NF-kappaB and apoptosis in colorectal tumourigenesis.

BACKGROUND: Nuclear factor-kappaB (NF-kappaB) may play an important role in colorectal tumourigenesis, controlling cell cycle and apoptosis gene expression. In addition, imbalances between cell proliferation and cell death are thought to underlie neoplastic development. The aims of this study were to investigate apoptosis and expression of several apoptosis-related proteins, and to determine correlations with colorectal tumour progression. MATERIALS AND METHODS: Apoptosis was evaluated by the TUNEL assay in 48 patient samples, including adenomas, adenocarcinomas and adjacent normal mucosas. Immunohistochemistry was performed for Bcl-2 and NF-kappaB. Expression levels of p53, Bax and IkappaB proteins were determined by immunoblotting. Cultured human colon cancer cells were used to evaluate NF-kappaB expression and nuclear translocation by immunocytochemistry and immunoblotting. RESULTS: Apoptosis and NF-kappaB immunoreactivity were significantly higher in tumour tissue compared with normal mucosa (P < 0.01), increasing in association with histological tumour progression (P < 0.01). Bcl-2 was consistently higher in normal mucosa (P < 0.01) and inversely correlated with the percentage of apoptosis (P < 0.01). Phosphorylated p53 and Bax levels were similar in tumour tissue and normal mucosa; however, the NF-kappaB inhibitor, IkappaB, tended to decrease in tumours. In vitro, nuclear translocation of NF-kappaB was greater in proliferative than in resting phases of colon cancer cells. CONCLUSIONS: NF-kappaB expression and apoptosis are increased from adenoma to poorly differentiated adenocarcinoma tissues. Apoptosis is correlated with suppression of Bcl-2 expression, but appears to proceed through a p53- and Bax-independent pathway. Activation of NF-kappaB may play an important role in colorectal tumour progression.

Trends of food intake in Portugal, 1987-1999: results from the National Health Surveys.

OBJECTIVE: To assess trends of food intake in Portugal. DESIGN: Analysis of three cross-sectional studies: 1987, 1995-1996 and 1998-1999. SETTING: Representative samples of free-living individuals. SUBJECTS: 64 734 men and 71 282 women. INTERVENTIONS: Food intake was assessed by questionnaires inquiring the number of meals and which foodstuffs (fish, meat, milk, rice/pasta/potatoes, soup, vegetables and fruit) had been consumed the day before. RESULTS: Age-adjusted average number of meals decreased from 3.3+/-0.1 in 1987 to 2.9+/-0.1 in 1998-1999 in both genders (P<0.001). In men, the percentage of subjects consuming meat, milk and potatoes/rice/pasta increased from 73, 66 and 91% in 1987 to 83, 74 and 95% in 1998-1999, respectively. The percentage of subjects consuming soup and fish decreased from 70 and 56% in 1987 to 62 and 53% in 1998-1999, respectively. In women, the percentage of subjects consuming meat, milk, potatoes/rice/pasta and vegetable increased from 70, 66, 89 and 71% in 1987 to 78, 77, 93 and 83% in 1998-1999, respectively. The percentage of subjects consuming soup and fish decreased from 70 and 55% in 1987 to 64 and 53% in 1998-1999, respectively. These trends were more pronounced in the younger age, which also displayed a higher frequency of snacking. Multivariate analysis adjusting for age group, region and educational level showed that the consumption of meat, milk and vegetables increased and the consumption of soup, fish and fruit decreased in 1998-1999 relative to 1995-1996. CONCLUSIONS: Within a decade, the Portuguese dietary pattern has changed considerably, shifting from a traditional, south European to a more Westernized, protein-rich diet. SPONSORSHIP: The Unidade de Nutrição e Metabolismo of the Instituto de Medicina Molecular is partially funded by a grant from the FCT (Fundação para a Ciência e a Tecnologia) ref. RUN 437.

How different is the dietary pattern in non-alcoholic steatohepatitis patients?

