Diet, Exercise, and Chronic Disease: The Biological Basis of Prevention

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Such an approach could be used in trials of calcium consumption for colorectal adenoma and colorectal cancer prevention. Intermediate outcome trials can usually be carried out with a much smaller sample size than an RCT with chronic disease outcomes, but they may not comprehensively address corresponding public health issues. Depending on the biologic effects of an intervention, high-risk individuals or those with prior disease history may not benefit as much from an intervention being tested as do other individuals.

Trials in populations at high risk for certain diseases may provide limited information on intervention effects for other diseases that might be helpful for benefit-versus-risk projections for healthy people. Hence, designing trials for high-risk subjects involves careful consideration of such tradeoffs and of the costs of identifying and managing high-risk study subjects versus subjects from the general population. Observational studies, particularly cohort studies, complement intervention trials for testing nutrition and physical activity and chronic disease hypotheses but, as discussed above, confounding and measurement error biases may limit their reliability for testing such hypotheses.

Judicious selection of a study population can help control these biases; for example, populations that have unusually broad distributions of food consumption and physical activity patterns may be particularly valuable because disease risk trends across exposure levels may be large relative to measurement error and confounding influences. Individuals in certain carefully selected populations could be comparatively good providers of data on dietary and physical activity patterns and may generally be highly reliable study participants.

One example is the Adventist Health Study, a cohort study of Seventh-day Adventists in the United States, which focuses on diet and cancer and involves an unusually broad range of nutrition and physical activity exposures compared with other U. Indeed, this cohort includes large populations of whites and blacks who consume soy protein at levels similar to that of Asians.

A second example is the Multiethnic Cohort MEC study in Hawaii and Los Angeles approximately study subjects , which includes approximately equal numbers of white, Latino, African-American, and Japanese-American subjects, along with a smaller number of native Hawaiians. This cohort study has a major focus on nutrition and cancer, and the subjects have considerable variation in their nutrient consumption and dietary patterns, with some noteworthy variations among ethnic groups. The MEC study allows nutrient—disease associations to be examined within ethnic groups and provides a type of built-in replication of study findings that is enhanced by variations in tumor characteristics and genetic susceptibility characteristics among ethnic groups.

A third example is the European Prospective Investigation into Cancer and Nutrition EPIC , which comprises cohorts in several western European countries that have wide variations in cancer incidence rates. The cohorts combined include more than study subjects. Different dietary data collection instruments across populations are calibrated using standardized hour dietary recalls as a common instrument, with some additional calibration using urinary nitrogen as an objective marker of recent protein consumption. The various dietary questionnaires are administered in each country's language, and they assess country-specific foods and dietary patterns.

The EPIC study is an excellent example of what is achievable a large sample size, a wide range of dietary intake patterns, and an ability to make absolute intake estimates only if mutually comparable calibration activities are funded and prospectively built in to observational studies. In addition, the effectiveness of a relatively short physical activity questionnaire was compared with more extensive questionnaires in the EPIC study In contrast to a typical ecologic study, which relates population estimates of mean nutrient consumption and estimates of mean confounding factors to disease rates, an aggregate data study relates individual-level nutrition and physical activity exposures and confounding factor values from representative surveys in each population to corresponding population disease rates 60 — The aggregate data study design is robust to classical additive measurement error in primary exposure and confounding factors and may also offer some robustness to systematic measurement error if there are disparate nutrition and physical activity patterns among the populations being compared.

On the other hand, it may be difficult to ascertain exposure data in a uniform and comparable manner across diverse populations, and there is little experience to guide data collection and analytic procedures to control between-population confounding. Thus, it seems reasonable to conduct an aggregate data study within existing multi-population cohort studies e. Analyses that examine the consistency of associations within and between populations may help determine the potential of a more worldwide aggregate data study of diet and cancer NIH funding for such a study has previously been requested by a subset of this commentary's authors.

