Biomedical subjects
Publications and source records attributed to R W Walker.
A 7 year old girl developed acute disseminated encephalomyelitis following a Mycoplasma pneumoniae respiratory infection. The illness followed a relapsing course during the first two months. Computed tomography (CT) showed cerebral lesions of a severity and extent out of proportion to the clinical manifestations. The CT abnormalities altered with changes in her clinical state.
5 Patients with intracranial mass lesions are described who experienced cerebral herniation and coma following intravenous cisplatin therapy. Although the pathogenesis of the acute cerebral swelling is unknown, it is most likely multifactorial. Possible contributing factors include pre-existing cerebral edema, acute hypo-osmolality with fluid shifts into an already swollen brain, seizures and possible direct neurotoxicity of cisplatin.
Thirty-three patients were treated with intravenous (IV) cisplatin (CPDD) of whom 32 were considered evaluable. There were 14 medulloblastomas, five primitive neuroectodermal tumors (PNET), nine gliomas, three ependymomas, and one germ cell tumor. The overall response rate was 13 of 32 (41%). Eleven responses (five complete [CR], five partial [PR], one mixed [MR]) were noted in the patients with medulloblastoma. The response rate within this group was 79%. Toxicity was tolerable, although it precluded further therapy in five patients.
The immunosuppressive agents that are an integral part of organ transplantation serve to protect grafts from rejection as well as to prevent or treat GVHD. They include CsA, corticosteroids, OKT3 monoclonal antibody, HDARA-C, azathioprine, and ATG. Of these, all but azathioprine and ATG have direct neurologic complications that are due to the drugs themselves and not just excessive immune suppression. With increasing success in solid organ and bone marrow transplantation and increasing patient survival, one can expect to see more patients who suffer neurologic toxicity.
From 1977 to 1986, 50 children aged 15 months to 18 years were treated for supratentorial malignant gliomas at the Memorial Sloan-Kettering Cancer Center and the New York University Medical Center. Thirteen patients had glioblastoma multiforme, 29 had anaplastic astrocytomas, and 8 had malignant gliomas. In 10 patients the tumor evolved from a low-grade lesion. Seven patients, including 2 patients with neurofibromatosis, developed multiple primary malignant neoplasms. The median time to tumor progression after surgery was 31 weeks, with local recurrence representing the mode of treatment failure in nearly all patients. Notable clinical features included symptomatic leptomeningeal metastasis (13 patients) and intratumoral hemorrhage (9 patients). The estimated median survival time for all 50 patients was 98 weeks, with a 3-year survival rate of 32%. A trend toward longer survival was seen in patients 12 years of age or younger at diagnosis. There was no apparent correlation between survival and tumor histology or tumor location. Recommendations for management are presented.
A series of 6 cases is described in which a chronic demyelinating neuropathy was associated with a relapsing multifocal CNS disorder, the clinical features of which resembled multiple sclerosis. Multifocal CNS lesions were demonstrated by CT and MR imaging and the presence of CNS demyelination was indicated by prolonged central conduction times. These cases are discussed in relation to the occurrence of combined peripheral and central demyelination in chronic relapsing experimental allergic encephalomyelitis and neuritis.
A syndrome is described, consisting of severe neurogenic distal wasting, generalised muscle weakness, absent ankle reflexes, pyramidal signs, mental retardation, optic atrophy and retinal colloid bodies. A sural nerve biopsy from one case showed loss of nerve fibres suggesting the diagnosis of hereditary motor and sensory neuropathy. Progression of the disorder was very slow, all patients still being able to walk more than 20 years after the onset. The persons affected with this syndrome were two brothers and their female cousin from a large Gujerati pedigree where consanguinity was high. Autosomal recessive inheritance is therefore suggested.
A transient acute neurologic syndrome occurred in 22 patients receiving high-dose methotrexate (HDMTX) (8 to 9 g/m2) for a variety of malignancies. The neurologic signs were similar in all cases. The syndrome occurred an average of six days after the second or third weekly treatment. Common findings included behavioral abnormalities, focal sensorimotor signs, and abnormal reflexes. Signs often alternated from one side to the other. Evaluations including computed tomography (CT) scan, lumbar puncture, hemogram, and blood chemistry were normal. The EEG revealed some slowing in all cases. The cause of this syndrome is unknown. It is transient and usually does not recur. Its appearance does not preclude further treatment with HDMTX.
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Cerebrospinal fluid (CSF) from 120 patients with multiple sclerosis was analyzed by polyacrylamide gel electrophoresis, as well as routine laboratory microscopy and assays of total protein and immunoglobulin G (IgG). Negative correlations were found between leucocyte counts and patient age, duration of disease and time from last clinical relapse. There was a positive correlation between the leucocyte count and amount of gammaglobulin. A correlation between gammaglobulin content and degree of disability was found. With increasing duration, the gammaglobulin concentration rose only if there was increasing disability. In terms of correlations with clinical features, differences existed depending on whether IgG was assayed immunologically or by electrophoresis and densitometry. Evidence of increased blood: CSF barrier permeability (transudation of high molecular weight proteins) was found in patients with progressive disease. The presence of oligoclonal bands was the CSF abnormality most frequently encountered.
