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Biomedical subjects

M Downing

Publications and source records attributed to M Downing.

At least 19 recordsLinked to original sources
PubMed1992

Metabolic deficiencies and SIDS.

The role of inherited metabolic defects in SIDS is controversial: some workers think that they may account for the cause of death in about 10% of cases. Many maintain that this is a gross overestimate, but it cannot be denied that the sudden onset and rapid deterioration known to occur in some metabolic disorders during the first year of life can mimic SIDS. This may remain undetected unless postmortem material is examined in specialist centres with individual metabolic disorders in mind. Defects in energy metabolism and the maintenance of glucose homeostasis frequently show this pattern of presentation precipitated by minor clinical infection. These disorders include the glycogen storage disorders, gluconeogenic enzyme defects, and the defects of fatty acid oxidation. Several reports have appeared since 1984 linking fatty acid oxidation defects with SIDS. Estimates of their prevalence vary, due partly to methodological heterogeneity and partly to the limited size of individual studies which have not permitted adequate statistical analysis. Nevertheless, the lack of adequate information has not precluded a great deal of debate. Over the past seven years a group in Sheffield has studied the occurrence of these defects in SIDS using three distinct approaches: retrospective analysis of SIDS cases, prospective analysis of SIDS cases, prospective analysis of urine obtained from siblings of SIDS cases during the first week of life. The result of these studies would suggest that the contribution to SIDS made by medium chain acyl CoA dehydrogenase deficiency may be in the region of 1%. Additional related metabolic disorders may account for a further as yet undefined small percentage. The eventual resolution of some of these uncertainties may be provided by harmonizing the results of existing studies and by DNA analysis of materials obtained at necropsy in SIDS cases.

Fatty Acids↗
PubMed1991

Localization of the multifunctional protein CAD in astrocytes of rodent brain.

The CAD multidomain protein, which includes active sites of carbamyl phosphate synthetase II (CPS II, glutamine-dependent), aspartate transcarbamylase, and dihydroorotase, was immunostained in normal rat brains, the gliotic brains of myelin-deficient mutant rats, and brains from normal weanling hamsters. In each of these tissues CAD was observed in cells resembling astrocytes. In hamster brain, CAD immunofluorescence was also found in cells closely related to astrocytes, i.e., the Bergmann glia in cerebellum and the tanycytes surrounding the third ventricle. The astrocytic identity of the CAD-positive cells in rat brain was confirmed by double immunofluorescence staining with antibodies against glial fibrillary acidic protein (GFAP). The two enzymes carbonic anhydrase and glutamine synthetase occur in the cytoplasm of normal astrocytes in gray matter and of reactive astrocytes during gliosis. Products of each enzyme, i.e., bicarbonate and glutamine, are required for the CPS II reaction, which is the first step in the biosynthesis of pyrimidines. Therefore, the present results suggest roles for carbonic anhydrase and glutamine synthetase, as well as CAD, in pyrimidine biosynthesis in brain and a role for the astrocytes in the de novo synthesis of pyrimidines.

Animals↗
PubMed1991

Immunocytochemical staining of the RLM6 form of cytochrome P-450 in oligodendrocytes and myelin of rat brain.

We used immunocytochemical staining to localize the RLM6 form of cytochrome P-450 in rat brain. Immunofluorescence staining in vibratome sections was positive in cells that resembled oligodendrocytes, which are the cells that synthesize and maintain myelin. Double immunofluorescence staining with anti-RLM6, plus mouse monoclonal antibodies (MAb) against 2',3'-cyclic nucleotide-3'-phosphohydrolase or galactocerebrosides, showed localization of each of these oligodendrocyte "markers" in the same cells as RLM6. In vibratome sections from brains of adult rats there was faint RLM6 immunostaining in some of the myelinated fibers as well as in oligodendrocytes. In paraffin sections from adult rat brains, myelinated tracts were RLM6 positive, as were oligodendrocytes and myelinated fibers in the gray matter. Oligodendrocytes were also shown to contain glucose-6-phosphate dehydrogenase. We suggest that RLM6, which is constitutive to liver, is also constitutive to brain and, via the acetone monooxygenase reaction, which also utilizes NADPH, may contribute to the conversion of ketone bodies to substrates that could provide energy for the synthesis and maintenance of myelin.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1991

Evaluating needle exchange: do distributed needles come back?