Studies that involve population comparisons may improve our understanding of the considerable variations in incidence rates of various cancers in relation to nutrition and physical activity exposures and of the genomic and proteomic biomarkers from blood specimens and shed cells; this type of study might also be useful for comparing histologic and molecular characteristics of diseases across populations. Studies of migrant populations provide unique opportunities to examine chronic disease associations.

Not only do such populations tend to have unusually broad exposure distributions, they are also suited to the examination of temporal relationships between ages at and durations of exposures and chronic disease risk. Two examples are the nutrient and disease associations among Japanese subjects in the MEC who migrated to the United States and the breast cancer incidence among Asians who migrated to the United States, according to age at and years since migration 2.

To date, however, few cohort or case—control epidemiologic studies have been conducted among migrants. It should also be noted that time for insightful migrant studies may be limited; for example, colorectal cancer incidence rates in Japan now exceed those in the United States 63 and, thus, colorectal time-trend studies within Japan may now be preferable to studies of Japanese migrants. Traditional sources of hypotheses in the areas of nutrition and physical activity and chronic disease areas have included observational epidemiology and therapeutic trials.

Although both sources are valuable, the former may lack specificity, given the highly correlated patterns for the consumption of various nutrients and the measurement error issues previously discussed. Additionally, hypotheses from therapeutic trials cannot be expected to include interventions that act predominantly at the early stages of disease development and are likely to be pharmaceutical rather than lifestyle interventions.

Given that practical and specific nutritional and physical activity approaches to obesity and chronic disease prevention have important potential for improving public health, basic research programs that include preclinical and early-stage clinical intervention trials for generating and screening hypotheses seem essential. Preclinical and early-stage clinical trials of nutrition and chronic disease can focus on the interaction between consumption of bioactive food components and genomic DNA nutrigenomics ; on the interaction between bioactive food components and DNA methylation and other epigenomic events; on gene expression changes in relation to dietary patterns; on corresponding proteomic changes, since there tends to be a modest correlation between mRNA and protein expression and post-translational modifications; and on metabolomics to incorporate aspects of metabolite regulation and metabolic pathways.

For example, diet and physical activity may influence genetic and epigenetic events associated with several cancer processes, including carcinogen metabolism, hormone regulation, cell differentiation, apoptosis, and cell cycle regulation. Identification of nutrition and physical activity interventions that have favorable effects on cancer processes and on corresponding processes for other chronic diseases e.

One interesting hypothesis that arose from rodent models is that dietary caloric restriction reduces the incidence of various chronic diseases and increases lifespan. This hypothesis has stimulated research to identify a metabolic serotype for dietary restriction in rodents 64 , to identify the disease prevention mechanism, to extend the results to nonhuman primates on defined diets, and to identify humans whose disease risk can be modified by changing their energy consumption. Termination of dietary restriction leads to a rapid return to insulin resistance and to pre-restriction gene expression patterns; thus, continued restricted caloric intake over most of the lifespan may be needed for the full benefits associated with lowered caloric intake to be realized.

If dietary restriction begins during early adulthood, rodents do have increased longevity, though the effects are considerably smaller than with lifelong dietary restriction Intermittent dietary restriction—as little as 1 day in 4—increases longevity in rats 66 , and both adult onset dietary restriction and fasting for 1 day in 7 have been shown to delay tumor onset in pdeficient transgenic mice Studies in rodent models, as well as in other model systems, can provide a valuable tool for the initial assessment of nutrition and physical activity hypotheses to define intervention mechanisms.

Simple, low-dimensional surrogate endpoints are unlikely to be available for this purpose, especially if chronic disease outcomes of interest include multiple biologic entities. Effective data analysis methods are needed to bring intervention effects for multiple intermediate markers into summary indices to be used for interpreting study results.

