The important life-supporting role of hydrogen sulfide (H2S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H2S had only been known for its toxicity and environmental hazard. Physiological importance of H2S has been appreciated for about a decade. It started by the discovery of endogenous H2S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H2S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H2S. The physiological functions of H2S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H2S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes...

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Physiological Implications of Hydrogen Sulfide: A Whiff Exploration That Blossomed

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673698110589.pdf

Homocysteine and vascular disease.

Background In 1996, the Food and Drug Administration issued a regulation requiring all enriched grain products to be fortified with folic acid to reduce the risk of neural-tube defects in newborns. Fortification (140 μg per 100 g) began in 1996, and the process was essentially complete by mid-1997. Methods To assess the effect of folic acid fortification on folate status, we measured plasma folate and total homocysteine concentrations (a sensitive marker of folate status) using blood samples from the fifth examination (January 1991 to December 1994) of the Framingham Offspring Study cohort for base-line values and the sixth examination (January 1995 to August 1998) for follow-up values. We divided the cohort into two groups on the basis of the date of their follow-up examination: the study group consisted of 350 subjects who were seen after fortification (September 1997 to March 1998), and the control group consisted of 756 subjects who were seen before fortification (January 1995 to September 1996). Resu...

https://www.nejm.org/doi/pdf/10.1056/NEJM199905133401901

The Effect of Folic Acid Fortification on Plasma Folate and Total Homocysteine Concentrations

disease. Study Selection: Prospective studies and major retrospective epidemiologic studies evaluating the association between homocyst(e)ine levels and cardiovascular disease and the association between blood levels or dietary intake of folate, vitamin B 6, and vitamin B12 and cardiovascular disease. Data Extraction: Relevant data on patient population, plasma homocyst(e)ine levels, duration of follow-up, and main results were extracted from studies that met the inclusion criteria. Data Synthesis: The designs and results of studies included in this review are summarized. A formal metaanalysis was not performed because the studies were heterogeneous in method and design. Conclusions: Results of epidemiologic studies suggest that moderately elevated plasma or serum homocyst(e)ine levels are prevalent in the general population and are associated with an increased risk for cardiovascular disease, independent of classic cardiovascular risk factors. Simple, inexpensive, nontoxic therapy with folic acid, vitamin B 6, and vitamin B12 reduces plasma homocyst(e)ine levels. Although the association between homocyst(e)ine levels and cardiovascular disease is generally strong and biologically plausible, the data from the prospective studies are less consistent. In addition, epidemiologic observations of an association between hyperhomocyst(e)inemia and cardiovascular risk do not prove the existence of a causal relation. Therefore, the effectiveness of folate, vitamin B 6, and vitamin B12 in reducing cardiovascular morbidity and mortality requires rigorous testing in randomized clinical trials. Several such trials are under way; their results may greatly affect cardiovascular morbidity and mortality, given the simplicity and low cost of vitamin therapy.

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Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.

Homocysteine is a sulfur-containing amino acid, rapidly oxidized in plasma to the disulfides homocystine and cysteine-homocysteine (Figure 1⇓). Plasma/serum total homocysteine, also termed homocyst(e)ine, is the sum of homocysteine in all 3 components. Figure 2⇓ displays factors involved in the metabolism of homocysteine, including its metabolic relationship to methionine. Although dietary intake of total protein and methionine does not correlate significantly with blood homocyst(e)ine,1 a single dose of oral methionine (100 mg/kg body weight) can elevate homocyst(e)ine levels, and as described further below, this has been used as a diagnostic test to detect disordered homocyst(e)ine metabolism. Because variable changes in homocyst(e)ine levels have been observed postprandially,2 it is customary to obtain measurements in the fasting state. Normal levels of fasting plasma homocyst(e)ine are considered to be between 5 and 15 μmol/L. Moderate, intermediate, and severe hyperhomocyst(e)inemia refer to concentrations between 16 and 30, between 31 and 100, and >100 μmol/L, respectively.3 Figure 1. 
Molecular species of homocysteine.





