker for Parkinson disease (PD), the diagnosis is based on the results of clinical assessment. The accuracy of diagnosis improves with time and repeated assessments. Studies that require only inclusion of early cases of PD present a diagnostic challenge. Previous studies concluded that initial diagnoses of PD made by general neurologists were incorrect in 24% to 35% of the cases when patients were examined at autopsy. Experts in movement disorders are expected to have greater accuracy of initial diagnosis of PD. OBJECTIVE: To determine the evolution of clinical diagnosis in patients with early PD made initially by experts in PD. DESIGN: Eight hundred patients with mild parkinsonian symptoms (Hoehn and Yahr stage 1 or 2) who received a diagnosis of PD less than 5 years before the beginning of the study were included in the original Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease study. These patients were followed up prospectively with repeated clinical assessments. The following clinical criteria were used to reassess the initial diagnosis: investigator's confidence in the diagnosis of PD, presence of atypical clinical features, findings of imaging studies, response to levodopa, and results of autopsy examinations. RESULTS: The mean +/- SD duration of illness in the 800 cases at enrollment was 2.2+/-1.3 years, and the mean +/- SD Hoehn and Yahr stage was 1.6+/-0.5. The mean +/- SD follow-up was 6.0+/-1.4 years (range, 0.2-7.6 years). In 5 cases, PD was not confirmed at autopsy, and in 15 patients, the results of imaging studies indicated the presence of other pathological conditions. Of the 550 cases treated with levodopa, 49 (8.9%) had little or no improvement; 6 of these cases overlap with either autopsy or imaging study exclusion criteria. Two other cases had at least 4 of the 6 atypical clinical features arguing against the diagnosis of PD. Thus, of the 800 patients, 65 (8.1%) did not have PD according to the study criteria. Compared with those patients with the final diagnosis of PD, in the diagnoses of 60 patients without autopsy, the duration of symptoms (mean +/- SD, 7.2+/-2.0 years vs. 8.3+/-1.9 years; P<.001) and the duration of follow-up (5.3+/-1.6 years vs. 6.1+/-1.3 years; P<.001) were shorter. CONCLUSIONS: We found that 65 (8.1%) of patients initially diagnosed as having PD were later found to have an alternate diagnosis based on multifactorial clinical diagnostic criteria. This alternate diagnosis indicated that experts in PD changed their diagnoses infrequently during the 7.6-year follow-up.

Age of Onset↗
PubMed1999

Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia.

OBJECTIVE: To determine the mechanism leading to striatal dopamine (DA) loss in dopa-responsive dystonia (DRD). BACKGROUND: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme guanosine triphosphate-cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydroxylase [TH]) is unknown. METHODS: The authors sequenced GCH1 and measured levels of total biopterin (BP) and total neopterin (NP), TH, and dopa decarboxylase (DDC) proteins, and the DA and vesicular monoamine transporters (DAT, VMAT2) in autopsied brain of two patients with typical DRD. RESULTS: Patient 1 had two GCH1 mutations but Patient 2 had no mutation in the coding region of this gene. Striatal BP levels were markedly reduced (<20% of control subjects) in both patients and were also low in two conditions characterized by degeneration of nigrostriatal DA neurons (PD and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate), whereas brain NP concentrations were selectively decreased (<45%) in the DRD patients. In the putamen, both DRD patients had severely reduced (<3%) TH protein levels but had normal concentrations of DDC protein, DAT, and VMAT2. CONCLUSIONS: The data suggest that 1) brain BH4 is decreased substantially in dopa-responsive dystonia, 2) dopa-responsive dystonia can be distinguished from degenerative nigrostriatal dopamine deficiency disorders by the presence of reduced brain neopterin, and 3) the striatal dopamine reduction in dopa-responsive dystonia is caused by decreased TH activity due to low cofactor concentration and to actual loss of TH protein. This reduction of TH protein, which might be explained by reduced enzyme stability/expression consequent to congenital BH4 deficiency, can be expected to limit the efficacy of acute BH4 administration on dopamine biosynthesis in dopa-responsive dystonia.

Adult↗
PubMed1998

Distal hereditary upper limb muscular atrophy.

