Biomedical subjects
Publications and source records attributed to G Cook.
Significant progress has been made recently in understanding axon guidance to and from choice points. Netrins have been shown to function as conserved midline chemoattractants in vertebrates and insects, and receptors for netrins and semaphorins/collapsins have been identified. More evidence has accumulated that repulsion plays a key role in guidance, including the involvement of the ephrin/Eph receptor system in contact repulsion.
This paper focuses on emerging British health policy which emphasizes the use of locally determined restrictive criteria to assess access to state provision for long-term health care and the individual's responsibility to plan to meet their own long-term health care needs. Inconsistency in current health policy and ambiguity in the relevant central guidance are explored. This is contextualized in a philosophical framework which seeks to highlight the moral justification underpinning different patterns for the distribution of health care. These issues are of direct relevance to nurse managers because these fundamental changes surface in dilemmas in the management of care and interaction in the multidisciplinary team.
The aarE1 allele was identified on the basis of the resulting phenotype of increased aminoglycoside resistance. The aarE1 mutation also resulted in a small-colony phenotype and decreased levels of aac(2')-Ia mRNA. The deduced AarE gene product displayed 61% amino acid identity to the Escherichia coli UbiA protein, an octaprenyltransferase required for the second step of ubiquinone biosynthesis. Complementation experiments in both Providencia stuartii and E. coli demonstrated that aarE and ubiA are functionally equivalent.
OBJECTIVE: To chart paediatric dental general anaesthesia activity following implementation of the Poswillo Report recommendations and to characterise the relationship between dmft/DMFT and rates of paediatric dental general anaesthesia. DESIGN: An ecological study, using results of the NHS dental epidemiological surveys and routine NHS activity data. SETTING: The general, community and hospital dental services. SUBJECTS: Former regional and district health authorities' residents. OUTCOME MEASURES: Correlations between the regional and district rates of dental general anaesthesia and dmft/DMFT from the NHS dental epidemiology surveys. RESULTS: About half of all paediatric dental general anaesthetics are carried out in the General Dental Service. There were significant correlations between regional mean dmft/DMFT and under 18 combined dental general anaesthesia rates in 1991/2 and 1992/3. In the North West Region there were significant correlations between 0-4-year-old district dental general anaesthesia rates and dmft of 5-year-old children in 1989/90 (r = 0.45, P < 0.05) and 0-17-year-old district dental general anaesthesia rates and 12-year-old DMFT (r = 0.49, P < 0.05) in 1992/3. CONCLUSIONS: The number of paediatric dental general anaesthetics provided since the Poswillo Report was implemented (1991) has increased in the last two years (1993/4 and 1994/5). District rates of dental general anaesthesia bore little relation to dental need as measured by dmft/DMFT, except in 1989/90 for 5-year-old children and in 1992/3 for 12-year-old children. This suggests dental general anaesthesia is not provided in response to dental needs at a district health authority level.
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The effects of using several nicotine replacement treatments on self-reported withdrawal symptoms and side effects during 2-day periods of smoking cessation, with 5 days of ad lib smoking between cessation days, were evaluated. Participants (N = 18) experienced the following conditions: nicotine gum, 24-hr patch, 16-hr patch, 24-hr patch plus gum, double 24-hr patch, and no nicotine replacement. The present study found morning urge to smoke was greater during the 16-hr than during the 24-hr patch condition. Double-patch use resulted in significantly greater insomnia than the smoking baseline and 16-hr patch conditions. The no medication and gum alone conditions resulted in similar withdrawal symptoms, and both tended to result in greater reported withdrawal symptoms than the smoking baseline condition. There were no significant withdrawal symptom differences between the 24-hr, patch-gum, and double-patch conditions. The 24-hr and double-patch conditions were preferred by two thirds of the participants (6 each).
We have carried out an analysis of 44 patients undergoing allogeneic PBSC transplants from fully HLA-matched related donors with particular emphasis on engraftment kinetics and the incidence and severity of GVHD. The recipients had a median age of 37 years (range 5-56 years), 16 patients had standard-risk disease and 28 had poor-risk disease. GVHD prophylaxis was with cyclosporin A and methotrexate (n = 41), cyclosporin A alone (n = 2) or cyclosporin A and methyl-prednisolone (n = 1). Stem cells were mobilised using G-CSF, collecting a median of 5.75 x 10(6) CD34+ cells/kg recipient weight (range 0.94-35 x 10(6) CD34+ cells/kg). Engraftment times to a neutrophil count > 0.5 x 10(9)/1 and platelets > 20 x 10(9)/1 were achieved at a median of day +14 (range 10-25) and day +14 (range 9-130) respectively. Patients receiving > or = 4 x 10(6) CD34+ cells/kg had significantly accelerated neutrophil and platelet engraftment and this number of CD34+ cells would appear to be a prerequisite for maximum engraftment using PBSC. Acute GVHD occurred in 25 of 43 evaluable patients although in only 12 was this clinically significant (grades II-IV). Chronic GVHD has occurred in 17 out of 36 evaluable patients, there was no significant difference between the standard- and poor-risk groups in incidence of either acute or chronic GVHD. In conclusion, these results confirm the feasibility of using PBSC for allogeneic transplantation without evidence for increased risk of either acute or chronic GVHD and provide further evidence supporting the potential of PBSC to replace bone marrow as the major source of haemopoietic cells for allogeneic transplantation.
