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Title:
Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease
Authors:
Omenn, G. S.; Goodman, G. E.; Thornquist, M. D.; Balmes, J.; Cullen, M. R.; Glass, A.; Keogh, J. P.; Meyskens, F. L.; Valanis, B.; Williams, J. H.; Barnhart, S.; Hammar, S.
Abstract:
BACKGROUND: Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. RESULTS: A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. CONCLUSIONS: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Published:
May 1, 1996
Title:
The Advanced Glycation End Product, N-(Carboxymethyl)lysine, Is a Product of both Lipid Peroxidation and Glycoxidation Reactions
Authors:
Fu, Min-Xin; Requena, Jesús R.; Jenkins, Alicia J.; Lyons, Timothy J.; Baynes, John W.; Thorpe, Suzanne R.
Abstract:
N-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.
Published:
April 25, 1996
Title:
Cohort studies of fat intake and the risk of breast cancer--a pooled analysis
Authors:
Hunter, D. J.; Spiegelman, D.; Adami, H. O.; Beeson, L.; van den Brandt, P. A.; Folsom, A. R.; Fraser, G. E.; Goldbohm, R. A.; Graham, S.; Howe, G. R.
Abstract:
BACKGROUND: Experiments in animals, international correlation comparisons, and case-control studies support an association between dietary fat intake and the incidence of breast cancer. Most cohort studies do not corroborate the association, but they have been criticized for involving small numbers of cases, homogeneous fat intake, and measurement errors in estimates of fat intake. METHODS: We identified seven prospective studies in four countries that met specific criteria and analyzed the primary data in a standardized manner. Pooled estimates of the relation of fat intake to the risk of breast cancer were calculated, and data from study-specific validation studies were used to adjust the results for measurement error. RESULTS: Information about 4980 cases from studies including 337,819 women was available. When women in the highest quintile of energy-adjusted total fat intake were compared with women in the lowest quintile, the multivariate pooled relative risk of breast cancer was 1.05 (95 percent confidence interval, 0.94 to 1.16). Relative risks for saturated, monounsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was little overall association between the percentage of energy intake from fat and the risk of breast cancer, even among women whose energy intake from fat was less than 20 percent. Correcting for error in the measurement of nutrient intake did not materially alter these findings. CONCLUSIONS: We found no evidence of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk even among women whose energy intake from fat was less than 20 percent of total energy intake. In the context of the Western lifestyle, lowering the total intake of fat in midlife is unlikely to reduce the risk of breast cancer substantially.
Published:
February 7, 1996
Title:
Intake of carotenoids and retinol in relation to risk of prostate cancer
Authors:
Giovannucci, E.; Ascherio, A.; Rimm, E. B.; Stampfer, M. J.; Colditz, G. A.; Willett, W. C.
Abstract:
BACKGROUND: Several human studies have observed a direct association between retinol (vitamin A) intake and risk of prostate cancer; other studies have found either an inverse association or no association of intake of beta-carotene (the major provitamin A) with risk of prostate cancer. Data regarding carotenoids other than beta-carotene in relation to prostate cancer risk are sparse. PURPOSE: We concluded a prospective cohort study to examine the relationship between the intake of various carotenoids, retinol, fruits, and vegetables and the risk of prostate cancer. METHODS: Using responses to a validated, semiquantitative food-frequency questionnaire mailed to participants in the Health Professionals Follow-up Study in 1986, we assessed dietary intake for a 1-year period for a cohort of 47,894 eligible subjects initially free of diagnosed cancer. Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992. We calculated the relative risk (RR) for each of the upper categories of intake of a specific food or nutrient by dividing the incidence rate of prostate cancer among men in each of these categories by the rate among men in the lowest intake level. All P values resulted from two-sided tests. RESULTS: Between 1986 and 1992, 812 new cases of prostate cancer, including 773 non-stage A1 cases, were documented. Intakes of the carotenoids beta-carotene, alpha-carotene, lutein, and beta-cryptoxanthin were not associated with risk of non-stage A1 prostate cancer; only lycopene intake was related to lower risk (age- and energy-adjusted RR = 0.79; 95% confidence interval [CI] = 0.64-0.99 for high versus low quintile of intake; P for trend = .04). Of 46 vegetables and fruits or related products, four were significantly associated with lower prostate cancer risk; of the four--tomato sauce (P for trend = .001), tomatoes (P for trend = .03), and pizza (P for trend = .05), but not strawberries--were primary sources of lycopene. Combined intake of tomatoes, tomato sauce, tomato juice, and pizza (which accounted for 82% of lycopene intake) was inversely associated with risk of prostate cancer (multivariate RR = 0.65; 95% CI = 0.44-0.95, for consumption frequency greater than 10 versus less than 1.5 servings per week; P for trend = .01) and advanced (stages C and D) prostate cancers (multivariate RR = 0.47; 95% CI = 0.22-1.00; P for trend = .03). No consistent association was observed for dietary retinol and risk of prostate cancer. CONCLUSIONS: These findings suggest that intake of lycopene or other compounds in tomatoes may reduce prostate cancer risk, but other measured carotenoids are unrelated to risk. IMPLICATIONS: Our findings support recommendations to increase vegetable and fruit consumption to reduce cancer incidence but suggest that tomato-based foods may be especially beneficial regarding prostate cancer risk.
