Observational studies supplements

Low levels of vitamin E have been associated with increased incidence of coronary artery disease. Observational studies have therefore suggested that supplemental a-tocopherol might have value in the treatment of cardiovascular disease. Clinical studies demonstrated contradicting results regarding the benefits of vitamin E in the prevention of cardiovascular disease. Four... 

The relative contribution, in intact microsomal preparations, of the two monooxygenases to the formation of N-oxygenated C=N functionalities has been frequently assessed by measurements in the presence and absence of selective enzyme inhibitors or positive effectors. These observations were supplemented by studies using highly purified native or recombinant proteins in reconstituted systems. 

In five of six nondietary tumor-promotion experiments, sodium selenide significantly reduced the number of mice with tumors induced by 7,12-dimethyl-benzanthracene (DMBA)-croton oil (1). In these experiments, sodium selenide was applied concomitantly along with croton oil to female Swiss albino mice initiated with DMBA. Riley has also observed a reduction in DMBA-phorbol ester carcinogenesis by sodium selenide (2). The effect of selenium-deficient and selenium-adequate diets on DMBA-croton oil and benzopyrene skin carcinogenesis has also been studied. Supplemental dietary selenium inhibited both types of carcinogenesis. 

Experiments by Curtis et al. (129) gave evidence that the observed effects of n-3 fatty acids were not always mediated by the alterations in eicosanoid metabolism. In that study, supplementation of IE-1-stimulated cultured chondrocytes... 

Several observational studies have shown that dietary supplementation of folate in women of childbearing age who might become pregnant can reduce the risk of fetal neural tube defects (e.g., spina bifida). 

Vitamin C positively influences coUagen production, and increases osteoblast formation and osteoclast formation and survival. Some, but not aU, observational studies showed that vitamin C supplementation (1000 mg or more) was associated with higher BMD than that of nonusers. Again, it is premature to suggest routine supplementation. 

Complications. In several cases, other relations are observed, and only for some of these have fitting explanations been found. From such studies, supplemented with some reasoning, the following complications may be derived. It will often be difficult to distinguish between them. We will not discuss the various types of kinetics observed or derived from inactivation models. 

Vol. 330, pgs. 1029-1035,1994. (Note This is interesting in that protective benefits of taking vitamin E supplements were not seen while beta carotene may have worsened the situation. The authors concluded that taking just supplements needs to be further evaluated and that possibly these vitamins are not the active cancer-inhibiting components of fruits and vegetables that are observed to protect in observational studies.)... 

Although the addition of dietary calcium can reduce diastolic blood pressure in healthy adults, it most visibly affects systolic blood pressure in patients with mild to moderate hypertension (Morris et al. 1984, McCarron and Morris 1985). Indeed, there is now cumulative evidence from more than 60 observational studies as well as randomized clinical trials, that low dietary calcium is a significant risk factor for primary hypertension, or, conversely, that calcium supplementation causes a consistent fall in blood pressure (McCarron and Reusser 1999). 

In summary, trials of antioxidant supplementation of smokers and nonsmokers with vitamin C, a-tocopherol, or p-carotene did not generally find significant decreases in biomarkers of oxidative DNA damage, in contrast to observational studies, which suggest an inverse association between dietary antioxidant intake and oxidative DNA damage. 

Observational studies Long-term octreotide LAR has been studied in 108 patients with midgut neuroendocrine tumors who were followed for 8 years [75 ]. Patients were followed at 6-monthly intervals and seven developed asymptomatic cholelithiasis (average time after the start of treatment 26 months). The rest of the adverse events occurred within 3 months of the start of therapy. Four patients developed severe reactions (an anaphylactic rash, severe abdominal pain, increased diarrhea, and bradycardia) to the test dose of subcutaneous octreotide and were excluded from the study 28 developed steatorrhea, which resolved after the introduction of pancreatic enzyme supplements. Six patients reported... 

Thus, epidemiological cohort studies can provide associations between vitamin intake either from food or from fortified food or supplements and a specific disease, and the RCTs can provide a proof whether this association is causal or not. The major differences are that the cohort studies usually include healthy people at baseline, while the RCTs usually include patients who suffer from the disease (secondary prevention). Observational studies usually have longer follow-up periods and they assess food intake, from which vitamin intake is calculated from. It may also be mentioned that an observational study may either find an increased disease risk at low intake or low plasma levels of a nutrient (usually in the lowest quartile or quintile of the cohort), which is opposite to the finding of a reduced disease risk at high intake or high plasma levels. RCTs, however, aim to find a reduced disease risk at high intake levels that is achieved through the nutrient supplement used. This difference is discussed in more detail below. 

Figure 2.2 Observational studies on folate intake and future risk of cardiovascular events. The point estimate is given, together with the 95% confidence interval. Usually the risk estimate is figured for the highest quartile or quintile of folate intake (also including intake of folic acid by dietary supplements) compared to the lowest quartile or quintile. Figure based on Al-Delaimy et al. (2004), Bazzano et al. (2002), He et al. (2004), Larsson et al. (2008), Rimm et al. (1998), Van Guelpen et al. (2005), Voutilainen et al. (2001) and Zee et al. (2007).

