Biomedical subjects
Publications and source records attributed to S Gray.
Across Canada, residency programs are attempting to train more physicians to practise in rural and remote areas. The Northern Family Education Program developed in Newfoundland and Labrador is proving that physicians can learn to like life in remote areas.
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We prospectively randomized 51 patients with haematological malignancy requiring platelet concentrates (PCs) to receive either single donor platelet-pheresis products (SD-PC), PCs made from pooled buffy coats (BC-PC) or pooled units of platelets made by the platelet-rich plasma method (PRP-PC). The leucocyte content of each type of PC was 0.33 (0.03-13.5), 5.68 (0.19-99.0) and 365 (65-910) x 10(6); median (range), respectively; P < 0.0001. All red cell transfusions were leucodepleted by filtration. Statistical comparison of the probability of the occurrence of a nonhaemolytic febrile transfusion reaction (NHFTR) following transfusion of PCs in patients in each group showed a significant decrease for the SD-PC and BC-PC groups (0.031 and 0.038, respectively) when compared with PRP-PC (0.171); P = 0.0001. The actual corrected platelet count increments (CCI) at 1-6 and 18-24 h post-transfusion for all three types of PC did not differ significantly. We conclude that transfusion of PRP-PC is associated with a significant increase in NHFTR.
Foreign body (FB) injury from aspiration or ingestion is a common pediatric health problem. Diagnosis relies on clinical judgment plus medical history, physical examination, and radiographic evaluation. A multi-institutional review of 1269 FB events revealed that 85% were correctly diagnosed following a single physician encounter. However, 15% of the children had an elusive diagnosis (>1 week), despite previous evaluation. Delays in diagnosis were seven times more likely to occur in aspirations than in ingestions. Secondary injuries (e.g., pneumonia and atelectasis) occurred in 13% of airway FBs but in only 1.7% of esophageal FBs. Plain radiographs were used in 82% of children, and special studies (e.g., fluoroscopy) in only 7%. We conclude that diagnosis of FB injury in children is frequently achieved at the initial evaluation but that continued surveillance by follow-up visits to health care facilities from parents and other caretakers is important, to reduce pulmonary injuries.
The comparative effects of the complement component C5a on coronary resistance and conductance arteries have not been evaluated. To clarify the coronary contractile actions of this anaphylatoxin, we studied the effects of C5a on development of isometric tension in isolated porcine coronary conductance and resistance arteries. Internal diameters of conductance and resistance vessels were 367 +/- 21 and 88 +/- 4 microns, respectively. Vessel ring segments were suspended in a microvessel myograph, stretched to the peaks of their length-tension curves, and precontracted with 30 mM K+ physiological salt solution. Dose-response curves to C5a (2, 10, and 50 nM) were obtained. At 50 nM, the C5a-induced increase in tension in resistance arteries (4.1 +/- 0.9 to 5.7 +/- 1.4 mN, 35.8 +/- 3.4%) was significantly greater (P < 0.05) than in conductance arteries (10.7 +/- 2.2 to 12.4 +/- 2.6 mN, 15.6 +/- 3.0%). A specific thromboxane A2 receptor antagonist, SQ-29548, virtually eliminated C5a-induced increases in tension. C5a did not impair endothelium-dependent relaxation in either conductance or resistance vessels, as indicated by the half-maximal effective dose (ED50) calculated from bradykinin dose-response curves before and after exposure of the vessels to 50 nM C5a (resistance: pre-C5a ED50 = 2 nM, post-C5a ED50 +/- 3 nM; conductance: pre-C5a ED50 +/- 13 nM, post-C5a ED50 +/- 14 nM). These results indicate that 1) C5a has a greater vasoconstrictive effect on isolated porcine resistance than conductance coronary arteries; 2) C5a-induced coronary constriction is mediated by thromboxane A2; and 3) C5a does not impair endothelium-dependent relaxation of isolated porcine coronary arteries.
A systematic computerized search of all databases was performed to review the scientific evidence in support of the efficacy of cisapride in reducing feeding intolerance in premature infants. Reference lists from these articles were used to identify relevant scientific literature to address important aspects of the use of cisapride. Three open prospective, uncontrolled studies were found. All studies reported improved clinical outcomes as evidenced by decreased gastric residuals, decreased incidence of vomiting, increased feeding volume, decrease in all reflux parameters measured, and increased weight gain. These observational studies reflect the current state of knowledge and have important research and clinical implications because of the profound effects of feeding intolerance on infant growth and development and on length of stay within NICUs.
