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Biomedical subjects

A Millar

Publications and source records attributed to A Millar.

At least 37 records · Page 2Linked to original sources

Cp50 of propofol with and without nitrous oxide 67%.

The target concentration of propofol required to prevent response to surgical incision was determined in 60 unpremedicated ASA I or II patients, who breathed either oxygen-enriched air or nitrous oxide 67% in oxygen. Propofol was infused using a target-controlled infusion system incorporating the standard 'Diprifusor' pharmacokinetic model, with the target concentration for each patient decided by up/down sequential allocation. Presence or absence of movement in response to a groin incision was determined by the surgeon. The calculated blood concentration at which 50% of patients responded (Cp50calc), determined by probit analysis, was 6.8 micrograms ml-1 for patients who breathed oxygen-enriched air and 4.9 micrograms ml-1 for those who breathed nitrous oxide 67% in oxygen.

Adolescent↗

Drinking and driving: explaining beverage-specific risks.

OBJECTIVE: This study tested whether the association of beer drinking with drinking and driving is due to cultural norms or is an artifact arising from the demographic profile of beer drinkers (young and male), the drinking patterns of this subpopulation (frequent and heavy), and the venues in which they prefer to drink (bars and restaurants). METHOD: Telephone survey data from six U.S. communities were used to establish the demographic characteristics of drinkers, their consumption patterns, beverage preferences, preferred drinking venues and self-reported drinking and driving rates. The survey completion rate was 64.6%. A total sample of 5,231 drinkers was divided into test and validity samples. After deletion of cases with missing data, the test sample included 2,275 drinkers, of whom 985 had driven after drinking. RESULTS: Controlling for a broad set of covariates, the analyses showed that frequent consumers were more likely to drink outside the home, preferred beer and spirits to wine, and were more likely than others to drink and drive. Beverage preferences were not directly associated with drinking and driving. Beer drinkers, however, were from the subpopulation most likely to drink and drive: heavier drinking younger men, who prefer to drink at bars and restaurants. CONCLUSIONS: These results suggest that the association of beer consumption with drinking-driving arises from the circumstances in which the subpopulation of beer drinkers more commonly find themselves (as a result of their efforts to maximize, within economic constraints, the social and amenity value of drinking), as opposed to any culturally induced disposition beer drinkers may have to drink and drive.

Age Factors↗

Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway.

Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in beta-catenin (encoded by CTNNB1) that result in decreased phosphorylation by GSK-3beta and increased signaling through the Tcf/Lef transcription factors. To investigate the relationship between CTNNB1 mutations and underlying pathways of genomic instability, we examined 80 colorectal cancers stratified by the presence or absence of microsatellite instability (MSI). CTNNB1 mutations were identified in 13 (25%) of 53 cancers with high frequency MSI (MSI-H), including 12 point mutations at exon 3 phosphorylation sites (codons 41 and 45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations were identified in 27 microsatellite stable or low frequency MSI (MSI-L) colorectal cancers (P < 0.01). In contrast, CTNNB1 mutations were identified in 3 of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting a more generalized involvement in these tumors. Only six (46%) of the endometrial carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK-3beta, and only one of these was at either codon 41 or 45. All point mutations in MSI-H cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were transversions (P < 0.01). The differences in the mutation profiles suggest that there may be molecular fingerprints of CTNNB1 mutations, determined by biological factors related to both tumor type and underlying pathways of genomic instability.

Adenocarcinoma↗

Intestinal ulceration, obstruction, and haemorrhage in congenital syphilis.

Intestinal obstruction and bleeding are uncommon complications of congenital syphilis (CS). A VDRL-positive infant developed incomplete intestinal obstruction and rectal bleeding. Despite conservative management, his symptoms continued. At laparotomy, terminal ileal inflammation and stenosis were demonstrated. He underwent ileal resection and primary end-to-end anastomosis with resolution of his symptoms. Histopathological examination demonstrated heavy plasmacytic infiltration of the lamina propria and submucosa with ulceration of the mucosa, consistent with syphilitic ileitis. This report documents for the first time bleeding from ileal ulcers associated with intestinal obstruction in CS and highlights an unusual presentation of the disease.

Gastrointestinal Hemorrhage↗

Is an organic/functional distinction psychologically meaningful in patients with dysphonia?

