Baseball teams beaten by jet lag.
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Baseball↗
Biomedical subjects
R A Lew
Publications and source records attributed to R A Lew.
Clinical correlates of patient satisfaction after laminectomy for degenerative lumbar spinal stenosis.
STUDY DESIGN: Prospective multicenter observational study of the outcome of surgery for degenerative lumbar spinal stenosis. OBJECTIVES: To identify correlates of patient satisfaction with the results of surgery. SUMMARY OF BACKGROUND DATA: Little published information exists on correlates of patient satisfaction after surgery for spinal stenosis. METHODS: Preoperative and 6-month follow-up data for 194 patients were analyzed. Associations between preoperative variables and satisfaction with the results of surgery were examined in univariate and multivariate models. RESULTS: In multiple linear regression models that adjusted for the effects of age, gender, individual surgeon, number of interspaces decompressed, whether a fusion was performed, depression score, and overall level of pain, the predominance of back (as opposed to leg) pain, greater comorbidity, and worse preoperative functional status were associated with lower patient satisfaction. The regression model explained just 15% of the variance in patient satisfaction. CONCLUSIONS: Patients bothered predominantly by back pain preoperatively and those with greater medical comorbidity and functional disability are significantly less satisfied with the results of surgery for degenerative lumbar spinal stenosis.
Aged↗
Substrate specificity differences between recombinant rat testes endopeptidase EC 3.4.24.15 and the native brain enzyme.
We have characterized and compared the substrate specificity of affinity-purified recombinant rat testes endopeptidase EC 3.4.24.15 (EP 24.15) with that reported for the isolated brain enzyme. Of the peptides tested, only bradykinin, dynorphin A1-8, and neurotensin were efficiently cleaved by the recombinant enzyme (kcat/Km = 3.0, 2.8 and 0.5 x 10(5) M-1sec-1, respectively); other peptides considered substrates of EP 24.15 (gonadotropin-releasing hormone, substance P, somatostatin and angiotensin) were not metabolized. The enzyme was inhibited by metal ion chelators and thiol-reactive agents, as well as a specific EP 24.15 inhibitor (N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate), thus confirming the enzyme as a thiol-dependent metalloendopeptidase. The observed discrepancies in substrate specificity of the recombinant testicular and the isolated brain enzymes may result from tissue-specific forms and/or post-translational modifications of EP 24.15.
Amino Acid Sequence↗
The early detection of and screening for melanoma. International status.
Cutaneous melanoma is an increasingly common public health problem in industrialized nations. In theory, education and early detection should decrease melanoma morbidity and mortality, because the lesion is external and visible, risk factors are known, and thin tumors are associated with a high 5-year survival rate. The efficacy of early detection and screening programs, however, remains untested by randomized trials. Some early data are available from melanoma prevention and control efforts that have begun in many nations over the past decade. Textbook definitions of cancer screening are particularly challenging when applied to skin cancer control. Although some propose that there are rigid differences among screening, education, and early detection of skin cancer, the visible nature of this cancer makes early detection through education and screening inextricably intertwined. This article discusses the intermediate measures of education and screening within the context of the American Academy of Dermatology programs. Over the next few decades, screening and education for melanoma and other skin cancer will receive increasing worldwide attention. Multiple strategies will be required to combat increasing incidence and mortality rates. Screening and educational programs have been implemented worldwide, but data on their effects are only just being collected. Future collaborative work in melanoma/skin cancer prevention, education, and early detection holds promise as a way to decrease mortality and save lives.
Australia↗
The independence and stability of socioeconomic predictors of morbidity in systemic lupus erythematosus.
OBJECTIVE: We studied the relationship between systemic lupus erythematosus (SLE) morbidity and socioeconomic status (SES) at 5 centers. METHODS: Ninety-nine patients who met American College of Rheumatology criteria for SLE were randomly sampled at each center, balancing by race and insurance status. Subjects were interviewed for current and past SES factors, such as insurance, occupation, employment, education, and income. SLE disease activity was measured by the SLE Activity Measure (SLAM). RESULT: Higher education, private insurance/Medicare, and higher income were associated with less disease activity at diagnosis. Controlling for SES, race, and center, the best predictors of less active disease at diagnosis were private insurance/Medicare (P = 0.002) and higher education (P = 0.007). From the time of diagnosis to the study visit (mean 3.5 years), insurance, income, and employment status changed for a significant number of subjects (37%, 16%, and 21%, respectively). CONCLUSION: Private insurance or Medicare and higher education are associated with less active disease at diagnosis of SLE. Health insurance, income, and employment status are unstable measures of socioeconomic status and may explain the variability in conclusions of previous studies on the role of SES in SLE.