 Figure 2. 
Simplified outline of methionine/homocysteine metabolism. Vitamin coenzymes and substrates: THF, tetrahydrofolate; B2, riboflavin; B6, vitamin B6 as its biological active form, ie, pyridoxal 5′-phosphate; and B12, methyl cobalamin. Intermediate metabolite: DMG, dimethylglycine.



Several vitamins function as cofactors and substrates in the metabolism of methionine and homocysteine (Figure 2⇑). Folic acid and cyanocobalamin (vitamin B12) regulate metabolic pathways catalyzed by the enzymes methylenetetrahydrofolate reductase (MTHFR) and methionine synthase, respectively, whereas pyridoxine (vitamin B6) is a cofactor for cystathionine β-synthase. A number of studies have shown inverse relationships of blood homocyst(e)ine concentrations with plasma/serum levels of folic acid, vitamin B6, and vitamin B12.4 5 6 

Administration of supplemental folic acid in doses between 0.2 and 15 mg/d can lower plasma homocyst(e)ine levels without apparent toxicity.7 8 …

Homocyst(e)ine, Diet, and Cardiovascular Diseases A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association

Background The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. Methods To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. Results Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 μg of folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increas...

Reduction of Plasma Homocyst(e)ine Levels by Breakfast Cereal Fortified with Folic Acid in Patients with Coronary Heart Disease

Polymorphisms in the CBS gene associated with decreased risk of coronary artery disease and increased responsiveness to total homocysteine lowering by folic acid.

Prostate-specific antigen (PSA) is a widely used biochemical marker for prostate cancer (1). PSA, a serine protease, forms complexes with serine protease inhibitors such as α2-macroglobulin and α1-antichymotrypsin (ACT) (2). The major immunoreactive forms of serum PSA are PSA-ACT complex and free PSA. PSA complexed to α2-macroglobulin is not measured by current immunoassays (3). Because the proportion of PSA complexed to ACT is higher in men with prostate cancer than in men with benign prostatic hyperplasia (BPH) (3)(4), the use of a ratio of free-to-total PSA may improve discrimination between men with BPH and prostate cancer (5)(6).

Results obtained with different PSA immunoassays are not interchangeable (7)(8)(9)(10). The variation among immunoassays reflects, in large part, the specificity of different PSA antibodies (7). To a lesser extent, the composition of the calibrator, the PSA values assigned to the calibrator, the test diluent, and the physical design of the immunoassays contribute to intermethod differences (6)(7). Assays using a monoclonal-monoclonal sandwich format yield, in general, an equimolar response to free and ACT-complexed PSA, whereas monoclonal-polyclonal formats tend to yield higher values for samples containing greater proportions of free PSA (8). We have recently described the Bayer Immuno 1TM PSA Assay (Bayer Corporation), which uses a monoclonal-polyclonal antibody format that yields an equimolar response to varying proportions of free and complexed PSA (11). This has now been found to be a result of the unique binding properties of the monoclonal antibody used for the capture of PSA (manuscript in submission).

Proficiency testing among clinical laboratories has indicated large intermethod variability in the quantitation of total PSA (12). The aim of this study was to determine the magnitude and cause of this intermethod variation. Here we report our multi-site analysis of …

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Peter H. Anderson

Papers

Reduction of Plasma Homocyst(e)ine Levels by Breakfast Cereal Fortified with Folic Acid in Patients with Coronary Heart Disease

Polymorphisms in the CBS gene associated with decreased risk of coronary artery disease and increased responsiveness to total homocysteine lowering by folic acid.

Variation in the Quantitation of Prostate-specific Antigen in Reference Material: Differences in Commercial Immunoassays,

Variation in the Quantitation of Prostate-specific Anti- gen in Reference Material: Differences in Commercial