Dysphonia (hoarseness) is a common clinical condition and, if persistent, patients are referred to otolaryngology clinics for clinical examination. During the examination, a clinical distinction is often made among three types of patients: (1) those with a clear organic basis for dysphonia (cancer, vocal cord palsy): (2) those with some degree of organic pathology; and (3) those with an apparently functional etiology. Functional patients are often characterized as having a psychogenic disorder. This study assessed the psychological validity of the functional category in 204 out-patients (aged 17 to 87 years) with persistent hoarseness of types (2) and (3). Following clinical examination, a consultant otolaryngologist categorized patients as having functional or organic etiology. Subjects were then compared on measures of personality and psychological distress. Dysphonic subjects showed marked psychological distress compared with norms, and reported significantly more previous psychosomatic symptoms than norms, but there were no differences in personality or psychological distress between organic and functional subgroups of dysphonics.

Adolescent↗

Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.

Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.

Adaptor Proteins, Signal Transducing↗

A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy.

BB-10010 is a variant of the human form of macrophage inflammatory protein-1alpha (MIP-1alpha), which has been shown in mice to block the entry of hematopoietic stem cells into S-phase and to increase their self-renewal capacity during recovery from cytotoxic damage. Its use may constitute a novel approach for protecting the quality of the stem cell population and its capacity to regenerate after periods of cytotoxic treatment. Thirty patients with locally advanced or metastatic breast cancer were entered into the first randomized, parallel group controlled phase II study. This was designed to evaluate the potential myeloprotective effects of a 7-day regimen of BB-10010 administered to patients receiving six cycles of 5-fluorouracil (5-FU), adriamycin, and cyclophosphamide (FAC) chemotherapy. Patients were randomized, 10 receiving 100 microgram/kg BB-10010, 11 receiving 30 microgram/kg BB-10010, and nine control patients receiving no BB-10010. BB-10010 was well-tolerated in all patients with no severe adverse events related to the drug. Episodes of febrile neutropenia complicated only 4% of the treatment cycles and there was no difference in incidence between the treated and nontreated groups. Studies to assess the generation of progenitor cells in long-term bone marrow cultures were performed immediately preceding chemotherapy and at the end of six dosing cycles in 18 patients. Circulating neutrophils, platelets, CD 34(+) cells, and granulocyte/macrophage colony-forming cell (GM-CFC) levels were determined at serial time points in cycles 1, 3, and 6. The results showed similar hemoglobin and platelet kinetics in all three groups. On completion of the six treatment cycles, the average pretreatment neutrophil levels were reduced from 5.3 to 1.7 x 10(9)/L in the control patients and from 4.3 to 1.9 and 4.5 to 2.5 x 10(9)/L in the 30/100 microgram/kg BB-10010 groups, respectively. Relative to their pretreatment values, 50% of the patients receiving BB-10010 completed the treatment with neutrophil values significantly higher than any of the controls (P = .02). Mobilization of GM-CFC was enhanced by BB-10010 with an additional fivefold increase over that generated by chemotherapy alone, giving a maximal 25-fold increase over pretreatment values. Bone marrow progenitor assays before and after this standard regimen of chemotherapy indicated little long-term cumulative impairment to recovery from chemotherapy. Despite the limited cumulative damage to the bone marrow, which may have minimized the protective value of BB-10010 during this regimen of chemotherapy, better recovery of neutrophils in the later treatment cycles with BB-10010 was indicated in a number of patients.

Adult↗

Clinical effects of human macrophage inflammatory protein-1 alpha MIP-1 alpha (LD78) administration to humans: a phase I study in cancer patients and normal healthy volunteers with the genetically engineered variant, BB-10010.

