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Biomedical subjects

C Walsh

Publications and source records attributed to C Walsh.

At least 127 records · Page 7Linked to original sources
PubMed1992

Phase I study of doxorubicin, ICRF-187 and granulocyte/macrophage-colony-stimulating factor.

A group of 16 patients with advanced malignancy were entered on a phase I trial of escalating doses of doxorubicin with ICRF-187 for cardioprotection and granulocyte/macrophage-colony-stimulating factor (GMCSF) for bone marrow protection. Patients received intravenous ICRF-187 (dose ratio 20:1 ICRF-187:doxorubicin) 30 min prior to doxorubicin. GMCSF at a dose of 15 micrograms kg-1 day-1 was self-administered subcutaneously on days 3-14 of the cycle. Doxorubicin was administered every 21 days. Substantial hematological and non-hematological toxicity was seen. Fever, malaise, and pulmonary symptoms, thought to be due to GMCSF, were not eliminated by reduction in the GMCSF dose to 10 or 5 micrograms kg-1 day-1. Severe hematological toxicity was seen despite GMCSF administration and it was not possible to escalate the doxorubicin dose above 72 mg/m2 with this combination. Dose escalation of doxorubicin may be more feasible with the use of other growth factors or growth factor combinations.

Dose-Response Relationship, Drug↗
PubMed1992

Total joint replacement: implication of cancelled operations for hospital costs and waiting list management.

OBJECTIVE: To identify aspects of provision of total joint replacements which could be improved. DESIGN: 10 month prospective study of hospital admissions and hospital costs for patients whose total joint replacement was cancelled. SETTING: Information and Waiting List Unit, Musgrave Park Regional Orthopaedic Service, Belfast. PATIENTS: 284 consecutive patients called for admission for total joint replacement. MAIN MEASURES: Costs of cancellation of operation after admission in terms of hotel and opportunity costs. RESULTS: 28(10%) planned operations were cancelled, 27 of which were avoidable cancellations. Five replacement patients were substituted on the theatre list, leaving 22(8%) of 232 operating theatre opportunities unused. Patients seen at assessment clinics within two months before admission had a significantly higher operation rate than those admitted from a routine waiting list (224/232(97%) v 32/52(62%), x2 = 58.6, df = 1; p < 0.005). Mean duration of hospital stay in 28 patients with cancelled operations was 1.92 days. Operating theatre opportunity costs were 73% of the total costs of cancelled total joint replacements. CONCLUSION: Patients on long waiting lists for surgery should be reassessed before admission to avoid wasting theatre opportunities, whose cost is the largest component of the total costs of cancelled operations.

Data Collection↗
PubMed1992

Postoperative femoral neuropathy.

Postoperative femoral neuropathy is more common than it is generally appreciated. It can occur by a number of different mechanisms after a wide variety of operations as a result of either direct or indirect injury. Most instances occur after abdominopelvic operations and are associated with the placement of self-retaining retractors. A large body of evidence suggests that, in these patients, nerve compression by the lateral blades of the retractor is the cause. There is, however, evidence that the intrapelvic portion of the nerve is particularly susceptible to ischemia. Usually, there is a mild sensorimotor disturbance and the diagnosis is easily made by accurate physical examination during the early postoperative period. A diminished or absent knee jerk is the most reliable clinical sign. Recovery is the rule; it occurs usually from a few weeks to months. During this time, physiotherapy may be beneficial. Occasionally the lesion may be severe or prolonged, or both. In these instances, EMG studies are justified, not only to allay the fears of patients and physicians, but to evaluate the progress of the lesion over time. With the exception of certain unusual instances, this potentially debilitating postoperative complication can be avoided by careful placement of self-retaining retractors.

Femoral Nerve↗
PubMed1991

Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma. A prospective multi-institutional trial.

