Biomedical subjects
Publications and source records attributed to G Wright.
In rheumatology practice and applied research, there are numerous psychologic issues that merit special attention, including depression, helplessness, self-efficacy, and coping. A wide variety of measures are available for addressing these issues. The tests themselves must meet the psychometric criteria of reliability and validity. Psychologic tests must be administered under standardized conditions.
This paper explores the potential for open learning to address the problem of training 60,000 ward managers in the UK. It describes the identification of the content, the production of material, the various models of implementation, and an evaluation conducted at national level.
PURPOSE: This retrospective, descriptive study was designed to determine the effectiveness of using clomiphene citrate in relatively high daily doses (100, 150, and 200 mg) with simplified monitoring for in vitro fertilization in a private office and surgical center. The self-selected study population comprised 109 women who were 25-42 years old, including 26 women whose husbands had mild male-factor infertility. RESULTS: During January 1992 through December 1993, 165 stimulation cycles resulted in 137 egg retrievals, 24 clinical pregnancies (17.5%), and 20 viable pregnancies (14.5%). Cycles that could not be completed (28/165 or 16.9% of all cycles) involved luteinizing hormone surges, insufficient follicles, or low estradiol levels. There were no pregnancies in patients who were 40 years or older or who received 200 mg daily doses of clomiphene citrate. The viable pregnancy rate among patients with male factor infertility was 7.7% (2/26). For non-male-factor infertility patients who were younger than 40, the viable pregnancy rate was 17.6% (18/102). CONCLUSION: The simplified monitoring method did not appear to compromise the results.
Reasons for fluctuations in the popularity of pulsatile cardiopulmonary bypass are discussed. The advantages of pulsatile flow have previously been stated in terms of physiologic parameters. This has produced a weak theoretic framework that has led to serious misunderstandings of the fundamental mechanical properties of pulsatile flow. Failure to consider these properties in the past may have allowed modified roller pumps to be accepted as "pulsatile," even though their pulsatile power outputs are small compared with those of the human heart. A fresh approach is required in which pulsatile blood flow is analyzed in terms of hemodynamic power and impedance parameters.
Older patients and those who consistently return for embryo transfer but without implantation were studied to see if a combination of day 3 assisted hatching and co-culture (AH+CC) might be beneficial compared to assisted hatching alone (AH-alone). Female patients of > or = 38 years and couples who had previously failed to implant embryos three times or more were prospectively and randomly assigned to either an experimental or a control group. In the experimental group all embryos were co-cultured on partial monolayers of bovine oviductal epithelial cells for 2 days followed by assisted hatching by zona drilling (AH+CC). All control embryos were cultured by standard procedures until day 3 when they also underwent zona drilling prior to uterine transfer (AH-alone). With 50 cycles in each group there was unfortunately a marginal bias against the AH+CC group in that these patients had undergone a higher number of previous transfer cycles. There was a marginally lower percentage of fragmentation and a significantly higher degree of zona thickness variability in the AH+CC embryo group. Embryonic implantation was significantly increased (P < 0.05) in the AH+CC group (18%) when compared to the AH-alone group (10%). This difference was reflected in a significantly higher (P < 0.05) initial pregnancy rate (52 versus 32%) in the AH+CC group, and a higher (not significant) viable pregnancy rate (38 versus 22%).
We separated the K(+)-induced contraction of rat aortic rings into its initial (fast) and secondary (slow) components. It was found that temperature sensitivity, K+ depolarization, and Ca2+ dependency could each be utilized to differentiate between these two components of the contractile response. Increasing the passive tension preload of the tissue increased the fast response but had no significant effect on the secondary slow rise in tension. Cytochalasins, which inhibit actin polymerization, reversibly inhibited tension development by rat aortic rings with the effect selectively confined to the slow component of the K(+)-induced contraction. In a similar fashion, cytochalasin was shown to attenuate the slow tension increase caused by phorbol 12,13-dibutyrate. Finally, it was found that low concentrations of the protein kinase C (PKC) inhibitor staurosporine (8 x 10(-9) M) selectively attenuated the slow component of the K(+)-induced contraction. The results suggest that distinctly different mechanisms regulate the initial fast and secondary slow contractile responses induced by elevation of extracellular K+. Both mechanisms are voltage sensitive and use extracellular Ca2+. The fast but not the slow component was altered by changing the passive tension preload in a fashion consistent with a sliding filament mechanism of force development. The specific nature of the slow component is not certain but may involve low-level PKC activity and require the integrity and capability for remodeling of a specific portion of the actin-containing cytoskeleton.