For example, in global gene expression studies, dietary modification e. These genes can be organized into functional categories e. The voluminous information on gene expression, proteomics, and metabolomics that is emerging relative to dietary restriction and other nutrition and physical activity hypotheses is difficult to assimilate because numerous metabolic pathways are likely to be involved for many diseases. Fortunately, a variety of new bioinformatics and data analysis tools for this type of task e. Human nutrition intervention studies are well-suited to improving the understanding of the effects of dietary patterns on metabolism and on biomarkers of disease susceptibility.

Such studies involve a controlled, administered diet and are typically limited to a few weeks or months. Crossover designs, in which study subjects are exposed to more than one of the dietary patterns under study for part of the follow-up period, are frequently used in these studies. Human nutrition intervention studies can provide an early evaluation of the plausibility of hypotheses generated from observational studies or from model systems. They can also provide a useful setting to identify exposure biomarkers, to study exposure bioavailability, and to identify nutrient—gene interactions.

Human nutrition intervention studies can be used to generate new hypotheses and can serve as pilot studies for larger scale intervention trials.

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Outcome measures may derive from tissue samples from organs of interest or peripheral tissues, including exfoliated cells. A broad range of biomarkers, including those for gene expression, protein expression, and epigenetic changes may be considered. For example, as the technical aspects of high-dimensional protein expression measurements become more refined, and as protein patterns that indicate susceptibility for specific chronic diseases are identified, human nutrition studies to broadly determine the relationship between diet and protein expression may become possible.

Small-scale physical activity intervention trials with biomarker or intermediate outcomes likewise have a role in physical activity hypothesis generation and development.

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Such studies involve controlled physical activity interventions and could examine the same range of gene expression, protein expression, and epigenetic biomarkers as nutrition trials. Intermediate outcome physical activity intervention trials to date have had somewhat larger sample sizes i. For example, a recent exercise intervention trial 68 was conducted in sedentary, overweight postmenopausal women randomly assigned to a moderate-intensity exercise program or to a control group, with outcomes that included sex hormone concentrations and body fat distribution 69 , Such physical activity hypothesis generation efforts need to consider both acute and chronic effects of physical activity.

Hypothesis development research in the nutrition and physical activity area needs to target both a medical model that aims to provide interventions for individuals according to their genotype and specific exposures and a public health model that aims to develop nutrition and physical activity interventions and recommendations that are applicable to the general population, or major segments thereof.

Each model has its own infrastructure and funding needs. Specifically, cooperative therapy groups may be well-suited for conducting trials under a medical model, but a different type of population-oriented structure may be better suited for screening and testing nutrition and physical activity public health interventions. Dietary and physical activity guidelines for health promotion and disease prevention have been promulgated by various government agencies, scientific panels, and professional groups 71 — For example, the Food and Nutrition Board of the Institute of Medicine periodically assembles expert panels to review the scientific literature and establish recommended dietary allowances 74 and has expanded its efforts to establish dietary reference indices for a broad range of nutrients.

The recent report on macronutrients 75 includes recommendations for physical activity that are somewhat different from those given earlier 76 ; it also reinforces the need for coordinated objectives in making public health recommendations on nutrition and physical activity. The dietary reference indices for a given nutrient include a recommended dietary allowance based on an estimated average requirement. When available scientific data are inadequate for establishing an average requirement, an adequate intake is given.

An upper limit of consumption that acknowledges safety concerns is also specified whenever practical. Reference intake levels are given separately by age and sex and for pregnant and lactating women and are used as the basis for determining the standards for nutritionally adequate diets for many federal assistance programs. Thus, the recommended allowances for specific nutrients, which are based on estimates of average requirement, are intended primarily to prevent deficiency syndromes.

When a recommended allowance is not available, observed intakes in healthy populations are used as a basis for recommending adequate intake. Likewise, human data on which to base tolerable upper intake levels are often sparse, and when uncertainty factors used to adjust from lowest observed adverse effects levels are applied to compensate for that lack, there may be some overlap between recommended intakes and upper intake limits.