Published:
December 5, 1995
Title:
Fables Of Abundance: A Cultural History Of Advertising In America
Authors:
Lears, Jackson
Abstract:
A "highly illuminating" ( "Publishers Weekly," starred review) book that fundamentally transforms the whole debate about the cultural significance of advertising."A work of prodigious research, of admirable historical imagination, of daring criticism."--Michael Schudson, author of "Advertising, the Uneasy Persuasion" "Simply brilliant. A major work in American cultural history."--Alan Trachtenberg, Yale University"Fascinating...fluent...and moving."--Alexander Star, "New Republic" "Lears is one of cultural history's masters of linnking popular moods and ideas with arts, philosophies, industries, and commodities." "--New York Review of Books"
Published:
November 2, 1995
Title:
The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system
Authors:
Hori, O.; Brett, J.; Slattery, T.; Cao, R.; Zhang, J.; Chen, J. X.; Nagashima, M.; Lundh, E. R.; Vijay, S.; Nitecki, D.
Abstract:
The receptor for advanced glycation end products (RAGE), a newly-identified member of the immunoglobulin superfamily, mediates interactions of advanced glycation end product (AGE)-modified proteins with endothelium and other cell types. Survey of normal tissues demonstrated RAGE expression in situations in which accumulation of AGEs would be unexpected, leading to the hypothesis that under physiologic circumstances, RAGE might mediate interaction with ligands distinct from AGEs. Sequential chromatography of bovine lung extract identified polypeptides with M(r) values of approximately 12,000 (p12) and approximately 23,000 (p23) which bound RAGE. NH2-terminal and internal protein sequence data for p23 matched that reported previously for amphoterin. Amphoterin purified from rat brain or recombinant rat amphoterin bound to purified sRAGE in a saturable and dose-dependent manner, blocked by anti-RAGE IgG or a soluble form of RAGE (sRAGE). Cultured embryonic rat neurons, which express RAGE, displayed dose-dependent binding of 125I-amphoterin which was prevented by blockade of RAGE using antibody to the receptor or excess soluble receptor (sRAGE). A functional correlate of RAGE-amphoterin interaction was inhibition by anti-RAGE F(ab')2 and sRAGE of neurite formation by cortical neurons specifically on amphoterin-coated substrates. Consistent with a potential role for RAGE-amphoterin interaction in development, amphoterin and RAGE mRNA/antigen were co-localized in developing rat brain. These data indicate that RAGE has physiologically relevant ligands distinct from AGEs which are likely, via their interaction with the receptor, to participate in physiologic processes outside of the context of diabetes and accumulation of AGEs.
Published:
October 26, 1995
Title:
[Influence of the diet on cell proliferation in the large bowel and the rectum. Does a strict vegetarian diet reduct the risk of intestinal cancer?]
Authors:
Almendingen, K.; Trygg, K.; Vatn, M.
Abstract:
Colorectal cancers are the most frequent cancer in Norway for men and women combined. Several theories have been suggested as etiological explanations. In this review the influence of dietary factors on the cell proliferation rate has been evaluated. A higher cell proliferation rate is statistically associated with increased risk of colorectal cancer. Foods associated with a lower cell proliferation rate match the staple foods in parts of the world were the incidence of colorectal cancer is low. Vegetarians show a low rate of cell proliferation, and low incidence of colorectal cancer. The low incidence of colorectal cancer among vegetarians may be due not only to the lack of animal foods, but also to several other healthy lifestyle habits. We conclude that a well planned lacto-vegetarian diet or a mixed diet with abundant amounts of vegetables and fruits is beneficial as regards the rate of cell proliferation, and most likely also reduces the risk of developing colorectal cancer.
Published:
August 9, 1995
Title:
The Hunter's Vision: The Prehistoric Art of Zimbabwe
Authors:
Garlake, Peter
Abstract:
Analyzes and compares the prehistoric rock paintings of Zimbabwe to show how the artists selected subjects and how the paintings were executed, and discusses the conventions that determined the paintings' styles and forms. Reconstructs the significance and meaning of the paintings by looking at them in the context of the basic tenets of the Sen societies that still survive on the outskirts of the Kalahari Desert. Includes b&w drawings and color photos of the paintings and their environment. Annotation copyright Book News, Inc. Portland, Or.
Published:
June 30, 1995
Title:
[Effects of a vegetarian life style on health]
Authors:
Ritter, M. M.; Richter, W. O.
