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.
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↗
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↗
Critical functional role of the COOH-terminal ends of longitudinal hydrophobic strips in alpha-helices of T4 lysozyme.
The sensitivity of bacteriophage T4 lysozyme function to amino acid substitutions at defined positions in and around the longitudinal, hydrophobic strips of 9 alpha-helices was assessed after systematic replacement of each residue in the protein with a series of 13 amino acids. The hydrophobic strips were defined by identifying the longitudinal sectors in the helices with the highest mean residue hydrophobicities. Sensitivity to mutation (the percentage of replacements leading to loss of function) was calculated for each residue in the following positions: whole protein, helices, hydrophobic strips, other positions within the helices, and various positions within the hydrophobic strips as well as their extensions beyond the helices. Substitutions at positions in the hydrophobic strips led more frequently to loss of function than substitutions in the protein as a whole. One subset, the COOH-terminal hydrophobic strip residues, is apparently critical; substitutions of these residues (but not of their NH2-terminal counterparts) led at least as frequently to loss of function as substitutions of solvent-inaccessible residues, and nearly as frequently as substitutions of the most highly conserved residues.
Algorithms↗
Residues in the longitudinal, hydrophobic strip-of-helix relate to terminations and crossings of alpha-helices.
An alpha-helix terminates when the virtual extension of its most hydrophobic, longitudinal strip containing Leu, Ile, Val, Phe, and Met lacks those residues. In each of 247 helices a template was fitted to maximize the mean hydrophobicity of positions forming a longitudinal strip-of-helix. The template was then extended into sequences beyond the ends of the helices. Leu, Ile, Val, Phe, and Met occurred in positions in the longitudinal strip-of-helix at an increased frequency (p less than 0.001), but in the first and second positions beyond either end of each true helix, they occurred at the same frequency as for their empirical distribution over all the proteins. Excesses of Asp and Glu were found in the N-terminal loop, and of Arg, His, and Lys in specific positions about the C terminus of helices. The longitudinal hydrophobic strip, the smallest amino acid in that strip, and charged amino acids in that strip, related to rotational and longitudinal orientation of alpha-helices in 15 proteins. Adjacent helices generally crossed through their longitudinal hydrophobic strips. They usually crossed through the smallest residue in the strip. Charged residues, when they occurred in the strips, were excluded from the crossing regions.
Amino Acid Sequence↗
Practices and beliefs concerning screening family members of patients with melanoma. Results of a survey of New England dermatologists.
BACKGROUND: First-degree relatives of patients with melanoma are roughly two to eight times more likely than the general public to be diagnosed with melanoma. Several organizations recommend regular screening for these and other persons at high risk for melanoma. However, there are no data as to how frequently such persons receive skin cancer examinations. OBJECTIVE: Our purpose was to determine the current screening recommendations and practices of dermatologists regarding family screening for melanoma. METHODS: With a one-page questionnaire, we surveyed dermatologists attending a 1989 meeting of the New England Dermatological Society. RESULTS: Seventy-three dermatologists completed the questionnaire. Most dermatologists (70%) reported that they encouraged screening of family members of patients with melanoma but also reported that family members infrequently appeared for skin examinations. CONCLUSION: Although most dermatologists encouraged screening of first degree relatives of melanoma patients, there appears to be infrequent acceptance by the patient of these recommendations. Recording family screening in the patients' charts, reminders to patients, and distributing literature on familial melanoma may increase acceptance by the patient of these recommendations.
Dermatology↗
Who discovers melanoma? Patterns from a population-based survey.
BACKGROUND: Melanoma is external and potentially detectable by many persons but little is known about who first discovers these lesions. An understanding of discovery patterns can shape future public and professional education programs. OBJECTIVE: Our purpose was to assess patterns of melanoma discovery and to determine the patients' role in finding their own lesions. METHODS: With a written, mailed questionnaire, we conducted a population-based statewide survey of 216 incident cases of melanoma in Massachusetts. RESULTS: Approximately half (53%) of melanomas were self-discovered, whereas the remainder were detected by medical providers (26%), family members (17%), and others (3%). Nearly one third of persons said they could not see their own lesions easily. Compared with men, women were more likely to discover their own lesions (66% vs 42%, p = 0.001) and those on their spouses (23% vs 2%, p less than 0.001). CONCLUSION: Improving early detection and reducing mortality of melanoma will require both public and professional education programs, with particular emphasis on targeting men at highest risk of this disease.
Adult↗
Biophysical mechanism of the scavenger site near T cell-presented epitopes.
We seek to identify consensus sequences in digested fragments of antigenic proteins regulating selection and major histocompatibility complex (MHC)-restricted presentation to T cells of epitopes within those fragments. One such pattern, of recurrent, hydrophobic sidechains forming a longitudinal hydrophobic strip when a sequence is coiled as an alpha-helix, is found in or near most T cell-presented epitopes. Such recurrent hydrophobicity may lead to protease-protected coiling of the fragment against endosomal membranes and transfer to MHC molecules. This concept leads to better identification of T cell-presented sequences and possible to engineering of T cell-presented vaccines to affect their potency and MHC restriction.
