Gender differences in hepatic phylloquinone and menaquinones in the vitamin K-deficient and -supplemented rat.

Gender differences in relation to vitamin K were investigated in the rat. Hepatic phylloquinone and menaquinone (MK-1 to MK-10) concentrations, gamma-carboxyglutamic acid (Gla) excretion, plasma phylloquinone and percent prothrombin were measured in male and female rats on a chow diet (24.5 ng phylloquinone and 8.8 microgram menadione), and on phylloquinone-deficient and -supplemented purified diets (0.38 and 1400 ng phylloquinone/g, respectively). Mean hepatic phylloquinone concentrations varied with dietary intake and ranged from 6.8+/-9.0 pmol/g in the deficient male, to 171. 1+/-56.9 pmol/g in the supplemented female. Menaquinones accounted for a large proportion of total vitamin K in the liver of males and females with MK-4, MK-6, and MK-10 present in highest concentrations. On the chow and supplemented diets, females had significantly higher MK-4, MK-6, and MK-10 concentrations in their livers (P<0.05). On the phylloquinone-deficient diet (-K1), hepatic phylloquinone, MK-4, and to a lesser extent MK-6 (but not MK-10) were significantly reduced (P<0.05). In the phylloquinone-supplemented male and female groups, which did not receive menadione during the experimental period, MK-4 increased above that in the chow groups suggesting synthesis of MK-4 from phylloquinone which was statistically significant in the female (P<0.01). A significant gender difference (P<0.05) was also observed for urinary Gla excretion with less Gla excreted by the females indicating that females may require less dietary phylloquinone than males of the same body weight.

Negative impact of depression on outcomes in patients with coronary artery disease: mechanisms, treatment considerations, and future directions.

Depressive symptoms are common in coronary artery disease (CAD) patients, and are associated with increased cardiac risk. Although an important relation exists between depression and CAD prognosis, the underlying pathophysiological mechanisms are poorly understood. Additionally, evidence including the recently published ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) trial suggests that depression treatments do not lower recurrent cardiac risk. The reason for the observed lack of benefit with depression treatment in CAD patients is unclear. In this review, we discuss the impact of depression in CAD patients, the possible mechanisms involved, the studies that have examined the effects of psychological and antidepressant therapies on recurrent cardiac events, and the direction that future research should take.

Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects.

The response of osteocalcin and other biochemical markers of vitamin K status to diets formulated to contain different amounts of phylloquinone was assessed in nine healthy subjects aged 20-33 y. Subjects resided in a metabolic ward for two 15-d cycles with a minimum of 6 wk between cycles. A mixed diet containing 100 micrograms phylloquinone/d was fed throughout both cycles; however, the phylloquinone content of one of the cycles was increased to a total of 420 micrograms/d on days 6 through 10 by fortifying corn oil in the diet with phylloquinone (supplemented diet). Total serum osteocalcin concentrations were not affected by either of the dietary treatments. The percentage of undercarboxylated osteocalcin increased an average of 28% over the 15-d cycle with the mixed diet (P < 0.05) and declined significantly an average of 41% with 5 d of the supplemented diet (day 6: 21.9 +/- 1.3%, day 11: 12.8 +/- 1.1%; P = 0.0001) with a rise after the return to the mixed diet (16.7 +/- 1.3%, P < 0.001). Plasma phylloquinone concentrations increased significantly with supplementation (day 6: 0.95 +/- 0.16 nmol/L, day 11: 1.40 +/- 0.29 nmol/L; P < 0.001) and then rapidly returned to presupplementation concentrations on returning to the mixed diet. Twenty-four-hour ratios of urinary gamma-carboxyglutamic acid to creatinine were unchanged with the supplemented diet; however, excretion declined to 91 +/- 2% of baseline after 10 d on the mixed diet (P = 0.01). These results show that undercarboxylated osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid excretion appear to be sensitive measures of vitamin K nutritional status because all of these variables were responsive to changes in dietary intake.

Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans.

The purpose of this study was to characterize the absorption and transport of phylloquinone (vitamin K1) by plasma lipoproteins. Twenty-six healthy subjects (11 men and 15 women) aged 20-78 y received phylloquinone in the amount of either 1.43 or 50 microg/kg body wt orally with a fat-rich meal containing 1.0 g/kg body wt of fat, carbohydrate, and protein and 7.0 mg cholesterol/kg body wt. Blood was obtained at baseline (0 h) and 3, 6, 9, and 12 h after the meal for the measurement of plasma lipid and phylloquinone concentrations in plasma and lipoprotein subfractions. In both groups of subjects, triacylglycerol concentrations peaked after 3 h in plasma and in the triacylglycerol-rich lipoprotein fraction, composed of chylomicrons and VLDLs. Plasma phylloquinone concentrations peaked at 6 h. At baseline and during the postprandial phase, > 53% of plasma phylloquinone was carried by the triacylglycerol-rich lipoprotein fraction. In 9 of the 11 subjects supplemented with 50 microg phylloquinone/kg, plasma lipoproteins were isolated by sequential ultracentrifugation. In these subjects the fraction of plasma phylloquinone carried by LDLs and by HDLs increased progressively from 3% and 4% at 3 h to 14% and 11% at 12 h, respectively. Our data indicate that whereas triacylglycerol-rich lipoproteins are the major carriers of phylloquinone, LDL and HDL may carry small fractions of this vitamin.

Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole.

Subjects taking a hydrogen pump blocking agent (omeprazole) develop bacterial overgrowth of the small intestine. We tested the hypothesis that this bacterial overgrowth produces menaquinones, which would meet the vitamin requirement in situations of vitamin K deficiency. In a crossover-type design, 13 healthy volunteers eating a phylloquinone-restricted diet for 35 d were randomly assigned to take omeprazole during the first period of study or starting on day 15 until the end of the study. Coagulation times, serum osteocalcin [total osteocalcin and undercarboxylated osteocalcin (ucOC)], plasma phylloquinone, urinary gamma-carboxyglutamic acid, and plasma undercarboxylated prothrombin (PIVKA-II) were measured. Plasma phylloquinone concentrations declined 82% with dietary phylloquinone restriction (P < 0.05) and were not significantly different in the period when the diet was combined with omeprazole treatment (P > 0.05). The mean value for PIVKA-II during the phylloquinone-restricted diet significantly increased 5.7-fold from baseline (P < 0.05); however, the combination of omeprazole treatment and the phylloquinone-restricted diet significantly reduced PIVKA-II values by 21% (P < 0.05) compared with the diet period alone. There were no alterations in total or percentage ucOC concentrations during the phylloquinone-restricted diet or during the period of diet plus omeprazole treatment. Our data support the hypothesis that bacterial overgrowth results in the synthesis and absorption of menaquinones. These menaquinones contribute to vitamin K nutriture during dietary phylloquinone restriction, but not enough to restore normal vitamin K status.

Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults.

BACKGROUND: Phylloquinone, found in dark-green vegetables and certain plant oils, is the primary dietary source of the fat-soluble vitamin K. Limited data suggest that the relative bioavailability of phylloquinone from vegetables is lower than that from a supplement. This finding is relevant to the maintenance of optimal vitamin K status. OBJECTIVE: The objective of this study was to compare, in younger and older adults, the relative bioavailability of phylloquinone from a vegetable with that of a fortified oil. DESIGN: In a crossover design with three 15-d residency periods in a metabolic unit, younger and older men and women (n = 36) consumed a mixed diet containing 100 microg phylloquinone/d. During 2 residency periods, the mixed diet was supplemented for 5 d with either broccoli (377 microg phylloquinone/d; broccoli diet) or phylloquinone-fortified oil (417 microg/d; oil diet). The relative bioavailability of phylloquinone was defined by the difference in plasma phylloquinone, percentage serum undercarboxylated osteocalcin (%ucOC), and urinary gamma-carboxyglutamic acid in response to 5 d of supplementation. RESULTS: For both younger and older adults, plasma phylloquinone concentrations were higher (P < 0.001) and %ucOC values were lower (P = 0.001) after the broccoli and oil diets than after the mixed diet only. Overall, the response to broccoli supplementation was not significantly different from the response to the fortified oil in either age group. Urinary gamma-carboxyglutamic acid did not change in response to supplementation. CONCLUSIONS: There was no significant difference in the relative bioavailability of phylloquinone, as evidenced by the lack of a significant difference in plasma phylloquinone and %ucOC between the 2 groups after either the broccoli or oil diets for younger and older adults.

The pharmacokinetics and lipoprotein fraction distribution of intramuscular vs. oral vitamin K1 supplementation in women of childbearing age: effects on hemostasis.