Abstract:
A vegetarian diet has a positive effect on various risk factors for coronary artery disease: these include usually lower average body weight, lower total and LDL cholesterol levels, and lower blood pressure. In conjunction with a generally more healthy way of life (more exercise, less alcohol and tobacco use), vegetarians have roughly 30% reduction in overall mortality. The prevalence of bronchial, colon and breast cancer is also lower. In particular in its strict form (total vegetarianism or veganism), a vegetarian regimen may lead to deficiency disorders, in particular vitamin B12 deficiency, which may occur especially in vegetarian children, pregnant or lactating women. Overall, however, a vegetarian regimen has a more beneficial effect on health than the usual Central European diet.
Published:
June 9, 1995
Title:
Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine.
Authors:
Zimmerman, G A; Meistrell, M; Bloom, O; Cockroft, K M; Bianchi, M; Risucci, D; Broome, J; Farmer, P; Cerami, A; Vlassara, H
Abstract:
Cerebral infarction (stroke) is a potentially disastrous complication of diabetes mellitus, principally because the extent of cortical loss is greater in diabetic patients than in nondiabetic patients. The etiology of this enhanced neurotoxicity is poorly understood. We hypothesized that advanced glycation endproducts (AGEs), which have previously been implicated in the development of other diabetic complications, might contribute to neurotoxicity and brain damage during ischemic stroke. Using a rat model of focal cerebral ischemia, we show that systemically administered AGE-modified bovine serum albumin (AGE-BSA) significantly increased cerebral infarct size. The neurotoxic effects of AGE-BSA administration were dose- and time-related and associated with a paradoxical increase in cerebral blood flow. Aminoguanidine, an inhibitor of AGE cross-linking, attenuated infarct volume in AGE-treated animals. We conclude that AGEs may contribute to the increased severity of stroke associated with diabetes and other conditions characterized by AGE accumulation.
Published:
April 24, 1995
Title:
Lipoprotein Lipase Association with Lipoproteins Involves Protein-Protein Interaction with Apolipoprotein B
Authors:
Choi, Sungshin Y.; Sivaram, Pillarisetti; Walker, Dee E.; Curtiss, Linda K.; Gretch, Daniel G.; Sturley, Stephen L.; Attie, Alan D.; Deckelbaum, Richard J.; Goldberg, Ira J.
Abstract:
Published:
April 6, 1995
Title:
Changes in energy expenditure resulting from altered body weight.
Authors:
Leibel, R. L.; Rosenbaum, M.; Hirsch, J.
Abstract:
BACKGROUND: No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly. METHODS: We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding. RESULTS: Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P
Published:
March 8, 1995
Title:
A Plio-Pleistocene hominid from Dmanisi, East Georgia, Caucasus
Authors:
Gabunia, L; Vekua, A
Abstract:
Archaeological excavations at the mediaeval site of Dmanisi (East Georgia) revealed that the town was built on a series of deposits yielding Late Villafranchian mammalian fossils and led to the discovery in late 1991 of a well preserved early human mandible. Dmanisi, where excavations are being carried out by a joint expedition of the Archaeological Research Centre of the Georgian Academy of Sciences and the Römisch-Germanisches Zentralmuseum (Mainz, Germany), is located southwest of Tbilisi, at about 44 degrees 20'N, 41 degrees 20'E (Fig. 1). The fossils date to the latest Pliocene (or perhaps to the earliest Pleistocene), probably between 1.8 and 1.6 million years ago (Myr). Here we identify the mandible as belonging to the species Homo erectus, of which it is the earliest known representative in western Eurasia. It shows a number of similarities to the African and Chinese representatives of this species.
Published:
February 8, 1995
Title:
Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.
Authors:
Maroulakou, I G; Anver, M; Garrett, L; Green, J E
Abstract:
A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands.
Published:
November 7, 1994
Title:
The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site.
Authors:
Hann, S. R.; Dixit, M.; Sears, R. C.; Sealy, L.
Abstract:
The myc proto-oncogene family has been implicated in multiple cellular processes, including proliferation, differentiation, and apoptosis. The Myc proteins, as heterodimers with Max protein, have been shown to function as activators of transcription through an E-box DNA-binding element, CACGTG. We have now found that the c-Myc proteins regulate transcription through another, noncanonical, DNA sequence. The non-AUG-initiated form of the c-Myc protein, c-Myc 1, strongly and specifically activates transcription of the C/EBP sequences within the EFII enhancer element of the Rous sarcoma virus long terminal repeat. In contrast, comparable amounts of the AUG-initiated form, c-Myc 2, fail to significantly affect enhancer activity. However, both c-Myc proteins trans-activate the CACGTG sequence comparably. In addition, Myc/Max heterodimers, but not Max homodimers, bind to the EFII enhancer sequence in vitro. Finally, c-Myc 1 overexpression, but not c-Myc 2 overexpression, significantly inhibits cell growth. These results reveal new transcriptional activities for the Myc proteins and demonstrate that the different forms of the Myc protein are functionally distinct. These results also suggest an interplay between two different growth regulatory transcription factor families.
Published:
October 14, 1994
Title:
Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions.