OBJECTIVES: To identify the clinical, electrophysiological, and genetic characteristics of a family with an unusual form of hereditary motor neuron disease. METHODS: Surviving members of a pedigree in which affected members presented with weakness and atrophy of distal musculature in the upper limbs were examined clinically and electrophysiologically, and had genetic testing. RESULTS: The disease was autosomal dominantly inherited and manifested as weakness and atrophy of distal musculature in the upper limbs, with minimal involvement of lower limbs, brisk reflexes, minimal sensory findings, and considerable variability in severity among the affected persons. Nerve conduction studies disclosed near normal motor conduction velocity, reduced motor compound action potential amplitude, prolonged distal motor latency, prolonged sensory latency, and normal sensory compound action potential amplitude. Needle electrode examination showed reduced number and increased size of motor unit potentials, but no fibrillations or fasciculations. CONCLUSION: Distal upper limb muscular atrophy is a distinct clinical entity.

Arm↗
PubMed1998

Tolcapone improves motor function in parkinsonian patients with the "wearing-off" phenomenon: a double-blind, placebo-controlled, multicenter trial.

We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off " phenomenon in levodopa-treated parkinsonian patients.

Aged↗
PubMed1997

Amantadine: an antiparkinsonian agent inhibits bovine brain 60 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase isozyme.

The effect of amantadine (an antiparkinsonian agent) on calmodulin-dependent cyclic nucleotide phosphodiesterase isozymes was investigated. Amantadine inhibited bovine brain 60 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase but not the bovine brain 63 kDa, heart and lung calmodulin-dependent cyclic nucleotide phosphodiesterase isozymes. The inhibition of bovine brain 60 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase was overcome by increasing the concentration of calmodulin. This suggests that amantadine may be an antagonist of calmodulin or act specifically and reversibly on the action of calmodulin. The bovine brain 60 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase isozyme is predominantly expressed in the brain and its inhibition may result in increased intracellular levels of cyclic AMP (cAMP). The increased intracellular levels of cAMP have a protective role for dopaminergic neurons. The present findings suggest that amantadine may be a valuable tool to investigate the physiological role of 60 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase isozyme in the progression of Parkinson's disease and gives a new insight into the action of this drug.

Amantadine↗
PubMed1997

Ophthalmoplegia and leg myorhythmia in Whipple's disease: report of a case.

Whipple's disease (WD) is a rare disorder that is more common in males than in females. Progressive supranuclear ophthalmoplegia (SNO) in conjunction with oculomasticatory myorhythmia (OMM) or oculofacioskeletal myorhythmia are characteristic movement abnormalities when WD involves the nervous system. Limb myorhythmia without facial or ocular myorhythmia has not been reported in WD. We report such a case who had SNO and leg myorhythmia but no facial or ocular myorhythmia. She had onset of WD at age 28 and 16 years later developed SNO and leg myorhythmia. The neurological manifestations did not respond to antimicrobial agents or to the drugs used for parkinsonism or essential tremor. Valproate produced a remarkable improvement in leg myorhythmia, but the efficacy declined after 3 months. Because WD may infest as a neurological disorder without gastrointestinal symptoms, all SNO cases, with or without OMM, and those with skeletal myorhythmia should be suspected of WD. These patients should be treated vigorously and followed carefully since neurological involvement is the most disabling feature and it has a propensity to relapse.

Adult↗
PubMed1997

Is levodopa toxic to human substantia nigra?

Levodopa (LD) is the most effective drug for symptomatic control of Parkinson's disease, but has been suspected to be toxic to substantia nigra (SN) dopaminergic neurons. Tissue culture and animal studies of LD toxicity have produced contradictory evidence, and one study reported that a human subject exposed to a large cumulative dose (cd) of LD over 4 years had no evidence of SN damage. We report the cases of five patients, each of whom received a large cd of LD over a long period. Fluorodopa positron-emission tomography performed in one case indicated parkinsonism. Autopsies in two cases indicated a normal SN in one and a hypopigmented SN with normal cell complement in the other. Three patients had essential tremor, one had nonprogressive parkinsonism, and one had dopa-responsive dystonia. LD (without decarboxylase inhibitor) was administered over 21 years (cd = 21.99 kg), 9 years (cd = 6.6 kg), 26 years (cd = 18.7 kg), 11 years (cd = 3 kg), and 26 years (cd = 23.93 kg), respectively. None of the patients with essential tremor developed clinical features of parkinsonism that indicated significant SN damage, and one had a normal SN at autopsy. The parkinsonian patient displayed no detectable acceleration of disease process, and the patient with dopa-responsive dystonia had a normal complement of SN neurons at autopsy. We conclude that LD, administered at a dose commonly used for treating Parkinson's disease, was not toxic to SN neurons in these cases.

Adult↗