Reasons for the divergent results achieved by observational studies and randomized clinical trials are largely unknown. Among possible reasons, there may be substantial residual bias in the observational studies (Lawlor et al. 2004) it is important to consider lifelong vitamin intake instead of short-term vitamin supplementation, different ehemieal stmetures of vitamins in food V5. in supplements (most pronouneed for folie add in supplements vs. the various forms of folate in food), and the differenees in treating patients already suffering from a disease (as in the randomized elinieal trials) from observing healthy subjects (as in the observational studies). Additionally, in the majority of studies, most patients randomized were without overt vitamin delidency and the interactive effects of other nutrients have not usually been considered. 

B vitamin intake or vitamin blood concentrations have also been related to various cancers. The cancer types that have been best investigated with respeet to folic acid are colon cancer and colorectal cancer. Convincing evidence from observational studies led to the initiation of randomized controlled trials with folic acid in colorectal adenomas. However, similar to cardiovascular disease, there seems to be a discrepancy between the observational epidemiological studies that reported in the majority an inverse association of folate and cancer risk, and the effect of folic acid supplementation in the randomized controlled trials, which reported no effect of folic add on recurrence of colorectal adenoma risk. 

To assess the relationship of Hey concentrations with vascular disease risk, a meta-analysis of observational studies was carried out, showing that elevated Hey is at most a modest independent predictor of ischemic heart disease and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood Hey concentrations will help determine whether Hey is causally related to vascular disease, as may large randomized trials of the effects on ischemic heart disease and stroke of vitamin supplementation to lower blood Hey concentrations (Homocysteine Studies Collaboration 2002). 

The homocysteine hypothesis of vascular disease has attracted considerable interest since homocysteine levels are readily lowered by daily dietary supplementation with folic acid, vitamin Bg and vitamin B12 (Homocysteine Lowering Trialists Collaboration 2005), raising the prospect that dietary supplementation with these B vitamins could prevent vascular disease. Indeed, dietary supplementation with B vitamins to lower homocysteine levels of affected individuals is remarkably effective for the prevention of cardiovascular disease and other complications of homocystinuria (Yap et al. 2001). This review examines the evidence from the observational studies of homocysteine and vascular disease and from the randomized trials of B vitamin supplementation for the prevention of vascular disease. 

In order to estimate reliably the associations of homocysteine with CHD and stroke outcomes, individual participant data were collected from all observational studies of homocysteine with CHD and stroke outcomes for the Homocysteine Studies Collaboration (Homocysteine Studies Collaboration 2002). With individual participant data, the Homocysteine Studies Collaboration meta-analysis was able to examine the shape and strength of association of homocysteine with vascular disease after adjustment for bias and confounding due to other risk factors (Homocysteine Studies Collaboration 2002). After excluding individuals with prior disease at enrolment and adjustment for smoking, blood pressure and cholesterol, a 25% lower usual i.e. longterm) homocysteine concentration (about 3 pmol/L, a difference typically achieved by folic add supplementation in populations without mandatory fortification of grain products with folic acid) was associated with an 11% (95% Cl 4-17%) lower risk of CHD and a 19% (5-31%) lower risk of stroke (Homocysteine Studies Collaboration 2002). 

Although the observational studies suggested modest associations of homocysteine with risk of vascular disease that were biologically plausible, such studies could not establish if these associations were causal. The randomized trials assessed the effectiveness of dietary supplementation with B vitamins to lower homocysteine levels on risk of cardiovascular morbidity and mortality. The initial trials were designed in the mid-1990s before the results of the Homocysteine Studies Collaboration meta-analysis (Homocysteine Studies Collaboration 2002) were reported in 2002. Consequently, few of the individual trials had sufficient statistical power to confirm or refute the 10% difference in... 

It has been shown that regular use of vitamin C supplements increases blood concentrations by 0.36 to 0.46 mg/dl (Dickinson et aL, 1994). There also seems to be no differences in bioavailability between dietary and supplemental vitamin C (Mangels et al., 1993). Therefore, theoretically, results from epidemiological investigations regarding the effect of vitamin C supplements on risk in observational studies should be considered a significant contribution to the evidence of a causal relationship since the pure substance is applied. 

Another observational study, the first National Health and Nutrition Examination Survey, examined vitamin C intake using both food frequency and 24-hr recall questionnaires (Enstrom et ai, 1992). The 11,349 men and women in the study, ages 25-74, were followed for a median period of ten years. CVD mortality rates were 34% lower (relative risk = 0.66 95% Cl = 0.53-0.82) than expected among participants with the highest vitamin C intake defined as 50 mg or more from the diet plus regular supplements (Table IV). One potential limitation of this study was the inability to examine and control for the possible correlation of vitamin C with other vitamin supplements, particularly vitamin E. 

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