Authors:
Schmidt A M; Hori O; Brett J; Yan S D; Wautier J L; Stern D
Abstract:
Advanced glycation end products (AGEs) form by the interaction of aldoses with proteins and the subsequent molecular rearrangements of the covalently linked sugars, eventuating in a diverse group of fluorescent compounds of yellow-brown color. This heterogeneous class of nonenzymatically glycated proteins or lipids is found in the plasma and accumulates in the vessel wall and tissues even in normal aging. As a consequence of hyperglycemia, AGE formation and deposition are much enhanced in diabetes, in which their presence has been linked to secondary complications, especially microvascular disease. This review summarizes the cellular interactions of AGEs and describes the central role of a novel receptor for AGE (RAGE). RAGE, an immunoglobulin superfamily member, mediates the binding of AGEs to endothelial cells and mononuclear phagocytes, interacts with a lactoferrin-like polypeptide that also binds AGEs, and appears to activate intracellular signal transduction mechanisms consequent to its interaction with the glycated ligand. RAGE is expressed by ECs, mononuclear phagocytes, smooth muscle cells, mesangial cells, and neurons, indicating a potential role in the regulation of their properties in homeostasis and/or their dysfunction in the development of diabetic complications. Since AGEs have been shown to generate reactive oxygen intermediates, tethering of AGEs to the cell surface by their receptors focuses oxidant stress on cellular targets, resulting in changes in gene expression and the cellular phenotype. The discovery of RAGE and development of reagents to block its interaction with AGEs should provide insights into the role of this ligand-receptor interaction in the pathogenesis of diabetic complications and, potentially, atherosclerosis.
Published:
September 30, 1994
Title:
Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3
Authors:
Sugaya, K.; Fukagawa, T.; Matsumoto, K.; Mita, K.; Takahashi, E.; Ando, A.; Inoko, H.; Ikemura, T.
Abstract:
Cosmid walking of about 250 kb from MHC class III gene CYP21 to class II was conducted. The gene for receptor of advanced glycosylation end products of proteins (RAGE, a member of immunoglobulin superfamily molecules), the PBX2 homeobox gene designated HOX12, and the human counterpart of the mouse mammary tumor gene int-3 were found. The contiguous RAGE and HOX12 genes were completely sequenced, and the human int-3 counterpart was partially sequenced and assigned to a Notch homolog. This human Notch homolog, designated NOTCH3, showed both the intracellular portion present in the mouse int-3 sequence and the extracellular portion absent in the int-3. It thus corresponds to the intact form of a Notch-type transmembrane protein. About 20 kb of dense Alu clustering was found just centromeric to the NOTCH3.
Published:
September 14, 1994
Title:
Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins.
Authors:
Schmidt, A M; Hasu, M; Popov, D; Zhang, J H; Chen, J; Yan, S D; Brett, J; Cao, R; Kuwabara, K; Costache, G
Abstract:
The extended interaction of aldoses with proteins or lipids results in nonenzymatic glycation and oxidation, ultimately forming AGEs, the presence of which in the plasma and vessel wall is associated with diabetic vascular complications. We show here that AGE albumin in the intravascular space interacts with the vessel wall via binding to an integral membrane protein, receptor for AGE (RAGE), a member of the immunoglobulin superfamily, resulting in clearance from the plasma and induction of interleukin 6 mRNA. Intravenously infused 125I-AGE albumin showed a rapid phase of plasma clearance with deposition in several organs. Rapid removal of 125I-AGE albumin from the plasma was prevented by administration of a soluble, truncated form of RAGE, which blocked binding of 125I-labeled AGE albumin to cultured endothelial cells and mononuclear phagocytes, as well as by pretreatment with anti-RAGE IgG. Ultrastructural studies with AGE albumin-colloidal gold conjugates perfused in situ showed that in murine coronary vasculature this probe was taken up by endothelial plasmalemmal vesicles followed by transport either to the abluminal surface or by accumulation in intracellular vesicular structures reminiscent of endosomes and lysosomes. Consequences of AGE-RAGE interaction included induction of interleukin 6 mRNA expression in mice. These data indicate that RAGE mediates the interaction of AGEs with the vessel wall, both for removal of these glycated proteins from the plasma and for changes in gene expression.
Published:
September 12, 1994
Title:
Risk of death from cancer and ischaemic heart disease in meat and non-meat eaters
Authors:
Thorogood, M.; Mann, J.; Appleby, P.; McPherson, K.
Abstract:
OBJECTIVE: To investigate the health consequences of a vegetarian diet by examining the 12 year mortality of non-meat eaters and meat eating controls. DESIGN: Prospective observational study in which members of the non-meat eating cohort were asked to nominate friends or relatives as controls. SETTING: United Kingdom. SUBJECTS: 6115 non-meat eaters identified through the Vegetarian Society of the United Kingdom and the news media (mean (SD) age 38.7 (16.8) years) and 5015 controls who were meat eaters (39.3 (15.4) years). MAIN OUTCOME MEASURES: Standardised mortality ratios for cancer, ischaemic heart disease, and total mortality in the two cohorts and death rate ratio in the non-meat eaters compared with meat eaters after adjustment for potentially confounding variables. RESULTS: Standardised mortality ratios (taking the value among the general population as 100) for ischaemic heart disease were 51 (95% confidence interval 38 to 66) for meat eaters and 28 (20 to 38) for non-meat eaters (P
Published:
June 24, 1994
Title:
Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus
Authors:
Garg, A.; Bantle, J. P.; Henry, R. R.; Coulston, A. M.; Griver, K. A.; Raatz, S. K.; Brinkley, L.; Chen, Y. D.; Grundy, S. M.; Huet, B. A.