We employed capture-recapture methods as a strategy for evaluating needle exchange. Needles distributed by the exchange at two time periods were marked with color coded bands indicating the date and site of distribution. Half of the marked needles (2,068/4,239) returned within two weeks of distribution, and 61 percent (2,593/4,239) returned during the study period. The rate of return for stationary exchange sites (63 percent) was greater than that for roving/mobile sites (51 percent; chi 2 = 28.6, p less than .001). Of all needles returned, 87 percent (2,248/2,593) returned to the site of original distribution.

Acquired Immunodeficiency Syndrome↗
PubMed1990

AIDS prevention for intravenous drug users in the community: street-based education and risk behavior.

Conducted a study of behavior change associated with a street-based AIDS education project targeted to intravenous (IV) drug users in San Francisco. Two cross-sections were sampled from drug detoxification clinics and street locations in 1986 (n = 438) and 1987 (n = 623). Significant increases were reported in the percentage of IV drug users who used bleach to decontaminate syringes, who did not share needles in past year, and in condom use. A significant reduction in an index of the number of needle-sharing partners was reported. Respondents ranked treatment program as most important source of AIDS information prior to implementation of the program, and ranked outreach workers as most important after implementation. Findings suggest that this community-based outreach program had at least some impact on knowledge about AIDS and may have led to reductions in behaviors known to transmit HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving dose-intensive chemotherapy without bone marrow transplantation.

Bone marrow colony-stimulating factors (CSF) ameliorate hematologic toxicity of standard chemotherapy regimens and may allow relatively safe use of intensive and more efficacious doses of anticancer drugs. Twenty-four patients with cancers for which no standard regimens were likely to be effective received repeated courses of a combination of cisplatin (150 mg/m2), etoposide (1,500 mg/m2), and cyclophosphamide (5,000 mg/m2) at doses for which bone marrow transplantation is usually used. A total of 10 patients received escalating doses of recombinant human granulocyte CSF (rhG-CSF); 11 patients receiving identical chemotherapy and supportive therapy without rhG-CSF served as controls for the first cycle of therapy. Five of these patients and 3 additional patients also served as their own controls, receiving rhG-CSF for all cycles after the first. No patient received bone marrow transplantation. rhG-CSF shortened the median duration of severe granulocytopenia (less than or equal to 100/mm3) in a dose-related fashion (P less than .03; Kruskal-Wallis test). Patients not receiving rhG-CSF had a median of 8.5 days of granulocytopenia. Those receiving 40 micrograms/kg of rhG-CSF for approximately 20 days from the third day after chemotherapy had a median of 7.0 days (P less than .23) and those receiving 60 micrograms/kg had a median of 5.5 days (P less than .007) of granulocytopenia. An rhG-CSF dose of 20 micrograms/kg had no effect. Recovery to a granulocyte count of at least 500/mm3 took a median of 12 days in the control group and 8 days (P less than .03) in patients receiving rhG-CSF at a dose of 60 mg/kg. The duration of antibiotic therapy (a median, 9.0 days v 5.0 days) was shortened with the two higher and effective doses of rhG-CSF compared with control patients. The duration of hospitalization (median of 20 days v 19 days) was not shortened. These findings that rhG-CSF decreases the risk of granulocytopenia associated with this particular dose-intensive chemotherapy regimen therapy administered without bone marrow transplantation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Phase I study of recombinant methionyl human consensus interferon (r-metHuIFN-Con1).

Consensus interferon (r-metHuIFN-Con1) is the product of a gene constructed to code for the most frequent amino acid residues known to occur in subspecies of alpha interferons. Twenty-one patients with advanced malignancy entered this phase I trial with dosing levels of 3, 7.5, 15, 30, and 45 mcg/m2/day given intramuscularly on days 1-5 and 8-10 of each 28-day cycle. The initial dose was randomly given by intravenous, intramuscular, or subcutaneous injection to facilitate pharmacokinetic studies. Vomiting and diarrhea were dose-limiting at 45 mcg/m2/day, preventing completion of therapy. Malaise, flu-like symptoms, nausea, and headache were frequent but tolerable at a dose of 30 mcg/m2/day. Patients were able to escalate to 45 mg/m2/day, suggesting tachyphlaxis to these toxicities. The initial distribution phase (T1/2 alpha) was 4.9-9.0 minutes with a T1/2 beta of 34-415 minutes in three patients for whom sequential values could be determined. r-MetHuIFN-Con1 was absorbed after both subcutaneous and intramuscular administration. 2'5'-Synthetase levels increased following treatment, although no consistent pattern was noted. One partial response was seen in a patient with gastrointestinal carcinoma. The recommended phase II starting dose of r-metHuIFN-Con1 is 30 mg/m2/day using this schedule by any of these routes of administration.