BACKGROUND/AIMS: This study aimed at evaluating whether patients with non-alcoholic steatohepatitis (NASH) had a specific dietary pattern and how it compared with data representative from the same geographical region individuals. SUBJECTS AND METHODS: Clinical, biochemical and anthropometrics: weight, height, body mass index (BMI) and waist circumference were collected in 45 NASH patients. Diet history was assessed using a validated semi-quantitative food frequency questionnaire, analysed with the Food Processor Plus, and was compared, after adjustment for BMI, with data from a sample of 856 free-living individuals, frequency matched for sex and age. RESULTS: Patients' mean age was 49.6+/-10.6 years, 26 F: 19 M, BMI: 31.2+/-5.0 kg/m2. Comparison of their diet history with control data (C) revealed that carbohydrate consumption was lower in patients (P): P-243.6+/-5.7 g vs. C-261.5+/-1.6 g, P<0.05, and most patients had very low fibre intake. Conversely, total fat consumption was higher in patients: P-79.7+/-1.7 g vs. 73.0+/-0.4, P<0.01. A significantly higher intake of n-6 fatty acids (P=0.003) and n-6/n-3 ratio was found in patients, P<0.001. CONCLUSIONS: Our results suggest that the quality and combination of carbohydrates and fat intake may be more relevant than their isolated amount; an increased fat intake with an excessive amount of n-6 fatty acids can be implicated in promoting necro-inflammation, and provides further grounds for individualized dietary therapy.

Nutritional risk and status assessment in surgical patients: a challenge amidst plenty.

BACKGROUND AND AIMS: No gold standard exists for nutritional screening/assessment. This cross-sectional study aimed to collect/use a comprehensive set of clinical, anthropometric, functional data, explore interrelations, and derive a feasible/sensitive/specific method to assess nutritional risk and status in hospital practice. PATIENTS AND METHODS: 100 surgical patients were evaluated, 49M:51F, 55 +/- 18.9 (18-88) years. Nutritional risk assessment: Kondrup's Nutritional Risk Assessment, BAPEN's Malnutrition Screening Tool, Nutrition Screening Initiative, Admission Nutritional Screening Tool. Nutritional status: anthropometry categorised by Body Mass Index and McWhirter & Pennington criteria, recent weight loss > 10%, dynamometry, Subjective Global Assessment. RESULTS: There was a strong agreement between all nutritional risk (k = 0.69-0.89, p < 0.05) and between all nutritional assessment methods (k = 0.51-0.88, p < or = 0.05) except for dynamometry. Weight loss > 10% was the only method that agreed with all tools (k = 0.86-0.94, p < or = 0.05), and was thereafter used as the standard. Kondrup's Nutritional Risk Assessment and Admission Nutritional Screening Tool were unspecific but highly sensitive (> or = 95%). Subjective Global Assessment was highly sensitive (100%) and specific (69%), and was the only method with a significant Youden value (0.7). CONCLUSIONS: Kondrup's Nutritional Risk Assessment and Admission Nutritional Screening Tool emerged as sensitive screening methods; the former is simpler to use, Kondrup's Nutritional Risk Assessment has been devised to direct nutritional intervention. Recent unintentional weight loss > 10% is a simple method whereas Subjective Global Assessment identified high-risk/undernourished patients.

Nutritional deterioration in cancer: the role of disease and diet.