OBJECTIVE: --To ascertain if low-dose multiagent chemotherapy, with central nervous system prophylaxis and antiretroviral therapy, might be associated with increased efficacy and decreased risk of intercurrent infection in patients with malignant lymphoma related to the acquired immunodeficiency syndrome (AIDS). DESIGN: --A phase II prospective clinical trial, with median follow-up of 33 months. SETTING: --Eight university hospitals, within the context of the AIDS Clinical Trials Units, sponsored by the National Institute of Allergy and Infectious Diseases. PATIENTS: --Forty-two patients with AIDS-related malignant lymphoma. All were evaluable for toxicity assessment, and 35 for response. INTERVENTION: --A low-dose modification of the M-BACOD regimen (day 1): cyclophosphamide, 300 mg/m2 intravenously (IV); doxorubicin, 25 mg/m2 IV; vincristine sulfate, 1.4 mg/m2 IV; bleomycin, 4 mg/m2 IV; dexamethasone, 3 mg/m2 orally on days 1 through 5; methotrexate, 500 mg/m2 IV on day 15, with leucovorin rescue. Intrathecal cytosine arabinoside (50 mg) to all on days 1, 8, 21, and 28, with radiation therapy to a helmet field to those with central nervous system involvement. Zidovudine for 12 months after completion of four to six cycles of chemotherapy. MAIN OUTCOME MEASURES: --Response rate and number of opportunistic infections. RESULTS: --Response rate was 51% with a complete response of 46%. Of 16 complete responses, relapse occurred in four, none isolated to the central nervous system. Opportunistic infections occurred in 21% of those receiving treatment. Median duration of survival among all 42 patients is 5.6 months, 6.5 months in 35 patients evaluable for response, and 15 months in patients with complete response. Lower concentration of CD4 cells, history of prior AIDS, bone marrow involvement, and stage IV disease were independently associated with decreased survival. CONCLUSIONS: --Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance may be associated with durable remissions in AIDS-related lymphoma with fewer opportunistic infections than noted in prior reports.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Molecular studies on trypanothione reductase, a target for antiparasitic drugs.

Trypanosoma and Leishmania are parasitic protozoa that cause a variety of diseases, which include African sleeping sickness and oriental sore. Attempts to determine pharmaceutically exploitable differences between host and parasite biochemistry have identified the unique trypanothione pathway as a possible target. This pathway includes the enzyme trypanothione reductase, the parasite analogue of glutathione reductase.

Animals↗
PubMed1991

Subcritical flutter in collapsible tube flow: a model of expiratory flow in the trachea.

Using an axisymmetric geometry that retains certain qualitative features of the trachea, we extend one-dimensional modeling of flow in collapsible tubes to include both curved shell effects and, for untethered tubes, wall inertia. A systematic scaling of the finite deformation membrane equations leads to an approximate set which is consistent with the one-dimensional fluid model; axial and normal wall variables are coupled elastically, but only axial inertia is retained. Transverse curvature causes elastic coupling that can give rise to axial wall motion and a flutter instability. The source of instability is the product of a nonzero reference axial curvature with axial tension variation due to axial stretching. The numerical results suggest that this mechanism may be significant even in processes which cannot be assumed one-dimensional.

Biomechanical Phenomena↗
PubMed1991

Mortality of 11,500 nickel workers--extended follow up and relationship to environmental conditions.

An extended follow-up from 1977-84 was achieved in a cohort of 11,567 nickel workers engaged in mining, milling and smelting originally studied from 1950-76. Exposure data were incorporated into the analysis. One nasal cancer occurred. The lung cancer Standardized Mortality Ratio beyond 15 years from first exposure was significantly high overall (128) and in miners (153). However, detailed analyses by era of first mining and duration of mining, as well as cumulative exposure to different nickel species, did not appear consistent with an occupational etiology since significant trends were not observed. At the levels of exposure incurred, large increases in lung and nasal cancer, observed in nickel refineries elsewhere, did not occur.

