Flashcard health education for British Asians with diabetes.
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Biomedical subjects
Publications and source records attributed to F Smith.
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With the collapse of fisheries in many parts of the world causing widespread economic harm, attention is focused on a possible cause and remedy of fishery collapse. Economic theory for managing a renewable resource, such as a fishery, leads to an ecologically unstable equilibrium as difficult to maintain as balancing a marble on top of a dome. A fishery should be managed for ecological stability instead--in the analogy, as easy to maintain as keeping a marble near the base of a bowl. The goal of ecological stability is achieved if the target stock is above that producing maximum sustainable yield and harvested at less than the maximum sustainable yield. The cost of managing for ecological stability, termed "natural insurance," is low if the fishery is sufficiently productive. This cost is shown to pay for itself over the long term in a variable and uncertain environment. An ecologically stable target stock may be attained either with annually variable quotas following current practice or, preferably, through a market mechanism whereby fish are taxed at dockside if caught when the stock was below target and are untaxed otherwise. In this regulatory environment, the goal of maximizing short-term revenue coincides with the goal of ecological stability, thereby also maximizing long-term revenue. This new approach to fishery management is illustrated with the recently collapsed Newfoundland fishing industry. The Newfoundland cod fishery is expected to rebuild to an ecologically stable level in about 9 years and thereafter support an annual harvest of about 75% of the 1981-1990 average.
Advances in screening technologies allowing the identification of growth factor receptors solely by virtue of DNA or protein sequence comparison call for novel methods to isolate corresponding ligand growth factors. The EPH-like receptor tyrosine kinase (RTK) HEK (human EPH-like kinase) was identified previously as a membrane antigen on the LK63 human pre-B-cell line and overexpression in leukemic specimens and cell lines suggested a role in oncogenesis. We developed a biosensor-based approach using the immobilized HEK receptor exodomain to detect and monitor purification of the HEK ligand. A protein purification protocol, which included HEK affinity chromatography, achieved a 1.8 X 10(6)-fold purification of an approximately 23-kDa protein from human placental conditioned medium. Analysis of specific sHEK (soluble extracellular domain of HEK) ligand interactions in the first and final purification steps suggested a ligand concentration of 40 pM in the source material and a Kd of 2-3 nM. Since the purified ligand was N-terminally blocked, we generated tryptic peptides and N-terminal amino acid sequence analysis of 7 tryptic fragments of the S-pyridylethylated protein unequivocally matched the sequence for AL-1, a recently reported ligand for the related EPH-like RTK REK7 (Winslow, J.W., Moran, P., Valverde, J., Shih, A., Yuan, J.Q., Wong, S.C., Tsai, S.P., Goddard, A., Henzel, W.J., Hefti, F., Beck, K.D., & Caras, I.W. (1995) Neuron 14, 973-981). Our findings demonstrate the application of biosensor technology in ligand purification and show that AL-1, as has been found for other ligands of the EPH-like RTK family, binds more than one receptor.
Mixed-model techniques are applied to incomplete longitudinal data from a double-blind, placebo-controlled, parallel-group, high-dose study of tacrine in patients with Alzheimer's disease. The study consisted of a 30-week double-blind treatment period. Patients were randomized to one of four treatment groups. Dosing was initiated at 40 mg/day and increased in increments of 40 mg/day every 6 weeks until the target dose was achieved. If the study medication was not well tolerated or there were significant elevations in alanine aminotransferase, patients were withdrawn from the study. The use of SAS procedure PROC MIXED for the analysis of incomplete longitudinal data is discussed. This approach is used to evaluate disease progression over time and the effect of incremental dose increases of tacrine on changes on the Alzheimer's Disease Assessment Scale-Cognitive subscale.
Survival analysis techniques using Cox proportional hazards regressions with time-dependent covariates, life table survival plots, and Kaplan-Meier estimates were used to evaluate the effect of long-term tacrine hydrochloride (Cognex) treatment on nursing home placement (NHP) and mortality in patients with Alzheimer's disease. Patients with probable Alzheimer's disease (NINCDS criteria) who were randomized in a 30-week double-blind, placebo-controlled, parallel-group, high-dose study of tacrine (1) were subsequently allowed to receive long-term, open-label treatment during which they could receive doses up to 160 mg/day. Using last tacrine dose, the analyses demonstrated a dose-response relationship where patients on higher tacrine doses were less likely to enter a nursing home or die than patients on lower doses. The Cox proportional hazards regression approach with time-dependent covariates is also compared to logistic regression, which looks only at the crude proportions of patients having the event. Since logistic regression does not allow for the use of time-dependent covariates, it provides somewhat less conservative estimates of the magnitude of the treatment effect.