Prenatal maternal vitamin K1 supplementation to improve the hemostatic status of the fetus may depend upon the route of administration and subsequent presentation at the placental barrier. We investigated intramuscular (IM) vs oral (PO) vitamin K1 supplementation in eight healthy, nonpregnant women of childbearing age. Pharmacokinetics were studied in each subject after a 5 mg IM dose and after a 5 mg oral dose of vitamin K1 approximately one month later. Plasma collected at the peak vitamin K level for each treatment was separated into very low density lipoproteins (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) and lipoprotein-free fractions by density gradient ultracentrifugation. Vitamin K1 was measured in the plasma and lipoprotein fractions using HPLC. The concentration of vitamin K1 in plasma reached a peak 2 h after an IM dose and remained high throughout the 30 h course of the study. In contrast, the oral dose of vitamin K1 peaked at 4 h and rapidly decreased to near baseline by 18 to 30 h. The distribution of vitamin K1 in the lipid fractions was different for IM compared to PO. The percentage of vitamin K1 in the VLDL fraction at the peak for an oral dose was significantly higher than for an IM dose (80.8% +/- 3.5 vs 10.8% +/- 6.5, p < 0.0001). After the oral absorption stage, the subjects took 5 mg of vitamin K1 orally, once a day, for 12 days. No significant differences were observed for the following coagulation proteins and hemostatic markers measured immediately before and after long-term oral vitamin K supplementation: factor II, factor VII, protein C, and thrombin-antithrombin III complex. In conclusion, physiological processing of supplemented vitamin K1 differs in the IM vs PO routes of administration and 12 days of oral vitamin K1 does not alter the concentration of selected vitamin K-dependent coagulation proteins or thrombin-antithrombin complex generation.

Comparison of three theories relating facial expressiveness to blood pressure in male and female undergraduates.

We examined differing predictions of how emotional expressions and blood pressure are related. Spontaneous positive and negative facial expressions, resting systolic blood pressure (SBP), and reactive SBP were each measured for 148 male and female undergraduates. The discharge theory of emotions proposes that few expressions will predict higher baseline SBP, and this was found for men. A mismatch theory of emotions proposes that an imbalance between positive and negative expressions will predict higher baseline SBP, and this was supported for women. Finally, coactivation theory proposes that many expressions will predict higher reactive SBP, and this was found for both men and women. These results reconcile previous conflicting findings by clarifying the conditions under which each of these theories may be supported.

The vitamin K content of intravenous lipid emulsions.

Commercially available intravenous lipid emulsions are largely derived from vegetable oils, a natural source of phylloquinone (vitamin K1). We therefore examined the concentration of vitamin K1 in two widely used intravenous lipid emulsions by using a previously validated high performance liquid chromatography technique. The vitamin K1 concentrations of 10% emulsions of Intralipid and Liposyn II were 30.8 and 13.2 micrograms/dL, respectively. The concentration of vitamin K1 in the 20% emulsions of these products was essentially double that in the 10% emulsions. The coefficients of variation between the vitamin K1 content in three different lots of each product were consistently less than 7.0%. The observed concentrations of the vitamin in these lipid emulsions paralleled the predicted content on the basis of the type of vegetable oil(s) used to make the product. The type of vegetable oil used for production therefore seems to be a major determinant of the final vitamin K1 content. The vitamin K1 contained in these intravenous lipid emulsions is substantial and may have great impact on the vitamin K status of the recipient.

Plasma concentrations of dihydro-vitamin K1 following dietary intake of a hydrogenated vitamin K1-rich vegetable oil.

Dihydro-vitamin K1 is a dietary form of vitamin K1 (phylloquinone) produced during the hydrogenation of vegetable oils. To determine if dihydro-vitamin K1 is present in plasma following dietary intake of a hydrogenated fat, eight healthy adults consumed each of two diets containing 30% of calories from fat, of which 20% was either soybean oil or a partially hydrogenated soybean oil-based stick margarine. Of the fats and oils analyzed, dihydro-vitamin K1 was only found in the hydrogenated products. The soybean oil diet contained 180 +/- 12 micrograms (mean +/- SD) of vitamin K1/day and nondetectable levels of dihydro-vitamin K1, whereas the stick margarine diet contained 199 +/- 7 micrograms of vitamin K1/day and 23 +/- 2 micrograms of dihydro-vitamin K1/day. After consuming each diet for five weeks, plasma dihydro-vitamin K1 concentrations were higher (P = 0.002) in all eight subjects when consuming the stick margarine diet (0.56 +/- 0.33 nmol/L) compared to the soybean oil diet (0.12 +/- 0.11 nmol/L). There was no significant change in plasma vitamin K1 concentrations when the two diets were compared. In conclusion, dihydro-vitamin K1 is detectable in plasma following dietary intake of a hydrogenated vitamin K1-rich vegetable oil.

The interaction between vitamin K nutriture and warfarin administration in patients with bacterial overgrowth due to atrophic gastritis.

