Biomedical subjects
Publications and source records attributed to J Macdonald.
The first of two articles on dialysis outlines the experience of patients from chronic renal failure to end stage renal failure and offers a historical perspective of continuous ambulatory peritoneal dialysis (CAPD). It relates to UKCC Professional Development categories: Care enhancement and Reducing risk.
The clinical significance of low serum vitamin B12 levels in elderly people is controversial. We aimed to document the prevalence of a low serum vitamin B12 (< 175 pmol/l) in patients referred to a geriatric medical unit, and to determine whether haemopoiesis is commonly affected in elderly patients with low serum vitamin B12. We studied prospectively 472 consecutive referrals to a geriatric medical unit; fifty-six (13%) had a low serum vitamin B12 level, of whom nineteen (34%) of the fifty-six also had evidence of Fe deficiency (serum ferritin < 45 ng/ml). Low vitamin B12 was associated with a raised mean erythrocyte volume (MCV; mean 96.0 (SD 6.7) fl), compared with a control group (91.7 (SD 6.0) fl; P = 0.001). However, only thirteen (23%) of the fifty-six patients with a low vitamin B12 had an MCV > or = 100 fl. Mean haemoglobin (Hb) levels were not significantly reduced in those with a low vitamin B12. In a subsequent study the haematological response to intramuscular hydroxocobalamin was examined in thirty-four patients with a low serum vitamin B12. Treatment resulted in a significant fall in MCV and rise in Hb; these effects could be detected both in those patients with an initially normal full blood count (change in MCV -1.2 (SD 1.2); Hb +0.5 (SD 0.6); P < 0.01) and in those with macrocytosis and/or anaemia (-9.1 (SD 11.8); +0.8 (SD 1.2); P < 0.05). A low serum vitamin B12 is common in geriatric medical patients. This is usually associated with an upset in erythropoiesis, although the abnormalities are often subtle and may not be apparent on inspection of the full blood count. Elderly patients with serum vitamin B12 < 175 pmol/l should be assumed to have vitamin deficiency even if their full blood count is normal.
We tested the effects of administration of a selective neuronal nitric oxide synthase (nNOS) inhibitor, ARL 17477, on ischemic cell damage and regional cerebral blood flow (rCBF), in rats subjected to transient (2 h) middle cerebral artery (MCA) occlusion and 166 h of reperfusion (n = 48) and in rats without MCA occlusion (n = 25), respectively. Animals were administered ARL 17477 (i.v.): 10 mg/kg; 1 mg/kg; 3mg/kg; N-nitro-L-arginine (L-NA) 10 mg/kg L-NA 1 mg/kg; and Vehicle. Administration of ARL 17477 1 mg/kg, 3 mg/kg and 10 mg/kg reduced ischemic infarct volume by 53 (p < 0.05), 23, and 6.5%, respectively. L-NA 1 mg/kg and 10 mg/kg increased infarct volume by 2 and 15%, respectively (p > 0.05). Administration of ARL 17477 (10 mg/kg) significantly (p < 0.05) decreased rCBF by 27 +/- 5.3 and 24 +/- 14.08% and cortical NOS activity by 86 +/- 14.9 and 91 +/- 8.9% at 10 min or 3 h, respectively, and did not alter mean arterial blood pressure (MABP). L-NA (10 mg/kg) significantly reduced rCBF by 23 +/- 9.8% and NOS activity by 81 +/- 7% and significantly (p < 0.05) increased MABP. Treatment with 3 mg/kg and 1 mg/kg ARL 17477 reduced rCBF by only 2.4 +/- 4.5 and 0%, respectively, even when NOS activity was reduced by 63 +/- 13.4 and 45 +/- 15.7% at 3 h, respectively, (p < 0.05). The data demonstrate that ARL 17477 inhibits nNOS in the rat brain and causes a dose-dependent reduction in infarct volume after transient MCA occlusion.
The relationships between the "stress hormones" corticotrophin (ACTH), vasopressin (AVP), corticotrophin releasing hormone (CRH) and cortisol, and the cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor were studied during an acute infection. Ten patients (7 female, 3 male, age range 16-56 years) with acute pyelonephritis and normal renal function were studied during the first 72 hours following hospital admission. Peptide hormones were measured by radioimmunoassay, cortisol and cytokines by ELISA. Reference ranges for all hormones were from samples donated by 40 or more volunteers from the electoral roll. The reference data for IL-6 was obtained from 20 normal donor sera. The mean plasma IL-6, AVP and CRH concentrations on admission to hospital were significantly raised above the mean 08:00h values of the normal volunteers (p < 0.001 for AVP and CRH, p < 0.01 for IL-6), but mean plasma ACTH and cortisol were not. Mean plasma IL-6 and AVP were raised more than two standard deviations above the mean of the reference range for 72 hours, although IL-6 tended to fall after 24 hours. No change in plasma IL-1 and tumour necrosis factor was observed in three patients. The correlation between plasma IL-6 and cortisol concentrations at all sampling times and in all subjects was highly significant (p < 0.001). Significant correlations between plasma IL-6 and AVP (p < 0.005), and IL-6 and ACTH (p < 0.05) were also observed. No correlation between IL-6 and CRH could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
Actinobacillus pleuropneumoniae serotype 2 secretes type II haemolysin and pleurotoxin activities. Here, the genes for type II haemolysin were cloned in Escherichia coli, but type II haemolysin antigen and haemolysin activity were only detected intracellularly and not exported to culture supernatant. It has been reported that the genes for type II haemolysin are not linked to functional secretion genes, while those for pleurotoxin are. In this report the means of secretion of type II haemolysin was examined by constructing a hybrid plasmid carrying the genes required for type II haemolysin expression, together with determinants which allow secretion of pleurotoxin and are linked to the pleurotoxin toxin genes. These genes facilitated the export of type II haemolysin from E. coli, and may perform this function in A. pleuropneumoniae.