In a study to assess the potential effect of nonpulsatile hypothermic cardiopulmonary bypass (CPB), intramucosal pH (pHi) of the gastric and colonic mucosae was determined by tonometry (n = 8). During the hypothermic phase of CPB, gastric and colonic pHi did not change significantly. Forty minutes after the start of rewarming, despite increases in the cardiac index and mean arterial blood pressure, gastric pHi fell from 7.53 +/- 0.02 to 7.31 +/- 0.03 (p = 0.017) and colonic pHi fell from 7.50 +/- 0.02 to 7.32 +/- 0.03 (p = 0.028). Forty minutes after the end of CPB both the colonic (p = 0.017) and gastric (p = 0.046) pHi remained depressed below pre-CPB values. The difference in the arterial (pHa) and the gastric mucosal pH changed from -0.097 before CPB to 0.016, 40 minutes after the end of CPB (p = 0.027). This alteration in the pHa-pHi underlines the importance of measuring intramucosal pH by tonometry, since the pHa and pHi may move in opposite directions during episodes of haemodynamic stress. Both the gastric and colonic pHi were found to have a linear correlation with the pHa, although changes in the gastric pHi (r = 0.41, p = 0.018) were more strongly correlated with the pHa than the colonic pHi (r = 0.23, p = 0.19) in the rewarming phase of CPB and the immediate post-CPB period when there was a tendency towards intramucosal acidosis. The development of intramucosal acidosis in the rewarming and immediate post-CPB phases following hypothermic nonpulsatile CPB may impair the gut barrier and predispose patients to the absorption of luminal toxins.
1. Sodium monofluoroacetate (1080), a vertebrate pesticide widely used in New Zealand, was administered orally to sheep and goats at a dose level of 0.1 mg kg-1 body weight to assess risk to humans of secondary poisoning from meat. Blood, muscle, liver, and kidney were analysed for 1080 residues. 2. The plasma elimination half-life was 10.8 h in sheep and 5.4 h in goats. Concentrations of 1080 in muscle (0.042 microgram g-1), kidney (0.057 microgram g-1), and liver (0.021 microgram g-1) were substantially lower than those in plasma (0.098 microgram ml-1) at 2.5 h after dosing. 3. Only traces of 1080 (< 0.002 to 0.008 microgram g-1) were found in sheep tissues after 96 hours. 4. Livestock are normally excluded from areas where 1080 is being used for pest control, reducing the risk of secondary poisoning. Even with accidental exposure to a sublethal dose 1080 would not persist in tissues for more than a few days because it is cleared rapidly from the body. Therefore the occurrence of 1080 in meat intended for human consumption is highly unlikely.
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In this prospective, randomized, double-blind, placebo-controlled study, the clinical, biochemical, and hemodynamic effects of xanthine oxidase inhibition in patients undergoing coronary artery bypass grafting were assessed. Allopurinol pretreatment significantly reduced the use of inotropic support after the operation (5 of 25 patients versus 13 of 25 patients, p < 0.01) and increased the rate of peripheral warming (11.4 +/- 0.85 hours versus 14.4 +/- 1 hours, p < 0.02). Twenty patients (9 in the allopurinol group and 11 in the placebo group) underwent invasive hemodynamic monitoring and intraoperative coronary sinus cannulation. The cardiac indexes of both groups were similar before the operation and for the first postoperative hour; thereafter, the cardiac index increased significantly in only the active treatment group (F = 3.33 and df = 5.90, p < 0.004). Products of lipid peroxidation (thiobarbituric acid reactive substances) increased significantly in only the placebo group, with increases being evident both in the systemic circulation (9.5 +/- 3.2 nmol/gm albumin, p < 0.007, and 24 +/- 5 nmol/gm albumin, p < 0.001, at 30 seconds and 2 minutes of reperfusion, respectively) and the coronary sinus (19.4 +/- 5.8 nmol/gm albumin, p < 0.004, and 28 +/- 4 nmol/gm albumin, p < 0.001, at 2 and 5 minutes of reperfusion, respectively. No significant difference was evident between the groups with respect to cardiac enzyme or vitamin E release. It is proposed that xanthine oxidase inhibition exerts its beneficial effects by reducing the level of free radical activity associated with reperfusion during coronary artery bypass grafting.
Both bacteriophage T4 and human type I DNA ligases in the presence of a mixture of ATP, AMP and PPi altered the topological properties of a supercoiled substrate by a step-wise reaction eventually leading to a population of fully relaxed, covalently closed products. In the presence of only AMP and PPi DNA products containing nicks with 3'OH/5'P termini accumulated in the presence of bacteriophage T4 DNA ligase, suggesting reversal of the entire joining reaction, but not in the presence of human DNA ligase I. Both DNA ligases became deoxyadenylylated in the presence of dATP, but the joining reaction did not proceed to completion. However, with both enzymes the full relaxing reaction took place in the presence of dAMP alone and in the presence of a mixture of dATP, dAMP and PPi. In no case could the joining reaction be reversed by dAMP and PPi. Related experiments with modified derivatives of deoxyribonucleoside 5'-triphosphates and PPi gave results in accord with these observations. The AMP dependent DNA relaxation catalysed by DNA ligases was insensitive to the presence of exonuclease III. These results indicate that controlled relaxation of the substrate by both DNA ligases occurs as a separate reaction rather than by simple reversal of the joining reaction. These findings support the hypothesis that in vivo the DNA topoisomerising ligases relax their substrate at the replication fork both during and separately from ligation of a pre-existing nick.