Amino Acid Sequence↗
Underreporting of cutaneous melanoma in cancer registries nationwide.
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Humans↗
Case-control study of melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use.
The rapid increase in melanoma incidence and mortality has given rise to nationwide and international campaigns that encourage the public to protect themselves from solar radiation with clothing, sunscreens, and other measures. The basis of these campaigns has been challenged by proponents of the theory that vitamin D, which is generated in the skin by ultraviolet B radiation, inhibits the development of melanoma. The present investigation tests this theory by examining the relation between dietary vitamin D and melanoma risk in a case-control study. Vitamin D intake was assessed by a food-frequency questionnaire in 165 melanoma patients and 209 controls. After controlling for age, hair color, and family history of melanoma, there was no association of melanoma risk with total vitamin D intake, calorie-adjusted vitamin D intake, vitamin D intake from foods, or consumption of milk or vitamin D supplements. We find no evidence to suggest that vitamin D protects against melanoma, and therefore continue to support the ongoing public health campaigns aimed at reducing sun exposure for the prevention of melanoma.
Adolescent↗
Endothelium-dependent ANF secretion in vitro.
Coculture of endothelial cells with atrial cells (R. A. Lew and A. J. Baertschi. Biochem. Biophys. Res. Commun. 163: 701-709, 1989) increased atrial natriuretic factor (ANF) release to 205 +/- 15% (n = 33 experiments) of basal secretion (2.02 +/- 0.33 ng/ml). Stimulation of ANF release by endothelial cells was significantly reduced (P < 0.05) by addition of the calcium channel antagonist nicardipine (Nic, 100 nM; by 69 +/- 4%), the guanylate cyclase activator sodium nitroprusside (SNP, 1 microM; by 97 +/- 27%), or acetylcholine (ACh, 10 microM; by 55 +/- 13%). Endothelial cell-conditioned medium elicited a 62 +/- 10% (n = 10) increase in ANF release. Rat and porcine endothelin (0.1-100 nM) each elicited a dose-dependent increase in ANF release [up to 84 +/- 14% (n = 18) over baseline]. The activity of conditioned medium was not affected by heat or trypsin treatment, but was significantly reduced by addition of Nic or SNP and was attenuated by ACh. Stimulation of ANF by 1 nM synthetic rat or porcine endothelin was also unaffected by heat or trypsin but was significantly reduced by Nic, SNP, and ACh. Addition of endothelin-specific antiserum abolished the ANF stimulatory activity of endothelial cell-conditioned medium. Neither inhibition of superoxide anion by superoxide dismutase nor inhibition of endothelium-derived nitric oxide production by NG-monomethyl-L-arginine affected the ANF release from coculture. Thus endothelial cells release a heat-stable, diffusible ANF stimulatory factor, which is not endothelium-derived relaxing factor or superoxide anion but is biologically and immunologically similar to endothelin.
Acetylcholine↗
Distribution and characterization of peptidylglycine alpha-amidating monooxygenase activity in the ovine brain and hypothalamo-pituitary axis.
The production of alpha-amidated peptide hormones from their glycine-extended precursors is catalyzed by the specific enzyme peptidylglycine alpha-amidating monooxygenase (PAM). In the present study, the distribution and subcellular localization of PAM activity in the sheep brain was examined and compared with known sites of amidated peptide synthesis and release. Of the brain regions assayed, the preoptic anterior and medial basal areas of the hypothalamus contained the greatest concentration of amidating activity. Lower concentrations (greater than 3-fold less) were found in the anterior and neurointermediate pituitary, median eminence, cerebral cortex, hippocampus, pons-medulla, and brainstem. Very low amounts of activity were present in the cerebellum and pineal gland. In most tissues tested, PAM activity was 40-75% higher in the membrane-associated fraction than in the soluble fraction. In the hypothalamus, affinity constants were identical for both membrane-associated and soluble fractions, and ranged from 12.3-13.3 microM. Maximal velocity was higher in the membrane fraction (4.7-4.8 pmol/microgram.h) than in the soluble fraction (2.6-2.9 pmol/microgram/h). Levels of amidating activity in hypophysial-portal and jugular plasma were similar and were 20- to 25-fold lower than in hypothalamic extracts. Insulin-induced hypoglycemia did not significantly alter PAM levels in portal or peripheral plasma, suggesting that amidating activity is not released during this stress. These results indicate that the hypothalamus is the richest source of amidating activity in the sheep brain, and suggest that amidation of neurohypophysial and hypothalamic releasing peptides may occur before axonal transport, given the much lower levels in median eminence, neurointermediate pituitary, and portal plasma.