Atrophic gastritis patients have intestinal bacterial overgrowth which could produce menaquinones. The aim of this study was to evaluate the interaction between a diet low in phylloquinone and minidoses of warfarin in subjects with and without bacterial overgrowth. Subjects with atrophic gastritis (indicated by serum pepsinogen ratio) and healthy volunteers were studied while fed a restrictive phylloquinone diet and while receiving a minidose of warfarin. Coagulation times, serum osteocalcin, serum undercarboxylated osteocalcin, plasma phylloquinone, plasma K-epoxide, plasma undercarboxylated prothrombin (PIVKA)-II and urinary gamma-carboxyglutamic acid (Gla) were measured. At baseline, there were no differences between groups for any variable measured. Comparisons between baseline and post intervention in both groups, showed significant increases in circulating levels of K-epoxide, PIVKA II and undercarboxylated osteocalcin. However, no differences were observed when comparisons were made between groups. Our data do not support the hypothesis that bacterial synthesis of menaquinones in patients with bacterial overgrowth due to atrophic gastritis confers considerable resistance to the effect of warfarin.

Three top Canadian and personal health concerns of a random sample of Nova Scotian women.

We sought to understand the subjective reports of women's health concerns. A randomly dialled telephone survey was conducted resulting in a sample of 458 women (Caucasian/European = 302, Native/Aboriginal = 81, Black = 75), aged 18-81. Women were asked in an open-ended format to list their three top health concerns for themselves and then for Canadian women. Responses were recorded verbatim and categorized into one of nine mutually exclusive health concern categories. The three main health concerns for Canadian women were: Psychosocial Issues, Other Specific Illnesses, and Cancer. The three most important personal health concerns were Psychosocial Issues, Other Specific Illnesses, and Heart and Related Diseases. Few ethnic differences were noted. Results suggest that it is important to recognize and attempt to alleviate health concerns about stress and depression, which are not usually considered as being major health problems by health care professionals.

Increases in depression after cholesterol-lowering drug treatment.

To investigate the possibility that increases in depressive symptoms might occur in patients who have undergone cholesterol-lowering interventions, the authors administered the Center for Epidemiological Studies-Depression scale before and after cholesterol lowering to 6 men who were referred to a lipid clinic. All of the patients' cholesterol levels were reduced after the 6-week intervention, and 4 of the patients' depression scores increased; scores of 2 of the 4 met the criteria for mild clinical depression. Further study of possible links among low cholesterol, depressive symptoms, and serotonergic activity is needed.

Advance directives in family practice.

Advance directives have emerged in medicine as an important method by which patients can express future treatment wishes. The major reasons medical professionals have been reluctant to use advance directives are not because of theoretical defects with advance directives, but because of procedural difficulties. Confusion over types of advance directives and their legal status will ease with increased knowledge of advance directives by health professionals. Additionally, that they are often formulated in ambiguous terms and under situations where the patient's competence is in question can be minimized. More widespread and effective use of advance directives will occur if the family physician takes an active role in identifying patients for whom an advance directive would be desirable, effectively communicating information about advance directives, advising their patients about the most effective way to state their directive in medically precise terminology, and explaining when necessary the patient's wishes to other medical specialists and family members.

Reduction of adverse drug reactions by computerized drug interaction screening.

Computerized drug-interaction screening systems (CDISS) have been developed as a tool to help decrease the enormous morbidity and expense related to adverse drug interactions. In previous studies the CDISS was used primarily by pharmacists in hospital settings to screen for interactions after the prescription had been written. This study tests the feasibility of family physicians using CDISS before writing the prescription to allow for changes in the prescription while the patient is still in the office. In a 30-day period, 103 patients were screened by family physicians for potential drug-drug, drug-alcohol, and drug-food interactions. Potential drug interactions of varying clinical significance were detected for 71 patients (68.9 percent). The prescription plan was changed for 16 patients (15.5 percent) as a result of using the CDISS. Participating physicians reported that they gained new information in 45.8 percent of the patient encounters, that their awareness of the potential for drug interactions was heightened by participation in this study, and that their exposure to the CDISS was worthwhile as an educational tool. While a few problems, mainly logistic, were noted with the CDISS as used in this study, the authors conclude that with modifications a CDISS can be of great educational and clinical value to the family physician and his or her patients.

Lacunar strokes: current concepts.

Lacunar strokes result from occlusion of penetrating arteries in the deeper, subcortical parts of the cerebrum and brain stem. Approximately 19 percent of all strokes are of the lacunar variety with lacunar strokes representing the most common cerebrovascular complication of chronic hypertension. Four major clinical syndromes are pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, and the dysarthria-clumsy hand syndrome. The advent of computed tomography (CT) has allowed the antemortem study of lacunar disease and has shed new light on the pathogenesis and clinical course of lacunar strokes. Recently, it has been demonstrated that lacunar strokes may be embolic or hemorrhagic in causation, are not invariably associated with hypertension, and may be larger and associated with hypertension, and may be larger and associated with neurological manifestations that do not conform to the classic patterns. In most instances, however, recognition of the characteristic clinical presentation and confirmation of the diagnosis with noninvasive studies spare many patients unnecessary risks associated with anticoagulation, arteriography, or vascular surgery.