The neoplastic plasma cells of multiple myeloma differ from normal plasma cells and other B-cell malignancies by an almost exclusive homing to the bone marrow microenvironment which clearly provides the appropriate support, both physical and cytokine, to mediate clonal proliferation and terminal differentiation. Cellular adhesion molecules are involved in the homing of malignant plasma cells to the bone marrow, the production of growth factors and the recirculation of these tumour cells in the advanced stages of disease. Neoplastic plasma cells express H-CAM (CD44), VLA-4 (CD49d/CD29), ICAM-1 (CD54), N-CAM (CD56) and LFA-3 (CD58). In addition VLA-5 (CD49e/CD29) expression seems to be related to cells with less proliferative potential and more potential for paraprotein production. In addition there are fundamental changes in the bone marrow stroma of patients with multiple myeloma including altered composition of the extracellular matrix, increased growth capability of the cellular elements and increased synthesis of interleukin-6 and interleukin-3, which are features postulated to localise and promote growth of the circulating neoplastic progenitors in the bone marrow. However, the evidence to date does not fully explain the inter-relationship of the clonal B cells and the bone marrow stroma in patients with myeloma, including factors which trigger and facilitate the extravasation and recirculation of neoplastic plasma cells as seen in advanced disease.
OBJECTIVES: To determine the i.v. pharmacokinetics of cisapride and measure systemic absorption after rectal administration. ANIMALS: 5 healthy adult mares (380 to 610 kg). PROCEDURE: Cisapride was administered, i.v., at a dosage of 0.1 mg/kg of body weight. In the same horses, after a 1-week washout period, cisapride was administered rectally at a dosage of 1 mg/kg by mixing crushed tablets with propylene glycol and administering the mixture into the rectum. After each drug administration, a series of blood samples were collected. Plasma was obtained and analyzed by high-performance liquid chromatography to determine cisapride concentration profiles after each drug administration. RESULTS: After i.v. administration, peak plasma concentration was 221.4 ng/ml and harmonic mean half-life was 1.9 hours. Rectal absorption of cisapride was negligible. Cisapride was detected in plasma from only 3 of 5 horses for which mean systemic availability was 1.23%. Mean maximal plasma concentration after rectal administration of cisapride was 13.5 ng/ml. CONCLUSION AND CLINICAL RELEVANCE: After i.v. administration of cisapride, plasma concentration is high for approximately 2 hours. Cisapride mixed with propylene glycol and administered rectally at a dosage of 1 mg/kg is poorly and incompletely absorbed. Thus, cisapride is not clinically useful for rectal administration in horses.
Difficulties associated with current intensive induction regimens for multiple myeloma and uncertainty as to how to achieve optimal peripheral blood progenitor cell mobilisation (PBPC) prompted this study of an oral induction regimen, Z-Dex (oral idarubicin and dexamethasone) followed by PBPC mobilisation using four different regimens. Thirty-patients received Z-Dex (median age 56 years, range 46-66 years) including 24 patients with previously untreated disease. The overall response rate was 75% with a CR rate of 16.7% and PR rate of 75.7% in patients with previously untreated disease. We compared four mobilisation regimens: low-dose (LD) cyclophosphamide, high-dose (HD) cyclophosphamide, cis-platin/VP16 and cis-platin, Ara-C and dexamethasone (DHAP). Failure to mobilise optimal numbers of PBPCs (>1.0 x 10(6) CD34+ cells/kg and >20 x 10(4) CFU-GM/kg) was seen in two patients who received LD cyclophosphamide, in two patients who received HD cyclophosphamide and three patients who received cis-platin/VP16. No patient failed to mobilise adequate numbers of PBPCs following DHAP. In previously untreated patients, DHAP mobilised significantly more PBPC than LD cyclophosphamide (P=0.02), HD cyclophosphamide (P=0.0015) and cis-platin/VP16 (P=0.021). This study demonstrates the efficacy of Z-Dex in inducing tumour responses in patients with multiple myeloma without limiting PBPC mobilisation in subsequent dose-intensive schedules. Furthermore, we also demonstrate that DHAP is superior to cyclophosphamide (low- and high-dose) and cis-platin/VP16 in mobilising PBPCs and demonstrated a degree of tumour control.