Adult↗
Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis.
The purpose of this study was to validate the results of a meta-analysis showing the efficacy of fish oil in rheumatoid arthritis with the results of a re-analysis of the complete primary data set. A Medline search yielded seven published papers. Three additional trials were found by contacting authorities in the field. Inclusion criteria included (1) a double-blind, placebo-controlled study, (2) use of at least one of seven predetermined outcome measures, (3) results reported for both placebo and treatment groups at baseline and follow-up, (4) randomization, and (5) parallel or cross-over design. Papers were scored for quality. Demographic and outcomes variables were collected. For the re-analysis of the primary data, the same variables were abstracted for the 395 individual patients randomized. The meta-analysis demonstrated that dietary fish oil supplementation for 3 months significantly reduced tender joint count (rate difference [RD] [95% CI] = -2.9 [-3.8 to -2.1] [p = 0.001]) and morning stiffness (RD [95% CI] = -25.9 [-44.3 to -7.5] [p < 0.01]) as compared with heterogeneous dietary control oils. The re-analysis of the primary data confirmed a significant reduction in tender joint count (p = 0.001) and in morning stiffness (p < 0.02) in the parallel analysis that ignored interaction terms. The analyses that included an interaction term between site and treatment again confirmed a significant reduction in tender joint count. The results for morning stiffness were similar to the meta-analysis, but did not quite reach statistical significance (p = 0.052-0.083). The relative improvements in the other outcome variables did not reach statistical significance. Use of fish oil improved the number of tender joints and duration of morning stiffness at 3 months as analyzed by both meta- and mega-analysis. The fuller mega-analysis confirmed the results of the meta-analysis. The advantages of mega-analysis were as follows: (1) the ability to analyze the homogeneity of the patient populations, (2) the ability to make clinically sensible adjustments in the form of the comparison, and (3) the ability to examine subsets of the data.
Arthritis, Rheumatoid↗
Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor.
1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.
Acetylcholine↗
The current status of melanoma early detection and screening.
Multiple strategies are required to combat the increasing incidence and mortality of cutaneous melanoma. Major questions about melanoma and skin cancer are reviewed, with particular attention to education and early detection.
Health Education↗
Is cutaneous T-cell lymphoma curable?
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Humans↗
Effect of maternal cigarette smoking on pregnancy complications and sudden infant death syndrome.
BACKGROUND: The purpose of this study was to estimate the annual morbidity and mortality among fetuses and infants that can be attributed to the use of tobacco products by pregnant women. METHODS: Published research reports identified by literature review were combined in a series of meta-analyses to compute pooled risk ratios, which, in turn, were used to determine the population attributable risk. RESULTS: Each year, use of tobacco products is responsible for an estimated 19,000 to 141,000 tobacco-induced abortions, 32,000 to 61,000 infants born with low birthweight, and 14,000 to 26,000 infants who require admission to neonatal intensive care units. Tobacco use is also annually responsible for an estimated 1900 to 4800 infant deaths resulting from perinatal disorders, and 1200 to 2200 deaths from sudden infant death syndrome (SIDS). CONCLUSIONS: Tobacco use is an important preventable cause of abortions, low birthweight, and deaths from perinatal disorders and SIDS. All pregnant women should be advised that smoking places their unborn children in danger. The low success rate of smoking cessation among pregnant women suggests that efforts to reduce the complications of pregnancy attributable to tobacco use by pregnant women should focus on preventing nicotine addiction among teenaged girls.
Abortion, Spontaneous↗
Evidence for a two-step mechanism of gonadotropin-releasing hormone metabolism by prolyl endopeptidase and metalloendopeptidase EC 3.4.24.15 in ovine hypothalamic extracts.