Abstract:
OBJECTIVE: To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: A four-center randomized crossover trial. SETTING: Outpatient and inpatient evaluation in metabolic units. PATIENTS: Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS: A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. RESULTS: The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P
Published:
May 10, 1994
Title:
Intake of fat, meat, and fiber in relation to risk of colon cancer in men
Authors:
Giovannucci, E.; Rimm, E. B.; Stampfer, M. J.; Colditz, G. A.; Ascherio, A.; Willett, W. C.
Abstract:
Some evidence suggests that diets high in animal fat or red meat may increase the risk of colon cancer, whereas high intake of fiber or vegetables may be protective. Frequently, intake of red meat has been a stronger risk factor than total fat. Because data from prospective cohort studies are sparse, we examined fat, meat, fiber, and vegetable intake in relation to risk of colon cancer in a cohort of 47,949 U.S. male health professionals who were free of diagnosed cancer in 1986. At baseline, these men, 40 to 75 years of age, completed a validated food frequency questionnaire and provided detailed information on other lifestyle and health-related factors. Between 1986 and 1992, 205 new cases of colon cancer were diagnosed in these men. Intakes of total fat, saturated fat, and animal fat were not related to risk of colon cancer. However, an elevated risk of colon cancer was associated with red meat intake (relative risk, 1.71; 95% confidence interval, 1.15-2.55 between high and low quintiles; P = 0.005 for trend). Men who ate beef, pork, or lamb as a main dish five or more times per week had a relative risk of 3.57 (95% confidence interval, 1.58-8.06; P = 0.01 for trend) compared to men eating these foods less than once per month. The association with red meat was not confounded appreciably by other dietary factors, physical activity, body mass, alcohol intake, cigarette smoking, or aspirin use. Other sources of animal fat, including dairy products, poultry, and fish as well as vegetable fat, were slightly inversely related to risk of colon cancer. No clear association existed between fiber or vegetable intake and risk of colon cancer. These data support the hypothesis that intake of red meat is related to an elevated risk of colon cancer.
Published:
April 30, 1994
Title:
Intake of fat, meat, and fiber in relation to risk of colon cancer in men
Authors:
Giovannucci, E.; Rimm, E. B.; Stampfer, M. J.; Colditz, G. A.; Ascherio, A.; Willett, W. C.
Abstract:
Some evidence suggests that diets high in animal fat or red meat may increase the risk of colon cancer, whereas high intake of fiber or vegetables may be protective. Frequently, intake of red meat has been a stronger risk factor than total fat. Because data from prospective cohort studies are sparse, we examined fat, meat, fiber, and vegetable intake in relation to risk of colon cancer in a cohort of 47,949 U.S. male health professionals who were free of diagnosed cancer in 1986. At baseline, these men, 40 to 75 years of age, completed a validated food frequency questionnaire and provided detailed information on other lifestyle and health-related factors. Between 1986 and 1992, 205 new cases of colon cancer were diagnosed in these men. Intakes of total fat, saturated fat, and animal fat were not related to risk of colon cancer. However, an elevated risk of colon cancer was associated with red meat intake (relative risk, 1.71; 95% confidence interval, 1.15-2.55 between high and low quintiles; P = 0.005 for trend). Men who ate beef, pork, or lamb as a main dish five or more times per week had a relative risk of 3.57 (95% confidence interval, 1.58-8.06; P = 0.01 for trend) compared to men eating these foods less than once per month. The association with red meat was not confounded appreciably by other dietary factors, physical activity, body mass, alcohol intake, cigarette smoking, or aspirin use. Other sources of animal fat, including dairy products, poultry, and fish as well as vegetable fat, were slightly inversely related to risk of colon cancer. No clear association existed between fiber or vegetable intake and risk of colon cancer. These data support the hypothesis that intake of red meat is related to an elevated risk of colon cancer.
Published:
April 30, 1994
Title:
Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus
Authors:
Hofer, F.; Gruenberger, M.; Kowalski, H.; Machat, H.; Huettinger, M.; Kuechler, E.; Blaas, D.
Abstract:
A protein binding to a minor-group human rhinovirus (HRV2) was purified from HeLa cell culture supernatant. The amino acid sequences of tryptic peptides showed identity with the human low density lipoprotein (LDL) receptor (LDLR). LDL and HRV2 mutually competed for binding sites on human fibroblasts. Cells down-regulated for LDLR expression yielded much less HRV2 upon infection than cells with up-regulated LDLR. Virus also bound to the large subunit of the alpha 2-macroglobulin receptor/LDLR-related protein (alpha 2MR/LRP). LDLR-deficient fibroblasts yielded considerably less virus in the presence of receptor-associated protein (RAP), providing evidence that alpha 2MR/LRP also acts as a minor group HRV receptor.