Thus, research studies that aim to close gaps in the scientific database for setting dietary reference indices related to chronic disease prevention would be useful. The panel also considers nutrient interactions and susceptible subpopulations when setting dietary reference indices and is moving toward a greater emphasis on the whole diet. Similarly, recommendations for using physical activity and weight control to reduce the risk of cancer and other diseases have been made by several groups 76 , 77 , Again, important knowledge gaps exist, both for individual disease outcomes and for overall health and, to date, no physical activity intervention trial with chronic disease outcomes has been conducted in the general population.

The FDA has regulatory responsibility for health claims i. Congress subsequently provided a mechanism whereby recommendations from authoritative bodies e. Dietary Guidelines could serve as the source for authorized health claims in lieu of FDA review. More recently, judicial decisions have confirmed the right of manufacturers, under the free speech protections of the Constitution, to make truthful and not misleading claims about substance and disease relationships that are based on preliminary evidence. Accordingly, the FDA has developed an evidence-based ranking system to rate the level and quality of scientific evidence available for a specific relationship.

Health claims on food labels have the potential for a helping consumers identify and use healthful foods as part of a lifestyle pattern that is effective in reducing the risk of chronic diseases, b increasing consumer awareness about the role of a healthful diet in disease risk reduction, and c motivating manufacturers to formulate and market healthful foods. Unfortunately, to date, the preliminary nature of much of the scientific information on food substance and disease relationships has limited the number of claims that can meet the evidentiary standard of significant scientific agreement.

Improved approaches for facilitating research on the nutrition and disease relationships discussed here could have significant impact on public health via food labeling provisions under the jurisdiction of the FDA. The workshop participants agreed on 10 general points regarding nutrition and physical activity and chronic disease from the topics discussed above, along with more specific research recommendations in four areas. Changes in nutrition and physical activity patterns may be key to reversing the obesity epidemic in North America and elsewhere and to reducing the risk of various chronic diseases in developed countries.

Related basic, epidemiologic, and public health research toward identifying practical nutrition and physical activity interventions and patterns that will benefit health should have a high priority on national and international health research agendas. Highly credible research results are needed to favorably influence individuals' choices about nutrition and physical activity, advice given by primary-care providers, agricultural policies, food production and processing choices, environmental design, educational choices, and food fortification and regulation.

The conduct of the needed research should be recognized as a demanding task that is now becoming scientifically achievable. In view of numerous methodologic challenges, a varied nutrition and physical activity research agenda is needed that includes large studies of long duration. Major research funding organizations should acknowledge these requirements. The nutrition and physical activity research agenda, as with other chronic disease prevention efforts, should emphasize overall health benefits versus risks, with implications for funding opportunities and mechanisms.

The nutrition and physical activity research agenda needs to include the following components: biologically based hypothesis generation and initial testing, observational studies of the association of nutrition and physical activity with chronic disease, screening and testing of promising interventions using intermediate outcomes, and full-scale nutrition and physical activity intervention trials with disease outcomes that are supported by earlier phase studies and that have potential for improving public health.

The relative emphasis among the listed program components should depend on the ability of specific research initiatives to address pertinent nutrition and physical activity questions in a reliable and interpretable fashion, while taking advantage of emerging technologies and research opportunities.

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Methodologic research that strengthens the efficiency and reliability of major study designs and elucidates the interplay among designs in the context of nutrition and physical activity and chronic disease should be a key element of the research agenda. Methodologic research on suitable biomarkers and measurement error models for self-report assessments of nutrition and physical activity is clearly needed.

Research that could inform nutrition and physical activity recommendations and regulations should be encouraged. The implications for improved public health and the research opportunities related to nutrition and physical activity are large and warrant the energies of a large cadre of basic, clinical, and population scientists, working across disciplines More specific research recommendations, following small-group and full workshop discussions, are given below for measures of nutrition and physical activity patterns and status, hypothesis development and phase II trials, cohort and cross-sectional studies, and criteria and strategies for initiating full-scale phase III trials with disease outcomes.