The metalloendopeptidase EC 3.4.24.15 is believed to degrade gonadotropin-releasing hormone (GnRH) (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) by cleavage at the Tyr5-Gly6 bond. We compared the ability of crude and partially purified endopeptidase 24.15 from ovine hypothalamus with recombinant rat testicular endopeptidase 24.15 to degrade synthetic GnRH. Both soluble and membrane hypothalamic fractions degraded GnRH to GnRH1-5, with some production of GnRH1-9 and GnRH1-3. Generation of the smaller fragments was blocked by a specific endopeptidase 24.15 inhibitor (CFP-AAY-pAB), but production of GnRH1-9 was reciprocally enhanced, suggesting this peptide may be an intermediate generated by prolyl endopeptidase. Indeed, both bacitracin and Z-Pro-prolinal, inhibitors of this enzyme, markedly reduced GnRH degradation to any product. Degradation of synthetic GnRH1-9 was more rapid than that of GnRH and was inhibited by CFP-AAY-pAB but not bacitracin. Activity against either substrate was greater in the soluble fraction. Repeated washing of the membrane fraction followed by extraction with Triton X-114 suggested that both endopeptidase 24.15 and prolyl endopeptidase, although predominantly soluble, can be peripherally associated with membranes. When fractionated by hydrophobic interaction chromatography, soluble endopeptidase 24.15 degraded GnRH only in fractions that also exhibited prolyl endopeptidase activity. In contrast, maximal degradation of GnRH1-9 was observed in adjacent fractions, which also contained the highest levels of immunoreactive endopeptidase 24.15. The affinity of recombinant endopeptidase 24.15 for GnRH was low (Km = 1.35 mM), was improved 10-15-fold by removal of the COOH-terminal amide or glycinamide (Km = 90 and 119 microM, respectively), and could be inhibited by CFP-AAY-pAB but not bacitracin. Taken together, these results suggest that GnRH metabolism in the hypothalamus may occur via a two-step process involving first removal of Gly10-NH2 by prolyl endopeptidase, followed by cleavage by endopeptidase 24.15 at the Tyr5-Gly6 bond.
Amino Acid Sequence↗
Assessment of homology with the helical mimicry algorithm.
Homologies based on structural motifs characterize conserved structures and mechanisms of maintaining function. An algorithm was developed to quantitate homology among segments of two proteins based upon structural characteristics of an amphipathic alpha-helix. This helical mimicry algorithm scored homology among sequences of two proteins in terms of: (i) presence of Leu, Ile, Val, Phe, or Met in a longitudinal, hydrophobic strip-of-helix at positions n, n + 4, n + 7, n + 11, etc. in the primary sequence, (ii) identity or chemical similarity of amino acids at intervening positions and (iii) exchanges of amino acids from positions n to n - 1, n + 3, n + 4, n + 1, n - 3, n - 4 around n (on the surface of a putative helix). While such exchanges of amino acids on the surfaces of homologous helices may conserve function, they did not maintain specific interactions of those residues with apposing groups.
Algorithms↗
Sunscreens and melanoma: implications for prevention.
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Animals↗
The role of EC 3.4.24.15 in the post-secretory regulation of peptide signals.
In the present studies, we characterized the degradation of gonadotropin-releasing hormone (GnRH) by tissues of the ovine hypothalamo-pituitary axis. Membrane and soluble fractions of the medial basal hypothalamus, the pre-optic area, the median eminence and the anterior pituitary demonstrated greater GnRH-degrading activity than either hypophysial-portal or jugular plasma. The primary stable product of the membrane fractions was GnRH1-3, while the major product of the soluble fractions was GnRH1-5, both fragments were generated by plasma. Of all tissue fractions, the highest specific activity was observed in the soluble median eminence. Partial purification and characterization of soluble hypothalamic peptidase activity suggested that GnRH degradation by this tissue occurs via a two-step mechanism involving both post-proline cleaving enzyme and the metalloendopeptidase 3.4.24.15.
Animals↗
A preliminary scoring system for assessing the outcome of carpal tunnel release.
Multiple outcomes are assessed in most studies of carpal tunnel syndrome, yet there are no validated methods of synthesizing these distinct measures into a single global score. We report a global score in which outcomes were selected and weighted according to their independent association with patient satisfaction with the results of surgery. Preoperative and 3-month follow-up data were analyzed on 104 subjects in a randomized controlled trial of open vs endoscopic carpal tunnel release. Patient satisfaction with surgery and a variety of subjective and objective outcome parameters were measured. In multivariate analyses, independent correlates of dissatisfaction included persistent numbness and paresthesia, incisional pain at follow-up evaluation, and decrease in grip strength. A global score was calculated by rounding to the nearest integer the model coefficients for these three variables. The global score correlated with patient satisfaction with surgery and time until return to work or full activities in patients undergoing open carpal tunnel release.
Adult↗
Responsiveness of self-reported and objective measures of disease severity in carpal tunnel syndrome.