Environmental Monitoring↗
PubMed1990

Cell lineage and cell migration in the developing cerebral cortex.

Modern techniques which trace lineages of individual progenitor cells have provided some clues about the processes that determine cell fate in the brain, and have also given us some information about migratory patterns of clonally related cells. In many parts of the central nervous system, progenitors are multipotent; single clones can contain multiple neuronal types or even mixtures of neurons and glia. In addition, one can observe a wide distribution in clone size, even when marking is done in a narrow time window. This suggests that progenitor cells may be fairly plastic and responsive to environmental signals. In the developing cortex, clonally related cells are initially grouped near each other, as in the retina and tectum. However, the subsequent migration of these cells from the ventricular zone to the cortex along glial fibers is accompanied by a progressive dispersion of clonally related neurons.

Animals↗
PubMed1990

Identification of amino acids in the gamma-carboxylation recognition site on the propeptide of prothrombin.

A gamma-carboxylation recognition site on the propeptide of the vitamin K-dependent blood coagulation proteins directs the carboxylation of glutamic acid residues by binding to the vitamin K-dependent carboxylase. To determine residues that define this site, we evaluated the effect of mutation of certain residues in the prothrombin propeptide on the extent of carboxylation. The prothrombin cDNA modified by site-specific mutagenesis was expressed in Chinese hamster ovary cells using a system that yields functional fully carboxylated prothrombin. The cell supernatants containing recombinant prothrombin were evaluated for the extent of gamma-carboxylation by immunoassay. Conformation-specific anti-prothrombin:Ca(II)-specific antibodies measure native completely carboxylated prothrombin; anti-prothrombin:total antibodies measure all forms of prothrombin, regardless of gamma-carboxyglutamic acid content. Mutation of His-18 to Gly, Val-17 to Ser, Leu-15 to Gly or Asp, or Ala-10 to Asp was associated with a partial (30-65%) inhibition of gamma-carboxylation. Mutation of Ala-14 to Ser or Ser-8 to Val did not inhibit gamma-carboxylation. From this and earlier work, residues whose mutation leads to a significant impairment of carboxylation include His-18, Val-17, Phe-16, Leu-15, and Ala-10. Residues whose mutation does not alter the carboxylation recognition site include Ala-14, Ser-8, Arg-4, and Arg-1. To determine the size of the recognition site, the in vitro carboxylation of propeptide-containing synthetic peptides was compared. A 28-residue peptide, based upon residues -18 to +10 of prothrombin, and a 54-residue peptide, based upon residues -18 to +36 of prothrombin, were carboxylated by partially purified bovine carboxylase with similar Km values of 2-5 microM. These results indicate that the gamma-carboxyglutamic acid-rich region of prothrombin makes a minimal contribution to carboxylase binding. A molecular surface of about five amino acids located within the propeptide appears to define the carboxylation recognition site on the precursor forms of the vitamin K-dependent proteins.

Amino Acid Sequence↗
PubMed1990

Reconstitution of Escherichia coli photolyase with flavins and flavin analogues.

Escherichia coli DNA photolyase contains two chromophore cofactors, 1,5-dihydroflavin adenine dinucleotide (FADH2) and (5,10-methenyltetrahydrofolyl)polyglutamate (5,10-MTHF). A procedure was developed for reversible resolution of apophotolyase and its chromophores. To investigate the structures important for the binding of FAD to apophotolyase and of photolyase to DNA, reconstitution experiments with FAD, FMN, riboflavin, 1-deazaFAD, 5-deazaFAD, and F420 were attempted. Only FAD and 5-deazaFAD showed high-affinity binding to apophotolyase. The apoenzyme had no affinity to DNA but did regain its specific binding to thymine dimer containing DNA upon binding stoichiometrically to FAD or 5-deazaFAD. Successful reduction of enzyme-bound FAD with dithionite resulted in complete recovery of photocatalytic activity.