We present the case of a 35-year-old man who developed symptoms of the neuroleptic malignant syndrome (NMS) after taking prescribed, moderately high, therapeutic doses of haloperidol. When brought to the emergency department, he was comatose, hypotensive, and had rigid muscle tone and a core body temperature of 42.2 C. Although initial treatment was supportive, intubation, ventilator support, and further care in the intensive care unit were necessary. Ensuing disseminated intravascular coagulation was treated successfully and the patient was weaned from the ventilator on the third day after admission. He was discharged from the hospital 11 days after admission. Recently recognized drug therapy for NMS, such as bromocriptine mesylate and dantrolene sodium, was not used in this case.
The [1-14C]pivaloyloxyethyl ester of methyldopa administered to man and cynomolgus monkeys resulted in the elimination in the urine of 14C-pivalic acid metabolites. Pivaloyl glucuronide and pivaloyl carnitine were identified as the major radioactive urinary metabolites in monkey urine and human urine, respectively. N.m.r. analysis indicated that pivaloyl carnitine had a cyclic structure. Although the role of carnitine is in the transport of fatty acids across mitochondrial membranes, it may also function in the conjugation of carboxylic acid xenobiotics in humans.
A capillary column gas-liquid chromatography selected ion monitoring-based method was developed for the measurement of [13C,15N]N-methyltryptamine ( NMT ) in human urine. The method was employed to establish the extent of conversion of [13C,15N]tryptamine to the correspondingly labeled NMT in schizophrenic patients in an attempt to demonstrate whether methylation of tryptamine plays a role in schizophrenia. Mass spectrometric detection in the assay procedure is via chemical ionization (Isobutane) with monitoring of the MH+ ions of the trimethylsilyl derivatives of [13C,15N] NMT and the internal standard, [2H3,13C,15N] NMT . The assay possesses a sensitivity limit (using 200 ml of urine) of ca. 0.1 ng/ml, corresponding to substrate conversion of ca. 0.00005% with a 75 mg dose (i.v.) of labeled tryptamine. Evidence for methylation was found with only one of seven patients studied; the extent of substrate conversion for the one individual was only 0.0001%. These results do not support the indoleamine--methylation hypothesis of schizophrenia.
When ronidazole (1-methyl-5-nitroimidazole-2-methanol carbamate) is reduced by either dithionite or rat liver microsomal enzymes in the presence of cysteine, ronidazole-cysteine adducts can be isolated. Upon reduction with dithionite ronidazole can react with either one or two molecules of cysteine to yield either a monosubstituted ronidazole-cysteine adduct substituted at the 4-position or a disubstituted ronidazole-cysteine adduct substituted at both the 4-position and the 2-methylene position. In both products the carbamoyl group of ronidazole has been lost. The use of rat liver microsomes to reduce ronidazole led to the formation of the disubstituted ronidazole-cysteine adduct. These data indicate that upon the reduction of ronidazole one or more reactive species can be formed which can bind covalently to cysteine. The proposed reactive intermediates formed under these conditions may account for the observed binding of ronidazole to microsomal protein and the presence of intractable drug residues in the tissues of animals treated with this compound. They may also account for the mutagenicity of this compound in bacteria.
One hundred and eighty one children with thrombocytopenia for which no cause could be found have been studied. One patient died with severe bleeding possibly from disseminated intravascular coagulation and one developed cerebral haemorrhage, both within two weeks of onset. Ninety one per cent of the 135 with acute disease but only 36% of those with chronic disease remitted spontaneously. Twenty per cent of spontaneous remission occurred more than one year after onset. Six patients have run an intermittent course for 10 to 20 years. Four patients have had symptomless thrombocytopenia for between 10 and 30 years. Of 32 children treated by splenectomy 24 maintained normal platelet values thereafter. One boy died from pneumococcal septicaemia two years after splenectomy but he had not received prophylactic penicillin. One hundred and fifty eight patients were followed up 3 to 37 years (mean 16.4 years) after onset. None who recovered spontaneously or after splenectomy had had further bleeding problems. No patient nor immediate relative had developed other autoimmune disease. We consider that a short course of corticosteroids immediately after diagnosis is justified in all cases even though we cannot produce proof that it influences the course of the disease. We do not accept any place for long term immunosuppressant treatment.
Assessment of the presence of immunoglobulin (Ig) of restricted heterogeneity i.e. oligoclonal Ig in cerebrospinal fluid subjected to isoelectric focusing (IEF) may be difficult because of the tendency of the technique to subdivide even normal polyclonal IgG into bands and zones. Focused Ig stained by the immunoperoxidase technique for kappa and lambda light chains shows correspondence between the two patterns in the case of normal polyclonal Ig, but a marked discrepancy between kappa and lambda patterns in disorders associated with oligoclonal Ig, and kappa and lambda immunofixation makes assessment of agarose IEF separations of IgG more reliable.
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