A phase I-II study was conducted in 15 patients to determine the tolerability, efficacy and optimal dose of s.c. yeast-derived granulocyte-macrophage colony stimulating factor (GM-CSF) for mobilization of peripheral blood stem cells (PBSC). PBSC were measured by the colony forming unit granulocyte-macrophage (CFU-GM) and burst forming unit erythroid (BFU-E) in vitro colony assays and CD34 flow cytometric analysis. GM-CSF was administered for 12 days as a single daily s.c. injection at 125 micrograms/M2 (n = 3), 250 micrograms/M2 (n = 3), 375 micrograms/M2 (n = 6) and 500 micrograms/M2 (n = 3). At these doses, sustained serum GM-CSF levels of approximately 100-400 pg/ml were observed for at least six hours. Most (97.2% or 175/180) of the planned GM-CSF doses were administered with no serious adverse effects at any of the dose levels. Three leukapheresis procedures were performed before and then after 8, 10 and 12 doses of s.c. GM-CSF. Compared with basal leukapheresis collections, s.c. GM-CSF mobilized leukapheresis collections yielded greater numbers of total white blood cells ([WBC] 15/15 patients or 100%, p < 0.001) mononuclear cells ([MNC] 8/15 patients or 53%, p = 0.55), CFU-GM (11/15 patients or 73%, p = 0.037), BFU-E (9/15 patients or 60%, p = 0.13) and CD34+ cells (6/15 patients or 40%, p = 0.15). The in vitro CFU-GM were augmented approximately two to tenfold in GM-CSF mobilized collections with no clear dose effects from 125-500/micrograms/M2. However, in vivo engraftment time to absolute neutrophil count (ANC) 500/mm3 correlated strongly with GM-CSF PBSC mobilizing dose (r2 = 0.99). We conclude that s.c. yeast-derived GM-CSF is a simple, effective and tolerable method for mobilization of PBSC.
This is an account of the initial stages in the analysis of Morton, a latency-age boy. Morton is an unusually interesting case for the exploration of fantasy, to which "we must look for the study of early mental phenomena because phantasy is the lingua franca of that period" (Grotstein, 1977, p. 412).
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In a randomized multi-center study, 83 patients with small cell lung cancer were randomly assigned to treatment with cisplatin 100 mg/m2 intravenously (IV) day 1 and etoposide 120 mg/m2 IV days 1, 2, and 3 or cisplatin 100 mg/m2 IV day 1 and etoposide 120 mg/m2 IV day 1 and 240 mg/m2 orally days 2 and 3. Both regimens were repeated every 4 weeks. Prior to randomization, patients were stratified by extent of disease, performance status, and gender. A total of 41 patients were randomly assigned to the parenteral treatment only regimen, and 42 patients received cisplatin and IV/oral etoposide therapy. Both treatment arms were comparable regarding patient characteristics. Limited disease (LD) patients constituted 52% and 49% of the patient population for the oral and IV etoposide regimens, respectively. The overall complete response (CR) and partial response (PR) rate was 50% (95% confidence interval [CI] 35% to 65%) for the oral etoposide regimen and 59% (95% CI 44% to 74%) for the IV etoposide regimen (P = 0.438). For both regimens, 55% of the LD patients achieved either CR or PR. Time to progression and survival were comparable for both treatment arms. Hematologic toxicity was comparable in both treatment arms, with 80% of patients experiencing grade 3 or 4 neutropenia or thrombocytopenia. Moderate to severe anemia and weight loss were more predominant with the IV than with the oral regimen.
Mutants of Actinobacillus pleuropneumoniae strain HK 361 (serotype 2) were isolated which were deficient in type II (Ca2(+)-dependent) haemolysin activity (Hly-). Some of the Hly- mutants secreted a potent, heat-labile extracellular cytotoxic activity against porcine alveolar macrophages. Comparison of cell-free culture supernatant from the parent strain and some Hly- mutants by SDS-PAGE and immunoblotting revealed the loss of a major extracellular polypeptide of 109 kDa. Two Hly- mutants which in addition failed to secrete a 120 kDa polypeptide produced no extracellular cytotoxic activity, suggesting that the 120 kDa protein was the cytotoxin. Antiserum raised to the culture supernatant from a Hly- mutant lacking the 109 kDa polypeptide recognized the 120 kDa band, but not the 109 kDa band, in immunoblots and neutralized the cytotoxic activity, but not the haemolytic activity, of A. pleuropneumoniae. The 120 kDa polypeptide and extracellular cytotoxic activity were widespread among A. pleuropneumoniae strains, but absent from related bacterial pathogens of the pig: Actinobacillus suis, Haemophilus parasuis and Pasteurella multocida. A clear correlation was found between the presence of the 120 kDa polypeptide and cytotoxic activity in culture supernatants. The cytotoxic activity of all the strains tested was neutralized by antibody to the Hly- extracellular material and by convalescent pig serum. It is proposed that the 120 kDa polypeptide represents the cytotoxin of A. pleuropneumoniae, that it is distinct from the haemolysin, and that it be termed pleurotoxin.
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Forty patients with locally extensive or metastatic squamous cell carcinoma of the esophagus were registered onto a phase II trial employing cisplatin, vinblastine, and mitoguazone. Of 36 eligible patients, four (11%) had partial responses. None had received prior chemotherapy or radiation therapy. Toxicity was mild to moderate and consisted mostly of nausea and vomiting. The activity of this regimen at the doses and schedule used was minimal. More aggressive use of therapy should be considered for further trials.
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