Prostaglandins and leukotrienes differentially regulate the production of interleukin-1 (IL-1) in monocytes. It was, therefore, decided to investigate the effects of some 5-lipoxygenase inhibitors compared with standard IL-1 synthesis inhibitors on the production of IL-1 by human synovial tissue explants in organ culture. Human synovial (from hip/knee arthroplasty) or porcine tibio-tarsal joint synovial explants were incubated in organ culture in Dulbecco's Modified Eagle's Medium + 5% foetal calf serum in the presence of the test compounds or solvents (controls), or media alone for 1-5 days. Total bioactive IL-1 was assayed in the medium (following serial dilution or with polyethylene glycol 8000 added in some assays to remove inhibitors) using the D-10 T-cell bioassay. Some assays of interleukins 1 alpha, 1 beta, 6 or 8 were performed by ELISA. Of the 5-lipoxygenase inhibitors investigated, MK-886(3-(1-(4-chlorobenzyl)-3-tert-butyl-thio-5-isopropylindol-2- yl)-2,2 -dimethyl propanoic acid), L-656,224 ((7-chloro-2-[4-methoxypenyl]methyl)-3 -methyl-5-propyl-4-benzofuranol), PF-5901 and tepoxalin were the most potent inhibitors of IL-1 production. While the PF-5901 was effective at 5-30 microM and tepoxalin was effective at 1-10 microM, the others were the most potent having minimal inhibitory activity in the range of 0.01-0.1 microM. The presumed IL-1-synthesis inhibitors, tenidap and IX-207,887, were inactive at concentrations of 30-50 microM. Leukotriene B4 (1-100 ng/mL-1) added to MK-886 (5 microM)-treated cultures reversed the inhibitory effects of the latter on IL-1, confirming the role of 5-lipoxygenase products in the regulation of IL-1 production. Addition of polyethylene glycol 8000 to MI-886-treated cultures eliminated the inhibitory effects of this drug, suggesting that this drug exerts its effects by promoting production of IL-1 inhibitors. MK-886 also inhibited synovial production of two other pleiotrophic cytokines which it regulates, IL-6 and IL-8. The results suggest that some 5-lipoxygenase inhibitors may be usefully employed in regulating production of those interleukins involved in joint cartilage destruction.
OBJECTIVE: To assess the possible association between tacrine (Cognex, manufactured by Parke-Davis, Morris Plains, NJ) dose and likelihood of nursing home placement (NHP) or death in patients with AD. DESIGN: A 30-week, randomized, double-blind, placebo-controlled, parallel-group multicenter clinical trial involving 663 patients, after which patients were treated openly and followed up a minimum of 2 years later. PATIENTS: At baseline, outpatients were at least 50 years of age, met criteria for probable AD, with baseline Mini-Mental State Examination scores between 10 and 26 (inclusive), were otherwise healthy, and had a caregiver who could provide assessments and ensure medication compliance. INTERVENTIONS: mandomized assignment to placebo or one of three ascending dosage regimens of tacrine over 30 weeks, followed by open label treatment for all patients who began the double-blind trial. OUTCOME MEASURES: NHP and death were examined using logistic regression. RESULTS: PATIENTS who remained on tacrine and were receiving doses > 80 mg/d or > 120 mg/d were less likely to have entered a nursing home than patients on lower doses (odds ratios > 2.7,2.8, respectively.) There was a trend for lower mortality for patients receiving > 120 mg/d (p = 0.063). CONCLUSIONS: Treatment with tacrine at doses > 80 mg/d was associated with a reduced likelihood of NHP. These data demonstrate that tacrine's 30-week effects on cognitive function and clinicians' global ratings may generalize to effects on a major milestone of AD. Future studies should attempt to replicate these findings prospectively.
OBJECTIVE: To examine in vitro the effect of prostaglandin E2 (PGE2) on synovial cell cytokine production. METHODS: Human synovial fibroblasts were stimulated with PGE2 alone or PGE2 in combination with interleukin 1 alpha (IL-1 alpha) (5 ng/ml) and/or indomethacin (10(6) M) and assessed for the production of IL-8, IL-6, and granulocyte macrophage colony stimulating factor (GMCSF) at the protein and messenger RNA (mRNA) levels. RESULTS: PGE2 alone had little detectable effect on IL-8 or GMCSF; however, a small enhancement of both IL-6 mRNA and protein levels was seen. While all cytokines were markedly stimulated by IL-1 alpha), co-addition of the cyclooxygenase inhibitor indomethacin enhanced IL-8 and GMCSF levels, but caused a reduction in IL-6 expression. The addition of PGE2 to cultures stimulated with IL-1 alpha and indomethacin resulted increases in IL-6 mRNA and protein expression while causing a concomitant reduction in GMCSF protein and mRNA expression. PGE2 and illoprost (PGI2 analog) enhanced IL-8 production in stimulated cells. CONCLUSION: While PGE2 alone has limited effects on synovial cell production of IL-8 and GMCSF, its effects are significant in context of IL-1 alpha stimulation; endogenous PGE2 may alter cytokines secreted by mesenchymally derived cells. PGE2 may be an important modulator of cytokine driven inflammation.