We have estimated the synthesis rates in vivo of precursor and brush-border (BB) polypeptides of lactase phlorhizin hydrolase (LPH) in newborn pigs fed with water or colostrum for 24h post partum. At the end of the feeding period, piglets were anaesthetized and infused intravenously for 3h with L-[4-3H]- phenylalanine. Blood and jejunal samples were collected at timed intervals. The precursor and BB forms of LPH were isolated from jejunal mucosa by immunoprecipitation followed by SDS/PAGE, and their specific radioactivity in Phe determined. The kinetics of precursor and BB LPH labelling were analysed by using a linear compartmental model. Immunoisolated LPH protein consisted of five polypeptides [high-mannose LPH precursor (proLPHh), complex glycosylated LPH precursor (proLPHe), intermediate complex glycosylated LPH precursor (proLPH1i) and two forms of BB LPH]. The fractional synthesis rate (Ks) of proLPHh and proLPHc (approx. 5%/min) were the same in the two groups but the absolute synthesis rate (in arbitrary units, min-1) of proLPHh in the colostrum-fed animals was twice that of the water-fed animals. The Ks values of proLPHi polypeptides were significantly different (water-fed, 3.89%/min; colostrum-fed, 1.6%/min), but the absolute synthesis rates did not differ. The Ks of BB LPH was not different between experimental treatment groups (on average 0.037%/min). However, the proportion of newly synthesized proLPHh processed to BB LPH was 48% lower in colostrum-fed than in water-fed animals. We conclude that in neonatal pigs, the ingestion of colostrum stimulates the synthesis of proLPHh but, at least temporarily, disrupts the processing of proLPH polypeptides to the BB enzyme.
The biology of normal plasma cells and the pathophysiology of human multiple myeloma remain poorly understood. Functional assays are scarce and at present cell phenotyping is providing the most information about how human plasma cells may behave. Three different types of human plasma cells: normal, fresh neoplastic myeloma cells and plasma cell lines, have been studied for their reactivity with antibodies to the beta-1 integrins (Very Late Antigens; VLAs), including a panel obtained from the Vth International Workshop on Leucocyte Differentiation Antigens. Most plasma cell targets express VLA-4 (CD49d positive) and the common beta chain recognized by CD29. CD49e (VLA-5) was occasionally positive. Other VLAs were not usually expressed. These data suggest the wide use by plasma cells of VLA-4, possibly as a ligand with fibronectin and high endothelial venules (HEV). Of other adhesion structures expressed by plasma cells, only CD44 is seen as frequently, and this is also a HEV ligand.
We designed an oral equivalent regime to mimic VAD and its hybrids, using idarubicin and dexamethasone (Z-Dex) given in four cycles to induce cytoreduction prior to dose intensification in multiple myeloma cases. 20 patients (de novo n = 15, replaced VAD n = 2, relapsed n = 2, and resistant n = 1), 13 males and seven females with a median age of 54 years (range 40-65 years) received Z-Dex therapy. The overall response rate was 70% (14/20), with one patient (5%) achieving complete remission (CR). The response rate for previously untreated patients was 80% (12/15), with a CR rate of 6.7% (1/15). Both patients who received Z-Dex in place of VAD continued to respond. Myelosuppression was seen in 14/20 patients (70%); 4/20 (20%) developing severe neutropenia with one death from neutropenic sepsis. Gastrointestinal toxicity and alopecia were infrequently reported. Satisfactory responses can be obtained using an oral regime equivalent to VAD with tolerable toxicity and morbidity.