Insulin-like growth factor (IGF)-binding protein 1 (IGFBP-1) contains an Arg-Gly-Asp (RGD) integrin recognition sequence. In vitro mutagenesis was used to alter this RGD sequence to Trp-Gly-Asp (WGD). Migration of Chinese hamster ovary (CHO) cells expressing the wild-type protein was more than 3-fold greater in 48 hr compared with cells expressing the WGD mutant form of IGFBP-1. Similarly, wild-type IGFBP-1 added to the media of control CHO cells stimulated migration 2-fold compared with the WGD protein. A synthetic RGD-containing peptide, when added to the medium with wild-type IGFBP-1, blocked the effect of IGFBP-1 on cell migration. The addition of IGF-I to the culture medium had no effect on the migration of cells expressing IGFBP-1 or vector alone. Affinity chromatography of 125I-labeled CHO cell membrane proteins, using IGFBP-1 coupled to agarose, identified the alpha 5 beta 1 integrin (fibronectin receptor) as the only cell surface molecule capable of binding IGFBP-1 in an RGD-dependent manner. Furthermore, wild-type IGFBP-1, but not the WGD mutant form, could be coprecipitated from CHO cells with an antibody directed against the alpha 5 integrin subunit. These studies demonstrate that IGFBP-1 stimulates CHO cell migration and binds to the alpha 5 beta 1 integrin receptor, both by an RGD-dependent mechanism. The effect of IGFBP-1 on migration is independent of IGF-I and is probably mediated through the alpha 5 beta 1 integrin.
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OBJECTIVES: To document the number of children aged less than 15 years who developed diabetes and were managed within one large health district, and to evaluate the outcome of those children managed without hospital admission at diagnosis. DESIGN: A retrospective study over 1979-88, when a paediatrician and a physician with special interests in childhood diabetes initiated joint clinics. Data collected from the district diabetes register and files of consultants and health visitors specialising in diabetes. SETTING: Referral of children to consultants in Leicestershire (total population 863,000). MAIN OUTCOME MEASURES: The proportion of children managed without hospital admission, comparison of readmission rates and glycated haemoglobin concentrations between children admitted and those not admitted. RESULTS: Over 10 years 236 children aged 10-14 years developed diabetes (annual incidence rate 12.8/100,000 child population (95% confidence interval 11.3 to 14.7)). In total 138 were not admitted to hospital but received supervised management based at home. Admitted children were younger or acidotic or their family doctors did not contact the diabetes team. Duration of admission declined from seven days in 1979-80 to three days in 1987-8. Ninety two were not admitted to hospital during the 10 years for any reason. Significantly fewer children who received management at home were readmitted for reasons related to diabetes than the group treated in hospital (30 (22%) v 40 (41%); p = 0.004). Concentrations of glycated haemoglobin were no different between the two groups. CONCLUSIONS: Children with newly diagnosed diabetes may be safely and effectively managed out of hospital. Domiciliary or community based management depends on the commitment of consultants specialising in diabetes working in close cooperation with general practitioners, specialist nurses in diabetes, and dietitians.
Serine phosphorylation of insulin-like growth factor binding protein-1 (IGFBP-1) has been shown to alter its affinity for the insulin-like growth factors (IGF-I and IGF-II) and to modify its capacity to modulate cellular responses to the IGFs. Because of this, we determined the sites of serine phosphorylation. Purification of 32P-labeled IGFBP-1 was followed by digestion with trypsin and endoproteinase Glu-C and radiosequencing of labeled peptides. Three serines were found to be phosphorylated, with Ser101, Ser119, and Ser169 containing 70%, 5%, and 25% of the incorporated 32P, respectively. A mutated IGFBP-1, substituting alanine for serine at positions 98 and 101, was expressed in CHO cells. On nondenaturing gels, the wild type protein migrated as five isoforms (one non-phosphorylated and four phosphorylated). However, in the mutated protein, the most rapidly migrating band (a phosphorylated form) was not present. The cells containing the mutated cDNA incorporated 60% less 32P into immunoprecipitable IGFBP-1. The mutated protein had a 3-fold reduction in affinity for IGF-I compared to the wild type protein. We conclude that Ser101 represents the major site of phosphorylation containing 63% of the total 32P incorporated and that phosphorylation of Ser101 is important for maintenance of high affinity binding for this growth factor.