Published:
February 28, 1994
Title:
Epidemiology of multiple sclerosis in Australia. With NSW and SA survey results
Authors:
McLeod, J. G.; Hammond, S. R.; Hallpike, J. F.
Abstract:
OBJECTIVES: (i) To determine the prevalence of multiple sclerosis (MS) in New South Wales and South Australia; (ii) to compare these prevalences with those in other areas of Australia and to determine the relationship between prevalence and latitude; (iii) to examine the relative contribution of genetic and environmental factors in the aetiology of the disease in Australia; and (iv) to ascertain whether there had been a change in the frequency of the disease since 1961. RESULTS: The crude prevalence of MS in New South Wales on prevalence day (National Census Day, 30 June 1981) was 37.2/100,000 and the age-standardised prevalence 36.6/100,000. The female:male ratio was 2.3:1. The crude prevalence in South Australia was 29.4/100,000 and the age-standardised prevalence 28.8/100,000. The female:male ratio was 2.4:1. No Aborigines or Torres Strait Islanders with MS were identified. There was a significant increase in the prevalence with increasing south latitude in Australia, MS being about seven times more frequent in Hobart than in tropical Queensland, but no genetic differences were found in the surveyed population in different parts of Australia. A significant increase in the prevalence of MS occurred in most areas of Australia between 1961 and 1981, but this may not reflect a true increase in incidence. CONCLUSION: The increasing prevalence with increasing south latitude cannot readily be explained by genetic susceptibility, and suggests that environmental factors are important for expression of the disease.
Published:
February 6, 1994
Title:
Interactions between physicians and the pharmaceutical industry: what does the literature say?
Authors:
Lexchin, J.
Abstract:
OBJECTIVE: To determine the effect of three types of interaction between physicians and the pharmaceutical industry--company-funded clinical trials, company-sponsored continuing medical education (CME) and information for physicians supplied by pharmaceutical detailers--on orientation and quality of clinical trials, content of CME courses and physicians' prescribing behaviour. DATA SOURCES: MEDLINE and HEALTH searches for English-language articles published from 1978 to 1993, supplemented by material from the author's personal collection. STUDY SELECTION: A total of 227 papers from the MEDLINE and HEALTH searches and about 2000 items from the author's library were initially reviewed. The following selection criteria were used: studies conducted in Australia, Canada, New Zealand, Britain and the United States; studies conducted after 1977; quantitative surveys containing details of the survey methods; studies on the orientation and quality of company-funded clinical trials and on the content of CME courses giving explicit criteria used in the evaluation; and reports on the outcome of interactions stating how the outcomes were assessed. Thirty-six studies met these criteria. DATA EXTRACTION: Information was extracted on five topics: physicians' attitudes toward drug industry interactions, frequency with which physicians participate in the interactions, orientation and quality of company-funded clinical trials, content of company-sponsored CME courses and changes in physicians' prescribing behaviour as a result of an interaction. DATA SYNTHESIS: Although most physicians participate only occasionally in company-sponsored clinical trials, most see detailers and attend company-sponsored CME courses. However, physicians do not have a very high opinion of the information from detailers or of company-sponsored CME events. Many doctors regard pharmaceutical companies as an important source of funding for clinical trials, but they also have concerns about accepting money from this source. Company funding of clinical trials may affect the quality of the trials and the types of research that physicians undertake. Company-sponsored CME courses may have a commercial bias even if conducted under guidelines designed to ensure the independence of the event. All three types of interactions affect physicians' prescribing behaviour and, in the case of obtaining information from detailers, physicians' prescribing practices are less appropriate as a result of the interaction. CONCLUSIONS: Physicians are affected by their interactions with the pharmaceutical industry. Further research needs to be done in most cases to determine whether such interactions lead to more or less appropriate prescribing practices. The CMA's guidelines on this topic should be evaluated to see whether they are effective in controlling physician-industry interactions. Further measures may be necessary if the guidelines fail to prevent negative effects on prescribing practices.
Published:
November 14, 1993
Title:
Integrin overexpression induced by high glucose and by human diabetes: potential pathway to cell dysfunction in diabetic microangiopathy
Authors:
Roth, T.; Podestá, F.; Stepp, M. A.; Boeri, D.; Lorenzi, M.
Abstract:
Published:
October 14, 1993
Title:
Women Like Meat: The Folklore and Foraging Ideology of the Kalahari Ju/'Hoan
Authors:
Biesele, Megan
Abstract:
Published:
August 31, 1993
Title:
[Thyroid hormone resistance. A significant cause of attention deficit, ADHD/DAMP?]
Authors:
Gillberg, C.