Transplantation of peripheral blood progenitor cells (PBPCs) has largely replaced autologous bone marrow transplantation. The same might occur in the allogeneic setting if the favourable initial experience with allogeneic PBPCT is confirmed. We analysed all primary transplants utilizing unmodified PBPC from HLA-identical sibling donors reported to the European Group for Blood and Marrow Transplantation (EBMT) for 1994. 59 patients with a median age of 39 years received myeloablative therapy for acute myelogenous leukaemia (23 patients, acute lymphoblastic leukaemia (13), chronic myelogenous leukaemia (nine), lymphoma (seven), or other diagnoses (seven) mostly of advanced stages followed by transplantation of allogeneic PBPC. Three patients died soon after grafting, the others showed prompt haemopoietic recovery with median times to recover an absolute neutrophil count (ANC) above 0.5 and 1.0 x 10(9)/I of 15 (range 9-27) and 17d (range 10-28) respectively. Time to platelet recovery above 20 or 50 x 10(9)/I was 16 (range 9-76) and 18d (range 12-100) respectively. 27 patients (46%) developed no or mild acute graft-versus-host disease (GVIID). The incidence of moderate (grade II) disease was 27%; 24% of the patients developed severe acute GVHD (grades III or IV), 55% of patients who were alive 90d after transplantation developed chronic GVHD, the probability to develop extensive chronic GVHD was 32% (95% confidence interval 22-42) with a median follow-up of 14 months. Overall and event-free survival (EFS) at 1 year were 54% (CI 48-60) and 50% (CI 43-57), respectively, the relapse incidence was 23% (CI 17-29). EFS was 67% (CI 55-79) in patients transplanted for acute leukaemias in first complete remission, chronic myelogenous leukaemia in first chronic phase, or severe aplastic anaemia. Transplantation of allogeneic PBPC resulted in prompt and durable engraftment. The incidence and severity of acute and chronic GVHD seemed comparable to that observed after allogeneic BMT. Overall and event-free survival in this cohort of patients, most of whom suffered from advanced leukaemia or lymphoma, is encouraging, suggesting that the high numbers of T lymphocytes and/or natural killer cells contained in a typical PBPC collection product exert a vigorous graft-versus-leukaemia effect. Further evaluation of allogeneic PBPCT is highly desirable.
BACKGROUND: A national target for coronary artery bypass graft (CABG) operations of 300 per million population was established by the Department of Health in 1987. Regional Health Authorities were required in 1993-1994 to achieve this target. The 1990-1991 Regional all-ages CABG rate was 239 per million population. The North Western Region planned to devolve the purchasing of certain services, including cardiac surgery, to districts in April 1993. Three districts had provider units within their boundaries. No means existed for estimating the appropriate operation rate, according to need, for district populations. A method was therefore devised for calculating guideline targets. METHODS: Based on the assumption that the ischaemic heart disease standardized mortality ratio (IHD SMR) is a valid proxy of the need for CABG operations and using a linear regression model, the existing district IHD SMRs and IHD hospitalization rates were used to derive guideline targets for districts, taking account of the need to raise the average operation rate for the Region to 300 per million population. Further targets using alternative Poisson regression model and weighting formulae were also derived. RESULTS: The derived operation targets based on the linear regression model were lower than the existing operation rate in the three provider districts and in the biggest provider's two neighbours. In all other districts, except one, targets were higher than the existing number of operations. The two further analyses produced essentially similar results. CONCLUSIONS: In the North Western Region wide variations in CABG operation rates existed. Access to CABG surgery in the North Western Region appears to depend on proximity to the provider districts. Operation rates should reflect need. This paper presents a method for deriving targets which take account of need.
This article concentrates on the imaging of intracranial structures and outlines some basic imaging strategies for common clinical presentations.
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Microleakage of Class V composite resin restorations with margins all in enamel were compared in this in-vitro study using Scotchbond MultiPurpose Adhesive (SMP) (3M Corp.), and Scotchbond II (SB II) (3M Corp). Twenty extracted human molars were randomly separated into two groups: Group One, which used the SMP system and Group Two, which used the SB II system. Circular Class V preparations were cut 1.8 mm deep and 3 mm in diameter using a #556 fissure bur. Cavosurface margins, all in enamel, were beveled. The enamel and dentin were treated following manufacturer's directions for each group, and a microfilled composite resin, Silux Plus (3M Corp), was applied in two hand-placed increments. All teeth were finished with Sof-Lex discs, stored in water for seven days, then thermocycled in a water bath for 100 cycles, alternating from 4 degrees C to 58 degrees C. The teeth were placed in a 5 percent solution of methylene blue, rinsed and then invested in resin. All teeth were sectioned vertically and horizontally and a ratio (percentage) of wall length to amount of leakage along each wall was established. The overall mean leakage of Group One was 15.27 percent and Group Two was 13.84 percent. Looking at individual walls, the mean occlusal wall leakage of Group One was 28.41 percent and Group Two was 12.45 percent. Mean gingival wall leakage of Group One was 15.96 percent and Group Two was 21.80 percent. Comparing the two groups, using a student's t test, there was no significant difference between the overall mean leakage or between the gingival wall leakage (p > 0.05); however, there was a significant difference between the occlusal wall leakage (p < 0.05), with SMP exhibiting more leakage.