AIMS: Under-nutrition is a major source of morbidity and mortality in cancer patients. This prospective, cross-sectional study aimed to evaluate the relative contributions of cancer staging, duration and diet on patients' nutritional deterioration. MATERIALS AND METHODS: We included 205 consecutive patients (133 men and 72 women) with head and neck, gastro-oesophageal, colon and rectum cancer, age 53 +/- 12 (33-86) years, referred for radiotherapy (primary, adjunctive to surgery, combined with chemotherapy or with palliative intent). We registered clinical variables, nutritional status (percentage of weight loss, Patient-Generated Subjective Global Assessment and body mass index), nutritional requirements, usual diet intake (diet history) and current intake (24-h recall). RESULTS: In stage III and IV, we observed a significant decrease of usual and current energy and protein intake (P=0.002), which were not observed in stage I and II. Reduction in nutritional intake was influenced by disease duration (P=0.04), but when the latter was evaluated in a multivariate analysis, current dietary intake was associated only with staging (P=0.004), thus disclosing a distinct pattern of nutritional intake between stages and diagnosis. Using a general linear model, advanced staging showed the most significant association with nutritional depletion (P=0.0001). We also found significant associations for tumour location (P=0.001), disease duration (P=0.002), nutritional intake (P=0.003) and previous surgery or chemotherapy (P=0.02). Percentage weight loss showed a consistently superior performance with regard to clinical variables and ability to detect mild to extreme nutritional changes. Patient-Generated Subjective Global Assessment had a very high sensitivity and specificity, and a strong capacity for detecting patients at nutritional risk compared with body mass index. CONCLUSIONS: Nutritional depletion is multifactorial, dependent mainly on the tumour burden of the host. Percentage weight loss is a sensitive and specific tool that can screen and identify malnutrition effectively. Its joint use with Patient-Generated Subjective Global Assessment, which establishes boundaries for nutritional therapy, will optimise the efficacy of nutritional assessment and support in cancer patients.

5,10-Methylenetetrahydrofolate reductase 677C-->T and 1298A-->C mutations are genetic determinants of elevated homocysteine.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C-->T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A-->C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C-->T) but its effect on plasma tHcy levels is not yet clear. AIM: To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. DESIGN: Prospective population survey. METHODS: We studied 117 healthy volunteers (71 females, 46 males). The 677C-->T and 1298A-->C mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined. RESULTS: The allele frequencies of the 677C-->T and 1298A-->C mutations were 0.33 and 0.28, respectively. Homozygotes for the 677C-->T mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298A-->C mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels. DISCUSSION: The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298A-->C mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.

Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH), the association of steatosis with an inflammatory response, is a novel liver disease of unknown pathogenesis and prognosis. Triacylglycerols and their precursors, the fatty acids, are the likely candidates to accumulate in the hepatocyte. Disturbed fatty acid metabolism can be involved in the pathogenesis of NASH but there is no information concerning its plasma fatty acid profile. The aim of this study was to evaluate plasma total (esterified plus free) and free fatty acids concentrations to assess the association of NASH with plasma fatty acid accumulation. MATERIALS AND METHODS: Overnight fasting blood samples from 22 biopsy-proven NASH patients and of 6 matched age healthy controls were studied. RESULTS: NASH patients had significantly higher concentration of total and free fatty acids than controls (P<0.05), higher total saturated and monounsaturated levels in both studied lipid fractions (P<0.05), mainly due to the increase of hexadecanoic, hexadecenoic and octadecenoic acids. Absolute polyunsaturated fatty acids (PUFA) concentrations were similar in both groups. The C20:4/C18:2 and the C18:1/C18:0 ratios as well as the peroxidability index were not significantly different. CONCLUSION: In overweight/obese patients NASH is associated with deranged fatty acid metabolism which may be involved in its pathogenesis and/or progression.

Long-term management of percutaneous endoscopic gastrostomy by a nutritional support team.