Amino Acid Sequence↗
From the CDC: death rates from malignant melanoma among white men--United States, 1973-1988.
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Adult↗
Highly restricted distributions of hydrophobic and charged amino acids in longitudinal quadrants of alpha-helices.
Helix formation in folding proteins is stabilized by binding of recurrent hydrophobic side chains in one longitudinal quadrant against the locally most hydrophobic region of the protein. To test this hypothesis, we fitted sequences of 247 alpha-helices of 55 proteins to the circular (infinite) template (symbol; see text) to maximize the strip-of-helix hydrophobicity index (the mean hydrophobicity of residues in (symbol; see text) positions). These template-predicted configurations closely matched crystallographic structures in 87% of four- or five-turn helices compared. We determined the longitudinal quadrant distributions of amino acids in the template-fitted, sheet projections of alpha-helices with respect to the best longitudinal, hydrophobic strip on each helix and to the N and C termini, interiors, and entire helices. Amino acids Leu, Ile, Val, and Phe were concentrated in one longitudinal quadrant (p less than 0.001). Lys, Arg, Asp, and Glu were not in the quadrant of Leu, Ile, Val, and Phe (p less than 0.001). Significant quadrant distributions for other amino acids and for termini of the helices were also found.
Amino Acids↗
Sunlight and dysplastic nevus risk. Results of a clinic-based case-control study.
The dysplastic nevus (DN) is the most important risk factor and precursor for malignant melanoma. The authors compared the responses of 132 consecutive cases of DN, 186 consecutive cases of cutaneous melanoma, and 239 controls attending the same subspecialty clinic to questions regarding sun sensitivity, sun exposure, and other possible risk factors. Dysplastic nevus cases were younger than controls and were of a higher social class, as indicated by more years of formal education. Sun sensitivity (assessed by reported depth of tan after multiple exposures) was associated with both DN risk and melanoma risk after controlling for age and education in logistic regression analysis (P = 0.009 and 0.03, respectively), but for DN risk this association was nonlinear: the relative risks (versus deep tan) were 2.3 for average tanners, 2.8 for light tanners, and 1.6 for those who reported practically no tan. Sun exposure measures were not associated with DN risk after controlling for age and education, whether or not depth of tan was controlled in the analysis. These observations suggest a role for either sunlight or a trait linked with sun sensitivity in the development of dysplastic nevi.
Adult↗
Prediction of alpha helices and T cell-presented sequences in proteins with algorithms based on strip-of-helix hydrophobicity index.
Recurrent aliphatic hydrophobic amino acids which occur in the sequence of a protein or a peptide at positions which form an axial, hydrophobic strip when the sequence is coiled as an alpha helix might stabilize coiling against hydrophobic surfaces. That effect can lead to helix formation against hydrophobic cores of nascent proteins or excised T cell-presented peptides and to protease protection and scavenging for presentation by MHC molecules. Such consensus sequences of recurrent hydrophobicity creating a scavenger "S" site might overlap to varying degrees the T cell-presented "T" epitope which actually sits in the antigen-binding site of a MHC molecules, as long as a cleavage "C" site does not fall between them when they are relatively separated. Cooperatively among the residues in an axial, hydrophobic strip to stabilize helix formation is reflected in the SOHHI, which is the mean hydrophobicity of residues in such potential strips. Algorithms based on the SOHHI, with additional considerations related to length and caps, lead to sensitive and efficient predictions of structural helices and of T cell-presented epitopes. In experimental tests of these ideas, the SOHHI was found to correlate to helical coiling of amphiphilic peptides in the presence of lipid vesicles. These principles lead to hypotheses to alter the potency and range of MHC restriction of peptide vaccines or to decrease the immunogenicity of therapeutic proteins.
Algorithms↗
Common principles in protein folding and antigen presentation.
The regular recurrence of hydrophobic amino acid residues along a peptide sequence determines the formation of a longitudinal hydrophobic strip when the peptide forms an alpha-helix. An understanding of the ways this may affect both folding of nascent proteins and antigen presentation should facilitate vaccine and therapeutics design.
Amino Acid Sequence↗
Who is being screened for melanoma/skin cancer? Characteristics of persons screened in Massachusetts.
We conducted a survey of persons who voluntarily attended melanoma/skin cancer screenings in Massachusetts in 1987. Of 1219 persons asked to fill out a questionnaire, 1116 (92%) completed it. Our study demonstrates that persons attending the melanoma/skin cancer screening program were, for the most part, at risk for the disease and appropriately selected themselves to be screened. Most were women, well educated (with college or advanced degrees), and white. More than 86% had at least one risk factor for melanoma/skin cancer whereas 78% had at least two risk factors. Future studies are necessary to determine whether our experience can be verified. Additional efforts should try to attract those who are at risk but perhaps are less willing to attend screening programs--men and those of lower socioeconomic status. These efforts can help target screening to those at highest risk and maximize the yield of these public health efforts.
Adolescent↗