Two hundred eighteen consenting patients entered a randomized study of the application of chemical zona pellucida thinning on their day 3 embryos, prior to uterine transfer. Of those control patients (n = 108), whose embryos remained unmanipulated, 40 (37.0%) have ongoing/delivered pregnancies, while in the experimental group (n = 110), whose embryos had their zonae pellucidae chemically thinned, there are 49 patients (44.6%) who have ongoing/delivered pregnancies. Although this difference is not significant, clearly the application of this micromanipulative intervention has not been detrimental, and this bodes well for routine application of embryonic micromanipulation procedures in general. Certain patient subgroups were studied including older women, those with elevated basal follicle stimulating hormone levels, patients with embryos of differing zona thickness, and patients with embryos of differing uniformity of zona thickness. No significant influence of chemical removal of the outside of the zona on the implantation rate of embryos in any of these subgroups was observed other than a marginally significant (P = 0.095) improvement of implantation of embryos with less than 4.0 microns variation in zona thickness when chemical zona thinning was applied. Failure of chemical zona thinning to enhance human embryo implantation significantly, compared to assisted hatching by complete zona drilling, strongly suggests that the bilayered human zona pellucida needs to be fully breached, unlike that of the mouse.
OBJECTIVE: Failure to fertilize eggs in vitro may be countered by micromanipulation of gametes to place selected spermatozoa underneath the zona pellucida of the egg or directly into the egg, thereby improving chances of fertilization and production of viable embryos. Analysis of our clinical data for assisted fertilization was undertaken to assess those factors of relevance in this therapy, and a description of our procedures are given. STUDY DESIGN: Retrospective analysis of 85 cycles (73 couples) of in vitro fertilization and embryo transfer performed at a private infertility clinic, in which micromanipulation for assisted fertilization was used to overcome either severe male factor infertility or idiopathic failure to fertilize, was performed. RESULTS: In 60 cycles where only embryos from under zona insemination were available for uterine transfer, 15 singleton and two twin pregnancies occurred (28.3% viable pregnancy rate per transfer, 14.1% embryonic implantation). In 14 of these cycles embryos arose only after repeated under zona insemination adding more spermatozoa; this accounted for four of the singleton and one of the twin pregnancies (38.5% pregnancy rate, 22.2% embryonic implantation). No embryos arose from partial zona dissection performed in five cycles on sibling eggs. However, in 16 cycles conventional insemination yielded fertilization in six cycles, and mixed transfer of these embryos and sibling embryos from under zona insemination gave rise to one pregnancy from four transfers (pregnancy rate 25%, embryonic implantation 7.1%). Likewise, in nine cycles donor spermatozoa yielded fertilization in eight cycles, and mixed transfer with sibling embryos fertilized by under zona insemination with partner's spermatozoa gave rise to two pregnancies from five transfers (pregnancy rate 40%, embryonic implantation 15.8%). Fertilization and pregnancy rates did not differ whether couples suffered either from male factor infertility or from previous idiopathic fertilization failure. Direct egg injection of a single spermatozoon into 105 eggs gave an 88.6% egg survival and 32.3% fertilization. Mixed transfers with sibling embryos from conventional and under zona insemination yielded one triplet, one twin, and three singleton pregnancies. CONCLUSIONS: Overall, a 24.7% (21/85) viable pregnancy rate per cycle initiated occurred when only embryos from assisted fertilization were available. This strongly indicates that assisted fertilization made a real contribution in cases where either insufficient spermatozoa were available for conventional insemination or in cases where previous fertilization failure had arisen. The wide range of seminal parameters were found to be unhelpful in defining chances of success with assisted fertilization.
We have previously described the generation of transgenic sheep expressing human alpha 1-antitrypsin (h alpha 1AT) in their milk. Here, we report the fidelity of transgene transmission and expression by these animals and their progeny. Transgene transmission has been demonstrated in four of six ovine lines studied. Three of these four lines have exhibited stable transmission of the transgene, whereas the fourth has produced some offspring with reduced copy numbers. Sequential lactations of founder animals has yielded very similar levels of h alpha 1AT protein in milk. Moreover, in one line, derived from a founder male, a flock of seven G1 ewes have yielded comparable levels of h alpha 1AT protein in first and second lactation milk. Two G2 ewes of this line have also produced levels of human protein equivalent to their mother. Although the inheritance of the same transgene in mice was reminiscent of the situation in sheep, stable expression was observed in only one or four lines studied. The importance of these observations to the use of transgenic livestock as bioreactors for the production of human proteins is discussed.