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) with improved pharmaceutical formulation properties. Although initially described as a pro-inflammatory cytokine, it is now recognised that hMIP-1 alpha has additional effects on haemopoietic stem cell cycling and on human immunodeficiency virus uptake by macrophages. In view of the potential clinical utility of the molecule, we have embarked on a clinical trials programme to evaluate the safety, tolerability and haematological effects of BB-10010. We now report the results of two phase I clinical studies in which 49 subjects (9 patients with advanced breast carcinoma and 40 normal healthy volunteers) received escalating doses of BB-10010, from 0.1 to 300 micrograms/kg using the subcutaneous (s.c.) or intravenous route (i.v.) of administration. Treatment was associated with a dose-related increase in monocyte count which peaked at 200% of steady-state levels and was preceded by an acute, short-lived, monocytopenia, 50-100% of baseline. no measurable effects were noted on other leucocyte subsets or on circulating progenitor cell numbers. In all cases, BB-10010 was extremely well tolerated with no significant toxicity observed at any dose level and a maximum tolerated dose was not defined. Pharmacokinetic analysis revealed that serum concentrations of BB-10010 were detectable using doses of > or = 10 micrograms/kg i.v. or > or = 30 micrograms/kg s.c., and that a single s.c. injection resulted in sustained plasma levels over a 24 h period. These preliminary studies have confirmed the safety and tolerability of BB-10010 using a dose range up to 300 micrograms/kg. Further clinical studies are ongoing to determine the biological effects and to investigate the potential myeloprotective properties using a variable dose range and schedule of BB-10010 in combination with cytotoxic chemotherapy.

Adult↗

Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung.

Human interleukin 13 (IL-13) is a cytokine that has a profound effect on primary immune cells by inducing immunoglobulin production, proliferation of B cells, and the differentiation of cells of the monocytic lineage. IL-13 can inhibit the production of inflammatory cytokines by both macrophages and monocytes. Previously, IL-13 expression has been reported only in cells of the T-cell lineage and the mast cell line HMC-1. We now report the presence of IL-13 mRNA and protein in human alveolar macrophages (AMs) analyzed by the reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunoabsorbent assay (ELISA), respectively, and IL-13 protein in bronchoalveolar lavage fluid (BALF) of subjects with pulmonary fibrosis. We have investigated 13 patients from 49 to 75 yr of age with forms of pulmonary fibrosis, and eight healthy volunteers from 24 to 61 yr of age. Their AMs were obtained by bronchoalveolar lavage (BAL) and purified by adherence. The proportion of BAL purified AMs expressing IL-13 mRNA was increased in those subjects with fibrotic lung disease, in comparison with those from control subjects (11 of 13 versus 2 of 8, P < 0.01). IL-13 protein was detectable in the BALF of 8 of 13 patients with pulmonary fibrosis, but in none of the control subjects. AMs of four subjects with systemic sclerosis were cultured and IL-13 protein was increased in the culture supernatants when compared to the control subjects, although this did not reach significance. These findings show that IL-13 mRNA is not only a product of T cells, but is also expressed in both normal AMs and those from subjects with pulmonary fibrosis, and that at least some of the IL-13 mRNA is translated into protein and secreted in subjects with pulmonary fibrosis. We hypothesize that IL-13 may be expressed by normal human AMs as part of the homeostatic control process but its production may be increased in the presence of inflammatory lung disease.

Adult↗

Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies.

This combined analysis investigated the effect of marimastat, a specific inhibitor of matrix metalloproteinases, on markers of tumor progression measured in patients with advanced cancer. By defining the tolerability and biological activity of the drug, it aimed to establish an appropriate dose range for use in Phase III trials. Patients with advanced, serologically progressive ovarian, prostatic, pancreatic, and colorectal cancer were recruited into six nonrandomized, dose ranging, multicenter clinical trials in North America and Europe. The biological activity of marimastat was assessed by serial measurements of the serum tumor markers carcinoembryonic antigen, CA125, CA19-9, and prostate-specific antigen. Patients were recruited with tumor markers rising by more than 25% averaged over a 4-week screening period. A biological effect was defined as a level of tumor marker at the end of treatment no greater than at study entry; a partial biological effect was defined as a rise in the level of tumor marker over the treatment period of 0-25% per 4 weeks. Pharmacokinetic and safety data were collected and assessed as the studies progressed. All patients were followed up for survival.

Adult↗

Delayed presentation of congenital diaphragmatic hernia.