Responsiveness, the ability to detect meaningful clinical change, is a critical attribute of instruments used to evaluate outcomes of treatments. The authors hypothesized that self-administered symptom severity and functional status questionnaires are more responsive to clinical improvement after carpal tunnel release than traditional physical examination measures of strength and sensibility. Data were obtained from a randomized clinical trial of endoscopic versus open carpal tunnel release conducted in four university medical centers. Patients were evaluated before surgery and 3 months after surgery. Seventy-four patients indicating that they were more than 80% satisfied with the results of surgery were assumed to have clinically meaningful improvement and were the focus of the analysis. Evaluations included questionnaires assessing symptom severity, functional status, and activities of daily living as well as measurement of grip, pinch, and abductor pollicus brevis strength, and 2-point discrimination and Semmes-Weinstein pressure sensibility. Responsiveness was calculated with the standardized response mean (mean change/standard deviation of change) as well as the effect size (mean change/standard deviation of baseline values). The symptom severity scale was four times as responsive, and the functional status and activities of daily living scales were twice as responsive, as the measures of strength and sensibility. Self-administered symptom severity and functional status scales are much more responsive to clinical improvement than measures of neuromuscular impairment and should severe as primary outcomes in clinical studies of therapy for carpal tunnel syndrome.
Activities of Daily Living↗
Characterization of membrane-associated peptidase activities expressed by endothelial cells of the ovine median eminence.
The capillary endothelial cells of the median eminence represent a potential site for the degradation/modification of both circulating and hypothalamic peptides passing through the hypophysial portal system toward the pituitary. This study examines endothelial cell peptidase expression in vitro by monitoring the metabolism of gonadotropin-releasing hormone (GnRH) by cultured endothelial cells from sheep median eminence. Cleavage of GnRH by median eminence endothelial cell membranes generated GnRH1-5 as the primary stable product, which was then degraded to GnRH1-3 and free amino acids. Degradation of GnRH was completely inhibited by TPCK, ZnCl2 and N-ethylmaleimide, and partially inhibited by EDTA and by a specific inhibitor of the metalloendopeptidase EC 3.4.24.15, CFP-AAY-pAB. Interestingly, an increase in GnRH1-9 production was seen with the latter inhibitors, suggesting a two-step mechanism of GnRH degradation involving a primary cleavage at the Pro9-Gly10-NH2 bond, inhibitable by TPCK, ZnCl2, and NEM, followed by cleavage by EC 3.4.24.15 to generate GnRH1-5. Phosphoramidon and angiotensin converting enzyme inhibitors (as well as other non-specific inhibitors) were without effect, indicating that endopeptidase EC 3.4.24.11 and angiotensin converting enzyme are not involved. Neither bovine aortic endothelial cell nor AtT-20 cell membranes exhibited this pattern of peptidase activity. Degradation of GnRH by intact median eminence endothelial cells in culture was also observed, suggesting an extracellular orientation for these enzymes; the potential role of such peptidases in the fine regulation of both pituitary function and local blood flow is currently under investigation.
Amino Acid Sequence↗
Etiology of melanoma.
Although the precise etiology of melanoma remains unknown, much data link sunlight to melanoma. The imperfect evidence associating sun exposure (particularly UVB radiation) with melanoma emerges from human data, obviating problems inherent in extrapolation from animal and other models. However, the mechanism by which sunlight might possibly initiate or promote melanoma remains obscure. Some clarification should emerge from the potential isolation of genes that carry susceptibility to melanoma in families prone to the disease; such work could serve as a basis to distinguish genetic and environmental influences in melanoma [167]. Continued studies of faulty DNA repair in XP patients may elucidate the steps in mutagenesis and carcinogenesis. Future case-control studies must address the limits on the accuracy of recall and the limits on statistical methods to separate the cluster of phenotypic risk needed in determining biologically effective dose. Animal and in vitro studies must contribute more insight. Further research in the South American opossum models appears promising [72]. Although ozone depletion has been documented, there has been little definitive evidence of subsequent increase of UVB at the Earth's surface. Nevertheless, the threat posed by ozone depletion deserves continued environmental action and public education. The role of precursor lesions, particularly dysplastic nevi/atypical moles, must be clarified with future research. The distribution of melanoma among various work forces suggests that occupational risk factors may play an important role in the etiology of this disease [168-170]. The consistent reports of excess melanoma among accountants, clerical workers, professional workers, and teachers deserve further study. Furthermore, evidence of excesses in printing and press, petrochemical, and the telecommunications industries require follow-up. Carefully planned studies that account for nonoccupational risk factors are recommended. Research over the last four decades has brought much information about melanoma etiology. More work is needed to learn the precise cause and ultimately to prevent avoidable mortality from malignant melanoma.
Animals↗