Apoenzymes↗
PubMed1989

Vitamin K-dependent carboxylation. In vitro modification of synthetic peptides containing the gamma-carboxylation recognition site.

Synthetic peptides including the gamma-carboxylation recognition site and acidic amino acids were compared as substrates for vitamin K-dependent gamma-carboxylation by bovine liver carboxylase. The 28-residue proPT28 (proprothrombin -18 to +10) and proFIX28 (pro-Factor IX -18 to +10) were carboxylated with a Km of 3 microM. The Vmax of proPT28 was 2-3 times greater than that of proFIX28. An analog of proFIX28 that contained the prothrombin propeptide had a Vmax 2-3-fold greater than an analog of proPT28 that contained the Factor IX propeptide. proFIX28/RS-1, based upon Factor IX Cambridge, proFIX28/RQ-4, based upon Factor IX Oxford 3, and proFIX28 had equivalent Km and Vmax values. Analogs of proPT28 containing Ala6-Glu7 or Glu6-Ala7 were carboxylated at equivalent rates. A peptide containing Asp6-Asp7 was carboxylated at a rate of about 1% of that of Glu carboxylation. Carboxylation of peptides containing Asp6-Glu7 and Glu6-Asp7 yielded results identical with peptides containing Ala6-Glu7 and Glu6-Ala7. Carboxymethylcysteine was not carboxylated when substituted for Glu6 in a peptide containing Asp7. These results indicate that the prothrombin propeptide is more efficient in the carboxylation process than is the Factor IX propeptide, but that both propeptides direct carboxylation; the gamma-carboxylation recognition site does not include residues -4 and -1; aspartic acid and carboxymethylcysteine are poor substrates for the carboxylase, but aspartic acid does not inhibit the carboxylation of adjacent glutamic acids.

Amino Acid Sequence↗
PubMed1989

Purification and properties of Methanobacterium thermoautotrophicum DNA photolyase.

We have purified DNA photolyase from the autotrophic anaerobic archaebacterium Methanobacterium thermoautotrophicum to near homogeneity by a two-column affinity chromatography. The purified enzyme has an Mr = 60,000 and shows near UV absorption peak at 440 nm and a fluorescence emission maximum at 462 nm indicating that it contains 8-hydroxy-5-deazaflavin (coenzyme F420) as an intrinsic chromophore. The photolyase binds with high specificity to thymine dimer in DNA with an equilibrium binding constant, KA = 1.4 x 10(9) M-1, and a dissociation rate constant, koff = 1.4 x 10(-4) s-1 (t1/2 = 43 min). Despite 6-fold higher affinity compared to the folate-containing Escherichia coli photolyase the two enzymes apparently contact the same phosphates around the thymine dimer: the phosphate immediately 5' and the three phosphates immediately 3' to the dimer on the damaged strand and the phosphate across from the dimer in the minor groove on the complementary strand. The absolute action spectrum of the Methanobacterium photolyase in the 400-500-nm region closely matches the absorption of the enzyme-bound F420. The quantum yield (phi) over this region is constant and is approximately 0.2. The value is measurably smaller than the quantum yields reported for other DNA photolyases.

Amino Acid Sequence↗
PubMed1989

Reducing alcohol consumption through television advertising.

Regular drinkers from the general public whose drinking behavior was known to be unaffected by a previous antidrug advertising campaign were involved in a field experiment to assess the impact of a television commercial based on controlled-drinking principles. In a 2 x 2 factorial arrangement of exposure to the advertising campaign (advertisement, no advertisement) and exposure to a letter announcing the campaign (letter, no letter), 96 subjects from two cities in tropical North Queensland provided baseline and posttreatment details of alcohol consumption and alcohol-related attitudes. Baseline measures were taken approximately 12 months prior to the start of the campaign, and posttesting occurred 3 weeks after the campaign. Results were consistent with the proposition that the advertisement reduced intake provided that subjects also received the standard letter alerting them to the start of the campaign.

Adolescent↗