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Phase II of the Trials of Hypertension Prevention is a multicenter, randomized, controlled trial designed to determine the efficacy of weight loss and reduction of sodium intake for lowering blood pressure and incidence of hypertension among persons with high-normal levels of blood pressure. The 2 x 2 factorial study design includes weight loss alone, restricted sodium intake alone, the combination of weight loss and sodium restriction, and a control group. Nine clinical centers used a variety of recruitment strategies to enroll 2382 participants over 17 months, which exceeded the sample size goal of 2250. Among randomized participants, 21% were minorities and 34% were women. Overall, direct mail generated the most randomized participants (73%), followed by community screening (12%) and media advertisement (11%). Referrals from community health care providers yielded few participants. Prescreening improved overall efficiency and reduced costs. Participants who were more likely to drop out voluntarily during the three-visit screening regimen tended to be younger, single, male, smokers, and less educated.
The aim of this study was to compare the clinical regenerative capacity of collagen membrane with and without demineralized freeze-dried bone allografts (DFDBA) in treating periodontal intrabony defects. Ten systemically healthy patients with similar bilateral periodontal defects were scheduled for surgery. Each patient had at least > or = 6 mm clinical probing depth and loss of attachment at selected sites. Baseline measurements included gingival index (GI), plaque index (PI), gingival recession (GR), clinical attachment level (CAL), probing depth (PD), and mobility. At the time of surgery, the defects were randomly assigned to either test (collagen membrane plus DFDBA) or control group (collagen membrane only). Stent to base of the defects, stent to crest bone, crest of bone to base of the defect, and width of the defects were recorded at the time of surgery and reentry. Eight patients returned after 6 months for reentry surgery. Statistical analysis with a paired t test was used to evaluate the treatment effect and comparison between test and control groups. In addition, a McNemar test was used to analyze the significance of GI, PI, and mobility at different times. The result of this study indicated that both the collagen plus DFDBA and the collagen alone treatment groups had a significant decrease of PD (3.4 +/- 0.4 and 3.2 +/- 0.4 mm), gain of CAL (2.3 +/- 0.5 and 2.0 +/- 0.4 mm), and defect fill (1.7 +/- 0.3 and 1.9 +/- 0.9 mm) (P < 0.05) when compared to the presurgery status. However, there was no significant difference in PD, AL, GR, defect fill, crestal bone resorption, GI, PI, or mobility between the test group and control group. No adverse tissue reaction, infection, or delayed wound healing was noted throughout the treatment in either group. This study suggests that the collagen membrane is well tolerated by the human tissues. Both treatments, either collagen membrane plus DFDBA or collagen membrane alone, promoted significant resolution of periodontal intrabony defects. The addition of a bone graft (DFDBA) with a collagen membrane appears to add no extra benefit to the collagen membrane treatment.
BACKGROUND: Compliance with an allergy immunotherapy regimen is obviously the difference between a potentially successful or unsuccessful outcome. OBJECTIVE: The purpose of this study was to assess retrospectively compliance of patients receiving immunotherapy in a private allergy practice. METHODS: The study evaluated retrospectively patient compliance with prescribed allergy injections for a private practice in Atlanta, Georgia. Patients who ordered allergy extract material for their injection immunotherapy program during an 18-month period served as the index population for this study. For the purposes of this study, noncompliance was defined as stopping the allergy injection program without the approval of the prescribing physician. Part of this investigation was to determine whether there were compliance differences between those who received their allergy injections within the confines of the clinic and those who received their injections at outside physician offices. A 12-month period of review was considered adequate to monitor compliance because of the 12-month expiration date placed on the allergy extracts. RESULTS: There was a noncompliance rate of 10: 77% for those who received their injections within the clinic. This contrasted with the noncompliance rate in the remote population of 34.82%. The difference between these two groups was statistically significant (P < .01). There were no statistical differences with respect to sex or diagnostic category. Significant differences were found between age groups in those receiving injections within or outside the clinic. CONCLUSIONS: There is a much higher rate of noncompliance in those who receive their injections in facilities outside the allergist's office. This suggests that to ensure better compliance either individuals should either be encouraged to receive their injections at the allergist's office, or better communications should be established between the referring allergist and the nonallergy physicians who are administering the injections.