Recommended research on markers of food consumption and health status would include studies of the tissue distribution and speciation of nutrients and research on non-nutrient biology in humans and in model systems. Similarly, augmented exercise physiology research in humans and model systems is needed. Recommended human research would aim to better describe and accommodate biases in self-reports and would study measurement error correlations across various self-report instruments.

Research on cognitive and behavioral methods to reduce bias and measurement error would also be desirable. Methods that combine dietary and physical activity recall, records, frequencies, and histories with multiple measurements using specific instruments in cohort studies would be helpful. Pattern recognition studies using high-dimensional biologic data e. Additional studies of variability are needed for many biomarkers, whether or not they have been validated for assessing nutrient consumption or physical activity. For some bioactive food components, biomarkers may provide the only way to assess intake or nutritional status.

More basic research, especially small-scale human nutrition and exercise intervention trials with biomarker outcomes, will invigorate hypothesis generation and initial testing of the relationships between nutrition and physical activity and chronic disease. Opportunities for training in clinical nutrition and exercise physiology research with a focus on specific chronic diseases, and directed funding opportunities for high-priority clinical trials to evaluate biomarker efficacy and safety outcomes would be especially welcome.

Phase II trials with a comprehensive set of biomarker outcomes are necessary for translating results from laboratory studies to full-scale intervention trials. Phase II trials can also increase the likelihood of a successful health benefit versus risk result in a subsequent phase III trial by refining the interventions, developing adherence strategies, evaluating the translation of efficacy results from studies in cells and animals to humans, developing safety indicators, and studying the relationship between intervention interactions and genetic and environmental factors.

Cohort and cross-cultural studies should continue to be a mainstay method for the epidemiologic study of nutrition and physical activity and chronic disease associations. However, the credibility and interpretation of observed associations is diminished by uncertainty concerning the measurement error properties of dietary and physical activity assessment instruments and the extent to which confounding has been controlled—both confounding by other difficult-to-measure nutrition and physical activity variables and residual confounding by non-nutrition and physical activity variables.

In response, research on methods for using validated nutrient consumption and physical activity biomarkers within subcohorts to calibrate self-reports of nutrition and physical activity in cohort studies is strongly indicated. Collaborations among investigators involved in existing cohort studies should be encouraged. An annual meeting of investigators who are studying cohorts that have collected comprehensive dietary and physical activity data could facilitate such collaboration and could provide a forum for interaction with basic scientists.

Additional research efforts are needed to ensure that existing major cohort studies include clinical outcomes that are comprehensive enough to allow meaningful assessments of overall benefit versus risk. Another issue is whether or not existing cohorts allow a sufficient response to current nutrition and physical activity opportunities.

Consideration should be given to whether additional cohort studies having nutrition and physical activity and chronic disease goals are needed among children, in understudied geographic areas e. Case—control studies may be useful for the initial exploration of some nutrition and physical activity issues, especially those concerning exposures at early ages.

Nutrition and physical activity hypotheses having biologic plausibility and substantial public health potential should be subjected to full-scale phase III intervention trials, when practical. Trans-NIH forums need to be established to identify the most promising nutrition and physical activity interventions for phase III trials and to review trial proposals by external investigators. Review criteria would include an assessment of biologic plausibility, an assessment of concordance with observational and other data sources, an evaluation of the public health importance, and a determination that less costly designs will not be able to resolve the benefit-versus-risk question in a reliable manner.

For example, the possibility of conducting a phase III physical activity intervention trial is currently of great interest, and the trans-NIH forum suggested above could assess whether a general population trial, say among persons aged 50 years or older, is currently merited. Alternatively, the assessment could consider whether new or additional intervention trials among those at high risk for targeted diseases e. One possibility for the development of a forum for identifying nutrition and physical activity and chronic disease hypotheses that are suitable for phase III testing would be a new nutrition and physical activity and chronic disease cooperative group comprising investigators who have interest and expertise in basic, clinical, and population aspects of nutrition and physical activity and who have interest and expertise in pertinent health-related outcomes.