Adolescent↗
PubMed1987

Childhood scoliosis: MR imaging.

The spinal cords of 28 scoliosis patients between the ages of 1 month and 17 years were examined with magnetic resonance (MR) imaging. Complete visualization was obtained in all cases. In 15 patients (53%) neuropathologic abnormalities demonstrated by MR imaging significantly affected their clinical course, including tethered cords (n = 7), syringomyelia (n = 5), Arnold-Chiari I malformation (n = 4), spinal cord tumors (n = 2), Arnold-Chiari II malformation (n = 3), and diastematomyelia (n = 1). The advantages of MR imaging in the evaluation of the scoliotic spine in children include a high sensitivity for the occult conditions associated with scoliosis, good anatomic demonstration of the cord, and absence of bone artifacts. MR imaging is recommended as a primary imaging modality in scoliosis, following conventional radiography.

Arnold-Chiari Malformation↗
PubMed1983

Mouse pituitary tumor line secreting only the alpha-subunit of the glycoprotein hormones: development from a thyrotropic tumor.

This report describes the conversion of a murine pituitary thyrotropic tumor (MGH 101) to a pure alpha-subunit-secreting tumor (MGH 101A) during a 6-yr period of serial transplantation. MGH 101 was a thyrotropic tumor originating from a hypothyroid mouse pituitary, growing only in hypothyroid hosts, and secreting large quantities of intact TSH and free alpha-subunit. Between the fourth and ninth transplantation generations, tumor TSH secretion declined progressively by at least 500-fold, to undetectable levels. In contrast, tumor secretion of free alpha-subunit decreased only 10-fold, and has since remained stable for nine transplantation generations. During the conversion to pure alpha-subunit secretion, MGH 101A exhibited growth in euthyroid as well as hypothyroid hosts, and increased its growth rate 2 to 3-fold. In contrast, the conventional thyrotropic tumor TtT 97 has maintained its secretion of both intact TSH and free alpha-subunit, its dependence on a hypothyroid environment, and its slower growth rate for nine generations. Gel chromatography of the media from tumor cell cultures confirmed that MGH 101A secreted only the free alpha-subunit, whereas TtT 97 secreted immunoactive TSH, TSH beta, and free alpha-subunit which eluted as separate peaks. We conclude that a dependent thyrotropic tumor has spontaneously developed into a pure alpha-subunit-secreting tumor which is independent of host thyroid function for its growth and alpha-subunit production.

Animals↗
PubMed1981

Prothrombin.

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Amino Acid Sequence↗
PubMed1980

Isolation of feline herpesvirus 1 from a young kitten.

Five kittens exposed neonatally to older cats exhibiting fever with nasal and ocular discharge became ill and died within 10 days of the onset of illness. One kitten which died at 16 days old was examined post mortem and feline herpesvirus 1 was isolated from the brain, liver, lung and spleen.

Animals↗
PubMed1968

Pyrimidine biosynthesis in Lactobacillus leichmannii.

Tracer studies of pyrimidine biosynthesis in Lactobacillus leichmannii (ATCC 7830) indicated that, while aspartate is utilized in the usual manner, the guanido carbon of arginine, rather than carbon dioxide, is utilized as a pyrimidine precursor. The guanido carbon of arginine also contributes, to some extent, to the carbon dioxide pool utilized for purine biosynthesis. The enzyme of the first reaction leading from arginine to pyrimidines, arginine deiminase, was investigated in crude bacterial extracts. It was inhibited by thymidylic acid and purine ribonucleotides, and to a lesser extent by purine deoxynucleotides and deoxycytidylic acid. Under the assay conditions employed, a number of nucleotides had no effect on the enzyme activity of the aspartate transcarbamylase of L. leichmannii. Growth of the cells in media containing uracil, compared to growth in media without uracil, resulted in a four- to fivefold decrease in the concentrations of aspartate transcar-bamylase and dihydroorotase and a twofold increase in the concentration of arginine deiminase, as estimated from specific enzyme activity in crude extracts of the cells. A small increase in specific enzyme activity of ornithine transcarbamylase and carbamate kinase was also observed in extracts obtained from cells grown on uracil. No appreciable change in concentration of any of the five enzymes studied was detected when the cells were grown in media containing thymidine or guanylic acid. A hypothetical scheme which suggests a relationship between the control of purine and pyrimidine biosynthesis in this bacterium and which is consistent with the experimental results obtained is presented.

Arginine↗