Patients with congenital diaphragmatic hernias (CDH) usually present soon after birth with respiratory distress. Occasionally presentation is delayed. Twelve patients with delayed presentation (outside the neonatal period) of a total of 91 with CHD were seen over 17 years (1977-1994). Case records were reviewed to identify reasons for late presentation, evidence of morbidity, treatment and outcome. Age at presentation ranged from 6 weeks to 30 months (mean 8 months). Ten patients were aged 6 months or younger and there was an equal number of boys and girls. Seven cases were left-sided, 4 right-sided and 1 was anteriorly placed and bilateral. Ten patients presented acutely, 5 with small-bowel obstruction and 5 with respiratory distress, but all of the latter had a history of previous recurrent chest infection. Diagnosis was confirmed by radiographic examination of the chest in 10, barium meal in 1 and a 5-month-old patient had an inappropriate laparotomy and gastrojejunostomy for duodenal obstruction at an outlying hospital. Two had documented normal chest radiographs 3 and 6 months prior to diagnosis. Patients who presented with gastro-intestinal symptoms were older (mean age 1 year) compared with those with predominantly respiratory symptoms (mean age 19 weeks). None had any evidence of bowel strangulation. All were repaired via an abdominal approach. A hernial sac was found in half the cases (4/7 left and 2/5 right). Five had non-rotation of bowel. Primary repair without patch was carried out in all. One child with lung hypoplasia and multiple cardiac abnormalities died; the others recovered well. Delay in presentation of CDH is not uncommon (14% in this series). Most patients will have respiratory symptoms. A normal previous chest radiograph does not exclude the diagnosis. All patients with recurrent chest infection should have a contrast meal investigation early on. Long-term prognosis is favourable and postoperative morbidity is minimal, despite late presentation.

Child, Preschool↗

Interleukin 10 (IL-10) regulation of tumour necrosis factor alpha (TNF-alpha) from human alveolar macrophages and peripheral blood monocytes.

BACKGROUND: Regulation of the inflammatory response within the human lung is essential to prevent this important part of the normal host defence response becoming a pathological process. Tumour necrosis factor alpha (TNF-alpha) is a cytokine involved in the pathogenesis of shock and in granuloma formation, tissue necrosis, and fibrosis in many organ systems including the lung. Interleukin 10 (IL-10) has been proposed as having an inhibitory effect on the production of several inflammatory cytokines including TNF-alpha. METHODS: The effect of IL-10 administration on TNF-alpha production was explored in human alveolar macrophages and peripheral blood monocytes from matched individuals. The effects of IL-10 on TNF-alpha protein production were determined by sandwich enzyme linked immunosorbant assay (ELISA), whereas the TNF-alpha mRNA response was established by Northeren blotting using a TNF-alpha specific oligonucleotide probe. The protein synthesis inhibitors actinomycin D and cyclohexamide were utilised to monitor IL-10 effects on mRNA degradation and de novo protein synthesis, respectively. RESULTS: The lipopolysaccharide-mediated TNF-alpha production in alveolar macrophages was reduced from 3.508 (0.629) to 2.035 (0.385) ng/ml by 100 U/ml IL-10. Lipopolysaccharide-induced TNF-alpha production in peripheral blood monocytes was reduced from 2.035 (0.284) to 0.698 (0.167) ng/ml. TNF-alpha gene expression was also inhibited in both alveolar macrophages and peripheral blood monocytes; lipopolysaccharide-induced TNF-alpha mRNA was reduced by 47.8 (15.2)% and 83.1 (4.2)%, respectively, by IL-10. The IL-10 mediated suppression of TNF-alpha mRNA was unaffected by addition of cyclohexamide, suggesting that de novo protein synthesis was not required for TNF-alpha inhibition. mRNA stability experiments indicated no acceleration in lipopolysaccharide-induced TNF-alpha mRNA degradation in response to IL-10. CONCLUSIONS: These findings suggest that IL-10 is a potent inhibitor of TNF-alpha expression and release from alveolar macrophages and peripheral blood monocytes, and thus it may have an important role in the cytokine network of the pulmonary immune response.

Adult↗

Risk-adjusted analysis of surgeon performance: a 1-year study.

A 1-year prospective analysis was undertaken of all non-day-case general surgery in a district general hospital. Using the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) scoring system 3004 patients were assessed. From the predictions of mortality and morbidity so obtained, a quality measure, the ratio of observed to expected numbers of deaths and complications (O:E ratio) was determined for each surgeon, both overall and within specialty zones. The present study demonstrates the serious hazard in using 'raw' uncorrected mortality and morbidity statistics to compare surgeon performance. Mortality rates varied from 1.0 to 4.9 per cent whereas O:E ratios ranged from 0.83 to 1.06; morbidity rates varied from 5.3 to 12.6 per cent with O:E ratios 0.86-1.02. Great misunderstanding may result from the publication of surgeon or hospital 'league tables'. The present study demonstrates a technique that might allow surgeon performance to be monitored adequately and accurately.

Day Care, Medical↗