BACKGROUND/AIMS: Percutaneous Endoscopic Gastrostomy (PEG) has become a commonly-performed procedure, to provide enteral nutrition for patients who are unable to eat. The aims of this study were to evaluate the long term efficacy, morbidity and mortality of percutaneous endoscopic gastrostomy (PEG). MATERIAL AND METHODS: We analysed 144 patients who underwent a PEG procedure. Survival curves were done with the Kaplan-Meier method. The indication was long-term enteral nutrition in patients unable to maintain adequate nutrition by mouth. RESULTS: The procedure was successful in all but one case. Mean age was 62 (18-85) years, 89 (62%) males. Seven patients recovered from their primary disease and gastrostomy tube was removed. Mean follow-up was 7.3+/-10.8 (1--66) months. Survival rates at 30 days, 1 year and 3 years following gastrostomy were 82%, 36% and 14%, respectively. Survival curves were better in females (P<0.0001). In almost all cases, patients were fed with current home-prepared food, and were ambulatory. There were no differences in survival curves according to the nutritional status. CONCLUSIONS: There were few procedure-related complications, but a high short-term mortality, probably related with the underlying disease. The use of home-prepared food through the gastrostomy was very well tolerated, and should be encouraged.

A critical approach to nutritional assessment in critically ill patients.

BACKGROUND AND AIMS: Nutritional assessment enhances quality of nutritional care, however, its practice bemuses professionals. This prospective study aimed to identify a feasible/informative nutritional parameter in intensive care. METHODS: 44 patients (APACHE II: 23.8+/-10.1), age 58.4+/-18.6 years, were evaluated at admission: clinical data, height, weight, body mass index (BMI), tricep skinfold thickness, mid-arm circumference (MAC), mid-arm muscle circumference (MAMC), albumin, total protein and lymphocyte count. Anthropometric parameters' performance was evaluated isolated or assembled according to Blackburn and McWhirter criteria. RESULTS: Oedema increased %IW and BMI (P<0.01); muscle depletion was frequent and agreed with MAC or MAMC ranked by both criteria, P=0.02. %IW and BMI overestimated well-nourished/overweight patients, whilst arm anthropometry, mostly MAC/MAMC, shifted towards +/-50% malnutrition. Patients were not equally ranked by both criteria; McWhirter's by using percentiles clarified the distribution and showed agreement between MAC and MAMC, P=0.007, unlike Blackburn's. Mortality was higher in patients with MAC<5th percentile, P=0.003; MAC;<15th percentile was able to predict mortality and major complications. In invasive ventilated patients, severe muscle depletion was associated with mortality, P=0.05. CONCLUSION: In intensive care most nutritional assessment methods are useless; MAC is simple, feasible and if classified by percentiles may prove functional with prognostic value.

Taurine: a conditionally essential amino acid in humans? An overview in health and disease.

Taurine, a sulphur containing amino acid, is the most abundant intracellular amino acid in humans, and is implicated in numerous biological and physiological functions. This comprehensive overview explores areas, from its characterisation to its potential clinical benefit as a conditionally essential amino acid and a pharmaconutrient. In healthy individuals the diet is the usual source of taurine; although in the presence of vitamin B6 it is also synthesised from methionine and cysteine. Taurine has a unique chemical structure that implies important physiological functions: bile acid conjugation and cholestasis prevention, antiarrhythmic/inotropic/chronotropic effects, central nervous system neuromodulation, retinal development and function, endocrine/metabolic effects and antioxidant/antiinflammatory properties. Taurine is an essential amino acid for preterm neonates and is assured by breast milk. Specific groups of individuals are at risk for taurine deficiency and may benefit from supplementation, e.g. patients requiring long-term parenteral nutrition (including premature and newborn infants); those with chronic hepatic, heart or renal failure. Further studies are required to determine the benefits of replenishing taurine pools as well as the need to include taurine routinely in parenteral nutrition regimens.