STUDY OBJECTIVE: To determine whether levels of thrombin-antithrombin III (TAT) in plasma, taken two weeks pre-operatively, predict the development of deep vein thrombosis (DVT) in patients undergoing major hip or knee surgery. DESIGN: Prospective cohort. SETTING: Tertiary-care referral centre, university-affiliated hospital. PATIENTS: Ninety eight consecutive patients undergoing elective hip or knee surgery. INTERVENTION: All eligible consenting patients were seen in a preoperative clinic two weeks prior to surgery and had blood taken for measurement of plasma TAT level. After surgery, they received a combination of unfractionated heparin 5000 Units 12-hourly subcutaneously, and antiembolism stockings (TEDS), as prophylaxis against DVT. Contrast venography was performed prior to discharge, and according to the results, patients were classified as having proximal (popliteal and/or more proximal) DVT (n = 12), calf DVT (n = 7) or no DVT (n = 79). MEASUREMENTS AND RESULTS: The mean TAT level was significantly higher in patients who developed DVT (5.7 micrograms/l) than in those who did not (4.1 micrograms/l), p = 0.035. Using cut-points of 3.5 and 5.5 micrograms/l for the TAT level, patients could be categorized as high, intermediate, and low risk for the development of DVT. The proportion of patients with TAT levels of > or = 3.5 micrograms/l who developed calf or proximal DVT was significantly higher than the proportion of patients with TAT levels of < 3.5 micrograms/l who developed calf or proximal DVT (p = 0.02). The proportion of patients with TAT levels > 5.5 micrograms/l who developed proximal DVT was significantly higher than the proportion of patients with TAT levels of < or = 5.5 micrograms/l who developed proximal DVT (p = 0.03). CONCLUSIONS: This study demonstrates that pre-operative TAT levels correlate with the risk of developing DVT after major orthopedic surgery. Further studies are needed to determine the reason(s) for this observation and whether rational recommendations about prophylaxis and screening for DVT can be made based on the results of a preoperative TAT level.
A novel strategy combining peptide fingerprinting of single neurons by matrix-assisted laser desorption ionization mass spectrometry, molecular cloning, peptide chemistry, and electrospray ionization mass spectrometry was used to study the intricate processing pattern of a preprohormone expressed in identified neurons, the neuroendocrine light yellow cells (LYCs) of the gastropod mollusc, Lymnaea stagnalis. The cDNA encoding the precursor, named prepro-LYCP (LYCPs, light yellow cell peptides), predicts a straightforward processing into three peptides, LYCP I, II, and III, at conventional dibasic processing sites flanking the peptide domains on the precursor. However, matrix-assisted laser desorption ionization mass spectrometry of single LYCs revealed trimmed variant peptides derived from LYCP I and II. The variants were much more abundant than the intact peptides, indicating that LYCP I and II serve as intermediates in a peptide-processing sequence. Using the molecular masses of the peptides as markers to guide their isolation by well established purification methods, the structural identities of the peptides could be confirmed by amino acid sequencing. Furthermore, matrix-assisted laser desorption ionization mass spectrometry could detect colocalization of a novel peptide with the LYCPs.
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BACKGROUND: Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem. METHODS: We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group). RESULTS: Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular-weight heparin as compared with warfarin was 16 percent, and the absolute difference in the incidence of venous thrombosis was 6 percent in favor of low-molecular-weight heparin (95 percent confidence interval, 0.8 to 11.4 percent). The incidence of major bleeding was 1.2 percent (9 of 721 patients) in the warfarin group and 2.8 percent (20 of 715 patients) in the low-molecular-weight-heparin group (P = 0.04), and the absolute difference was 1.5 percent in favor of warfarin (95 percent confidence interval, 0.1 to 3.0 percent). CONCLUSIONS: Our data demonstrate that the small reduction in the incidence of venous thrombosis with low-molecular-weight heparin, as compared with warfarin, was offset by an increase in bleeding complications. Although the use of low-molecular-weight heparin is simpler, because it is administered subcutaneously without the need for monitoring, it may be more costly than warfarin. Warfarin is inexpensive, but the overall cost of its use is increased by the need to monitor the intensity of anticoagulation. At this time it is unclear which of these approaches is the most cost effective.
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To determine the role of 5-LO regulation of IL-1 in synovial tissues, we examined the effects of 5-LO inhibitors compared with standard IL-1 synthesis inhibitors on IL-1 production by human synovial tissue explants from patients with inflammatory arthropathies. MK886, L-656,224, PF-5901, and tepoxalin all inhibited IL-1 production in concentrations up to 10 microM, whereas other 5-LO inhibitors (ICI-211,965, zileuton), as well as IL-1 synthesis inhibitors (IX-207,887, tenidap), were inactive. LT products, thus regulate IL-1 production and inhibition thereof is one strategy for inhibiting this cytokine.