Abstract:
Published:
August 31, 1993
Title:
Commonly occurring plant flavonoids have estrogenic activity
Authors:
Miksicek, Richard
Abstract:
A remarkable diversity of naturally occurring and synthetic compounds have been shown to mimic the biological effects of 17 beta-estradiol by virtue of their ability to bind to and activate the nuclear estrogen receptor. This report extends the family of nonsteroidal estrogens to include several multiply hydroxylated chalcones, flavanones, and flavones. The hormone-like activity of these natural plant products is indicated by their ability to stimulate an estrogen receptor-dependent transcriptional response and to promote growth of estrogen-dependent MCF7 cells in culture. The transcriptional response can be inhibited by the steroidal estrogen antagonist ICI-164,384 and is specific for the estrogen receptor. Evidence is presented to show that selected hydroxylated flavonoids interact directly with the estrogen receptor, based on their ability to compete for the binding of 17 beta-[3H]estradiol to the receptor in cell-free extracts. These compounds are less active, on a molar basis, than 17 beta-estradiol or the synthetic dihydroxystilbene estrogens, but they have potencies comparable to those of other known phytoestrogens. Together, these findings broaden our understanding of the structure-activity relationships for nonsteroidal estrogens and present a series of new chemical prototypes for the future development of potentially useful agonists and antagonists for this nuclear receptor. The wide distribution of weakly estrogenic flavonoid pigments in food crops and medicinal plants raises additional questions about the possible health risks and benefits of these compounds, meriting closer examination of their presence in the human diet.
Published:
July 31, 1993
Title:
Cholesterol loading of macrophages leads to marked enhancement of native lipoprotein(a) and apoprotein(a) internalization and degradation
Authors:
Bottalico, L. A.; Keesler, G. A.; Fless, G. M.; Tabas, I.
Abstract:
Lipoprotein(a) levels in the plasma are strongly correlated with atherosclerotic coronary artery disease. Although the mechanism of this effect is not known, the interaction of lipoprotein(a) with macrophages may be important. Previous work has shown that macrophages in culture internalize and degrade native lipoprotein(a) poorly. In the present study, the interaction of Lp(a) with mouse peritoneal and human monocyte-derived macrophages that were cholesterol-loaded, such as occur in atheromata, was investigated. 125I-Lp(a) degradation was increased 4-5-fold in macrophages that had been loaded with cholesterol by incubation with acetyl-LDL for 2-4 days. The enhanced degradation of Lp(a) by foam cells was chloroquine-sensitive and dependent upon the presence of calcium in the extracellular medium. Incubation of the macrophages with acetyl-LDL plus an inhibitor of acyl CoA:cholesterol acyltransferase, which increased the free cholesterol content and decreased the cholesteryl ester content of the cells, resulted in an even greater up-regulation of 125I-Lp(a) degradation (8-23-fold over control macrophages). The interaction of Lp(a) with cholesterol-loaded macrophages involved the apoprotein(a) moiety of Lp(a) since 125I-apoprotein(a), but not 125I-Lp(a-), was degraded to a much greater extent by foam cells compared to control macrophages. The uptake and degradation of Lp(a) in foam cells was not mediated by LDL, scavenger, LDL receptor-related protein (LRP), or plasminogen receptors. Thus, cholesterol loading of macrophages markedly enhances the internalization and lysosomal degradation of Lp(a) and apo(a) by a calcium-dependent receptor activity different from known lipoprotein receptors.
Published:
April 24, 1993
Title:
Transforming growth factor-beta up-regulates low density lipoprotein receptor-mediated cholesterol metabolism in vascular smooth muscle cells
Authors:
Nicholson, A. C.; Hajjar, D. P.
Abstract:
The effects of transforming growth factor-beta (TGF-beta) on low density lipoprotein (LDL) receptor-mediated cholesterol metabolism were evaluated in vascular smooth muscle cells. TGF-beta significantly increased the binding, uptake, and degradation of 125I-LDL. This increase was paralleled by an increase in LDL receptor mRNA steady state levels and an increase in cholesterol esterification. The increase in LDL cholesterol metabolism was independent of proliferation. LDL receptor expression in response to TGF-beta was not affected by coincubation with an antibody against platelet-derived growth factor or by cyclooxygenase inhibitors in arterial smooth muscle cells, suggesting that TGF-beta's effect was not mediated through platelet-derived growth factor or prostaglandins, as demonstrated in other cell systems. However, coincubation with pertussis toxin abrogated the effect of TGF-beta on LDL receptor expression, suggesting that a pertussis toxin-sensitive G-protein may be involved in the signal transduction pathway. These results are discussed in terms of their potential effects on cellular cholesterol trafficking.
Published:
December 24, 1992
Title:
Evidence for decreasing quality of semen during past 50 years
Authors:
Carlsen, E.; Giwercman, A.; Keiding, N.; Skakkebaek, N. E.
Abstract:
OBJECTIVE: To investigate whether semen quality has changed during the past 50 years. DESIGN: Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991). SUBJECTS: 14,947 men included in a total of 61 papers published between 1938 and 1991. MAIN OUTCOME MEASURES: Mean sperm density and mean seminal volume. RESULTS: Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p
Published:
September 11, 1992
Title:
Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins
Authors:
Neeper, M.; Schmidt, A. M.; Brett, J.; Yan, S. D.; Wang, F.; Pan, Y. C.; Elliston, K.; Stern, D.; Shaw, A.