Transcriptional repression is essential for establishing localized patterns of gene expression during Drosophila embryogenesis. Several mechanisms of repression have been proposed, including competition, quenching and direct repression of the transcription complex. Previous studies suggest that the knirps orphan receptor (kni) may repress transcription via competition, and exclude the binding of the bicoid (bcd) activator to an overlapping site in a target promoter. Here we present evidence that kni can quench, or locally inhibit, upstream activators within a heterologous enhancer in transgenic embryos. The range of kni repression is approximately 50-100 bp, so that neighboring enhancers in a modular promoter are free to interact with the transcription complex (enhancer autonomy). However, kni can also repress the transcription complex when bound in promoter-proximal regions. In this position, kni functions as a dominant repressor and blocks multiple enhancers in a modular promoter. Our studies suggest that short-range repression represents a flexible form of gene regulation, exhibiting enhancer- or promoter-specific effects depending on the location of repressor binding sites.
The early Drosophila embryo provides a unique system for the analysis of transcriptional repression since a broad spectrum of repressors are distributed in spatially distinct patterns. Krüppel (Kr) and snail (sna), two zinc finger repressors, are essential for segmentation and for the establishment of the mesoderm/neuroectoderm boundary, respectively. Both repressors were examined in the context of synthetic gene complexes containing modular promoters and divergently transcribed reporter genes. These studies indicate that Kr and sna function as short-range repressors, which can mediate either quenching or direct repression of the transcription complex, depending on the location of repressor sites. When located within an upstream enhancer, the repressor locally quenches nearby activators and permits other enhancers to interact with the transcription complex (enhancer autonomy). In contrast, when bound to promoter-proximal regions the repressor functions in a dominant fashion and blocks multiple enhancers. Local quenching and dominant repression require close linkage (<100 bp) of the repressor with either upstream activators or the transcription complex. These studies establish short-range repression as a flexible form of gene regulation and suggest that the key distinction among repressors is their range of action.
The best means for optimal delivery of drugs into lungs of infants with bronchopulmonary dysplasia (BPD) is uncertain. We aimed to measure radio-aerosol deposition of salbutamol by jet nebulizer and metered dose inhalers (MDI) in ventilated and non-ventilated BPD infants. In a randomized, crossover sequence, salbutamol lung deposition was measured using an MDI (2 puffs or 200 micrograms) or sidestream jet nebulizer (5 minutes of nebulization with 100 micrograms/kg) in 10 ventilated (mean birthweight, 1,101 g) and 13 non-ventilated (mean birthweight, 1,093 g) prematurely born infants. Non-ventilated infants inhaled aerosol through a face mask, connected to a nebulizer or an MDI and spacer (Aerochamber). Ventilated infants received aerosol from an MDI + MV15 Aerochamber or a nebulizer inserted in the ventilator circuit. Lung deposition by both methods was low: mean (SEM) from the MDI was 0.67 (0.17)% of the actuated dose, and from the nebulizer it was 1.74 (0.21)% and 0.28 (0.04)% of the nebulized and initial reservoir doses, respectively. Corresponding figures for the ventilated infants were 0.98 (0.19)% from the MDI and 0.95 (0.23)% and 0.22 (0.08)% from the nebulizer. In both groups, and for both methods of delivery, there was marked inter-subject variability in lung deposition and a tendency for the aerosol to be distributed to the central lung regions.
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It is becoming increasingly clear that transcriptional repression is at least as important as transcriptional activation for establishing cell-type specific patterns of gene expression during embryogenesis. Recent studies in Drosophila suggest that repressors fall into two categories, short-range and long-range repressors. The former permit enhancer autonomy in modular promoters, whereas the latter function in a dominant fashion to silence multiple enhancers.
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BACKGROUND: A number of different therapies have been used for postherpetic neuralgia. We decided to conduct a systematic review of existing randomized controlled trials. OBJECTIVE: To determine the efficacy of available therapies for relieving the pain of established postherpetic neuralgia. METHODS: We performed a systematic review, including meta-analysis, of existing randomized controlled trials. Eleven published trials and one unpublished trial were identified which met the inclusion criteria and were included in the current review. RESULTS: Pooled analysis of the effect of tricyclic antidepressants demonstrate statistically significant pain relief (OR 0.15, CI 0.08-0.27). Pooling of the results of the three trials comparing the effects of capsaicin and placebo could not be done due to heterogeneity. This heterogeneity was mainly attributable to an unpublished trial which differed in terms of the dose and duration of treatment. When this study was omitted, no heterogeneity was found and the pooled analysis revealed a statistically significant benefit (OR 0.29, 95% CI 0.16-0.54). However, problems with blinding in patients using capsaicin may have accounted for the positive effect. One small study of vincristine iontophoresis compared to placebo also yielded a favourable result (OR 0.05, 95% CI 0.01-0.26). Other treatment evaluated include lorazepam, acyclovir, topical benzydamine, and acupuncture. We found no evidence that these are effective in relieving pain associated with postherpetic neuralgia. CONCLUSION: Based on evidence from randomized trials, tricyclic anti-depressants appear to be the only agents of proven benefit for established postherpetic neuralgia.