Such a cooperative group could conduct studies of various phases of nutrition and physical activity hypotheses and could receive and evaluate concepts from the scientific community for new studies, including phase III clinical trials. Concepts endorsed by the cooperative group could then be developed into full proposals for appropriate peer review. We recommend that the NIH consider initiating such an entity as a way of stimulating and capitalizing on opportunities in this most important research area. Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. W orkshop B ackground and G oals. C ontrolled I ntervention T rials.

I ntermediate O utcome C linical T rials. S tudies in S pecial P opulations and P opulation C omparisons. N utrition and P hysical A ctivity R ecommendations and R egulations.

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D iscussion and R ecommendations. R eferences. Correspondence to: Ross L. Oxford Academic. Google Scholar. Walter C. Peter Greenwald. David Alberts. Leslie Bernstein. Norman F. Tim Byers. Steven K. Gary Fraser. Laurence Freedman. David Hunter. Victor Kipnis. Laurence N.

Bruce S. Alan Kristal. Johanna W. Anne McTiernan. John Milner. Ruth E. John D. Elio Riboli. Arthur Schatzkin. Allison Yates. Elizabeth Yetley. Cite Citation. Permissions Icon Permissions. Abstract A shortage of credible information exists on practical dietary and physical activity patterns that have potential to reverse the national obesity epidemic and reduce the risk of major cancers and other chronic diseases.

Wang, and Emily White for their workshop comments and participation. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. N Engl J Med. Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst. Calcium supplements for the prevention of colorectal adenomas. A randomized trial of aspirin to prevent colorectal adenomas. Risks and benefits of estrogen plus progestin in healthy postmenopausal women; principal results from the Women's Health Initiative randomized controlled trial. The influence of finasteride on the development of prostate cancer.

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. Vitamin D3 and calcium to prevent hip fractures in elderly women. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria.

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Diabetes Prevention Program Research Group. Tannenbaum A. Genesis and growth of tumors.

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Effects of a high fat diet. Cancer Res. Greenwald P. Role of dietary fat in the causation of breast cancer: point.

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Cancer Epidemiol Biomarkers Prev. Hunter DJ. Role of dietary fat in the causation of breast cancer: counterpoint. Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. Cohort studies of fat intake and the risk of breast cancer—a pooled analysis.

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  • Dietary fat and breast cancer revisited: a meta-analysis of the published literature. Br J Cancer. Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial. Design of the Women's Health Initiative clinical trial and observational study.

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    Women's Health Initiative Study Group. Control Clin Trials. Adherence to a dietary fat intake reduction program in postmenopausal women receiving therapy for early breast cancer. The Women's Intervention Nutrition Study. J Clin Oncol. Premenopausal fat intake and risk of breast cancer. Are imprecise methods obscuring a relationship between fat and breast cancer?

    Nutrition and lung cancer. Cancer Causes Control. Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers among male smokers. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

    Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.

    Vitamin E consumption and the risk of coronary disease in women. Vitamin E supplementation and cardiovascular events in high-risk patients. Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat in relation to body mass.

    Physical Activity and Chronic Disease Prevention

    They cover aspects such as disease etiology, effects of diet and exercise, and the cellular and molecular mechanisms of how various dietary components and repeated exercise alter disease etiology to contribute to disease prevention. Since inflammatory signaling is a fundamental component of the chronic diseases discussed, the book includes a separate chapter on inflammation and innate immune responses. Obesity as a contributing factor is addressed within the specific disease chapters. The book also reviews what is known about the factors that influence food intake in humans.

    This reference translates molecular-based data on etiology and prevention into a clinical prescription for the prevention of chronic disease. Product Image. Company Details. About the Company. Year of Establishment Nature of Business Manufacturer. Number of Employees Upto 10 People. Annual Turnover Rs. I agree to the terms and privacy policy. View Mobile No. Send SMS. Send Email. Save time! Get Best Deal. Follow us on: Facebook Twitter. All rights reserved.