Abstract:
Advanced glycosylation end products of proteins (AGEs) are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. A approximately 35-kDa polypeptide with a unique NH2-terminal sequence has been isolated from bovine lung and found to be present on the surface of endothelial cells where it mediates the binding of AGEs (receptor for advanced glycosylation end product or RAGE). Using an oligonucleotide probe based on the amino-terminal sequence of RAGE, an apparently full-length cDNA of 1.5 kilobases was isolated from a bovine lung cDNA library. This cDNA encoded a 394 amino acid mature protein comprised of the following putative domains: an extracellular domain of 332 amino acids, a single hydrophobic membrane spanning domain of 19 amino acids, and a carboxyl-terminal domain of 43 amino acids. A partial clone encoding the human counterpart of RAGE, isolated from a human lung library, was found to be approximately 90% homologous to the bovine molecule. Based on computer analysis of the amino acid sequence of RAGE and comparison with databases, RAGE is a new member of the immunoglobulin superfamily of cell surface molecules and shares significant homology with MUC 18, NCAM, and the cytoplasmic domain of CD20. Expression of the RAGE cDNA in 293 cells allowed them to bind 125I-AGE-albumin in a saturable and dose-dependent manner (Kd approximately 100 nM), blocked by antibody to RAGE. Western blots of 293 cells transfected with RAGE cDNA probed with anti-RAGE IgG demonstrated expression of immunoreactive protein compared to its absence in mock-transfected cells. These results suggest that RAGE functions as a cell surface receptor for AGEs, which could potentially mediate cellular effects of this class of glycosylated proteins.
Published:
July 24, 1992
Title:
Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface.
Authors:
Schmidt, A. M.; Vianna, M.; Gerlach, M.; Brett, J.; Ryan, J.; Kao, J.; Esposito, C.; Hegarty, H.; Hurley, W.; Clauss, M.
Abstract:
A M Schmidt, M Vianna, M Gerlach, J Brett, J Ryan, J Kao, C Esposito, H Hegarty, W Hurley, M Clauss
Published:
July 24, 1992
Title:
Induction of low density lipoprotein receptor and a transcription factor SP-1 by tumor necrosis factor in human microvascular endothelial cells
Authors:
Hamanaka, R.; Kohno, K.; Seguchi, T.; Okamura, K.; Morimoto, A.; Ono, M.; Ogata, J.; Kuwano, M.
Abstract:
We have previously reported that tumor necrosis factor-alpha (TNF-alpha) enhances expression of interleukin-6, collagenase, plasminogen activator inhibitor-1, and basic fibroblast growth factor genes in human omental microvascular endothelial (HOME) cells in culture. In this study, we found that treatment of HOME cells with TNF-alpha or interleukin-1 (IL-1) caused enhanced expression of low density lipoprotein (LDL) receptor. A few-fold increase in both LDL binding activity and the receptor mRNA levels was observed when HOME cells were treated with either TNF-alpha or IL-1. Northern blot analysis showed that cellular expression of LDL receptor gene was significantly increased 12-24 h after exposure to TNF-alpha. No significant changes in the life-span of LDL receptor mRNA were observed in untreated and TNF-alpha-treated cells. Scatchard analysis showed an increased receptor number for LDL in TNF-alpha-treated cells. Parallel to increased LDL binding activity, internalization and degradation of LDL were also increased in HOME cells treated with TNF-alpha or IL-1. TNF-alpha-induced enhancement of LDL receptor gene expression was not observed when cycloheximide was present. Cellular mRNA level of SP-1 gene was increased about 3-4-fold at 12 h after treatment with TNF-alpha. Nuclear run-on assays showed increased transcription of LDL receptor gene as well as SP-1 gene by TNF-alpha. Gel retardation assay with the SP-1 consensus fragment showed that SP-1 binding activity was increased about 4-5-fold 12-24 h after treatment with TNF-alpha. NF-kB binding activity was also dramatically increased, but there is no NF-kB motif on the promoter for LDL receptor gene. The induction of LDL receptor by TNF might be mediated through a transcription factor, SP-1.
Published:
July 4, 1992
Title:
Interleukin-10
Authors:
de Waal Malefyt, René; Hans, Yssel; Roncarolo, Maria-Grazia; Spits, Hergen; de Vries, Jan E.
Abstract:
Despite the short history of interleukin-10, accumulated evidence indicates that this interleukin plays a major role in suppressing immune and inflammatory responses. Yet interleukin-10 also maintains cell viability and acts as a cofactor to promote the growth of lymphoid and myleloid cells in vitro. Here we review the present knowledge on the structure and function of interleukin-10.
Published:
May 31, 1992
Title:
Uncle Sam's Groceries: How Dietary Recommendations Have Changed
Authors:
Burros, Marian
Abstract:
Published:
May 2, 1992
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