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BACKGROUND: Patients with HIV infection frequently experience disease or treatment-related myelosuppression leading to neutropenia. Neutropenia often leads to dose-reduction or discontinuation of important myelosuppressive therapy. OBJECTIVE: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. DESIGN: Open-label, non-comparative, multicentre study in 200 HIV-positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0 x 10(9)/l]. Filgrastim was started at 1 microgram/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 micrograms on 1-7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2-5 x 10(9)/l. RESULTS: Filgrastim reversed neutropenia in 98% of patients (ANC > or = 2 x 10(9)/l), with a median time to reversal of 2 days (range 1-16) and a median dose of 1 microgram/kg/day (range 0.5-10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of < or = 300 micrograms/day (< or = 1 vial/day). Normal ANCs were then maintained with a median of 1 microgram/kg/day (range 0.22-10.6) during the treatment phase and 3 x 300 micrograms vials/week (range 1-7) during the maintenance phase. Ganciclovir, zidovudine, co-trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose-levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV-1 p24 antigen levels. CONCLUSION: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life-threatening complications of neutropenia.
Forty-eight astrocytic tumours were stained immunohistochemically with antibodies to the cell cycle-regulating protein, cyclin D1, and to the proliferation marker MIB1 (Ki-67) using formalin fixed paraffin embedded tissue and a microwave antigen retrieval system. Cases were classified by the WHO system (1993). The labelling indices (LI) for both antibodies were compared with each other and with the tumour type. The mean labelling indices for both antibodies increased with the degree of malignancy, and a significant difference was seen between the pilocytic astrocytoma and diffuse astrocytoma together vs anaplastic astrocytoma and glioblastoma together. However, within each tumour type there was considerable variation in the labelling indices and a clear cut off value could not be demonstrated. There was a strong positive correlation between labelling indices for cyclin D1 and MIB1 in diffuse astrocytoma, but this correlation broke down increasingly in anaplastic astrocytoma and glioblastoma. There was poor correlation between cyclin D1 and MIB1 in pilocytic astrocytoma, a feature which appeared to separate them from the diffuse astrocytoma. Average labelling indices for cyclin D1 were higher than those of MIB1, which suggests that cyclin D1 positive cells represent a pool of cells from which proliferation and hence MIB1 expression can take place. In conclusion, cyclin D1 is overexpressed in astrocytic tumours, more so with increasing grade of malignancy and in a way which approximately correlates with MIB1 expression.
The currently used serological subtyping scheme for the pathogen Neisseria meningitidis is not comprehensive, a proportion of isolates are reported as not subtypeable (NST), and few isolates are fully characterized with two subtypes for each strain. To establish the reasons for this and to assess the effectiveness of DNA-based subtyping schemes, dot blot hybridization and nucleotide sequence analyses were used to characterize the genes encoding antigenic variants of the meningococcal subtyping antigen, the PorA protein. A total of 233 strains, including 174 serologically NST and 59 partially or completely subtyped meningococcal strains, were surveyed. The NST isolates were chosen to be temporally and geographically representative of NST strains, isolated in England and Wales, and submitted to the Meningococcal Reference Unit in the period 1989 to 1991. The DNA-based analyses demonstrated that all of the strains examined possessed a porA gene. Some of these strains were serologically NST because of a lack of monoclonal antibodies against certain PorA epitopes; in other cases, strains expressed minor variants of known PorA epitopes that did not react with monoclonal antibodies in serological assays. Lack of expression remained a possible explanation for serological typing failure in some cases. These findings have important implications for epidemiological analysis and vaccine design and demonstrate the need for genetic characterization, rather than phenotypic characterization using monoclonal antibodies, for the identification of meningococcal strains.
In order to determine the cellular distribution of androgen receptors (AR) in normal liver and to examine whether phenotypic changes occur in a variety of non-neoplastic liver diseases, cryostat sections of explanted livers removed from 52 consecutive patients undergoing orthotopic transplantation were immunostained using an anti-androgen receptor monoclonal antibody. In histologically normal liver, AR was immunolocalised to the nuclei of hepatocytes. The proportion of positive hepatocytes varied from about 50% to greater than 90%. Staining, of variable intensity, was restricted to parenchymal cells with no evidence of zonal heterogeneity with respect to labelling intensity. In tissue from patients with biliary cirrhoses and in some cases of alcoholic cirrhosis, labelling for AR was observed in areas of ductular metaplasia but not in areas of "typical" ductular reaction (ductular proliferation). Otherwise, no consistent abnormalities in immunolabelling were seen in any of the diseased livers.