Hepatic stellate cell activation occurs in nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Hepatic stellate cell activation has a major role in the pathogenesis of hepatic fibrosis, considered to constitute part of the healing response to a necroinflammatory stimulus. However, steatosis per se, has also been shown to induce this activation. This study evaluates if hepatic stellate cell activation is present, and how it correlates with steatosis, in nonalcoholic steatohepatitis, whose hallmark is steatosis. METHODOLOGY: Steatosis, hepatocyte damage, inflammation and fibrosis were graded from 0 to 3+, in liver biopsies from 15 well documented nonalcoholic steatohepatitis and 5 normal controls. Activated hepatic stellate cell activation were identified immunohistochemically using a monoclonal antibody raised against cytoplasmic alpha-smooth muscle actin, and semiquantitatively graded using a scoring method. RESULTS: Nonalcoholic steatohepatitis patients showed significantly greater numbers of alpha-smooth muscle actin-reactive hepatic stellate cell than controls: hepatic stellate cell index of 3.6 +/- 1.9 versus 1.5 +/- 0.5, P < 0.05. The distribution of alpha-smooth muscle actin-reactive hepatic stellate cell was higher in the perivenular areas, than in the intermediate zone and portal area, with no significant association between steatosis and alpha-smooth muscle actin-expressing hepatic stellate cell. However, a significant association was found between portal and lobular inflammation and hepatic stellate cell index, r = 0.72, P = 0.0005 and r = 0.75, P = 0.0002, respectively. CONCLUSIONS: This study demonstrates that hepatic stellate cell activation occurs in nonalcoholic steatohepatitis, clearly correlating with portal and lobular inflammation, but not with steatosis, suggesting that the mechanisms implicated in fibrosis in nonalcoholic steatohepatitis are probably related with inflammation.

Parenteral nutrition and cyclosporine: do lipids make a difference? A prospective randomized crossover trial.

AIMS: This prospective, controlled, randomized crossover trial was conducted to assess the effects of parenteral nutrition, with or without lipids, in cyclosporine (CyA) pharmacokinetics. METHODS: 10 adult patients were randomized on the day of allogeneic bone marrow transplantation to receive isocaloric and isonitrogenous parenteral nutrition admixtures without (regimen A) or with lipids (regimen B). Admixtures were started on average by day + 7.4; 5 patients received regimen A followed by B, 5 in reverse order. Blood samples were collected at day 4 after transplantation, under oral diet, and 4 days after the initiation of each regimen as the sole nutrition support. At each time point, 8 whole blood samples were analysed for CyA to evaluate: area under the curve (AUC), trough concentration and systemic clearance. Clinical/laboratory events were recorded until 31 months of follow-up. RESULTS: There was no evidence of a period or treatment-by period interaction, thus results were combined for further analysis. There were no statistically significant differences between regimens in any CyA pharmacokinetic parameters; there were no significant differences from baseline values, except for a higher systemic clearance of CyA with regimen A (0.40+/-0.09 vs 0.29+/-0.06 L/Kg/h, p=0.03). CONCLUSIONS: The provision of 0.8 g/Kg/d of a 50:50 mixture of medium and long chain triglycerides did not affect CyA parameters, which were closer to baseline. In the short or long term there were no attributable side effects.

Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status.

The objective of this review is to present and discuss the current perspectives of homocysteine and one carbon metabolism in chronic alcoholism. Chronic alcoholics frequently suffer from specific micronutrient deficiencies, including vitamins involved in one carbon metabolism, i.e., folate, vitamin B(6) and vitamin B(12). The possible link between homocysteine and alcoholism stems from the fact that homocysteine metabolism is closely linked to the metabolism of these three vitamins. In fact, homocysteine stands at the intersection of two pathways: methylation and transsulfuration. In methylation, homocysteine acquires a methyl group from N-5-methyltetrahydrofolate in a vitamin B(12) dependent reaction, whereas in the transsulfuration pathway, homocysteine condenses with serine to form cystathionine in an irreversible reaction catalyzed by the pyridoxal-5'-phosphate-containing enzyme, cystathionine-beta-synthase. Due to these relationships, nutritional deficiency of one of these vitamins, as a consequence of chronic alcohol intake, could lead to metabolic disruption and potentially to hyperhomocysteinemia. Consistent with an interference of alcohol in these metabolic pathways, a previous study performed in chronic alcoholics in whom hyperhomocysteinemia was observed along with disturbed vitamin status, DNA hypomethylation in peripheral lymphocytes was demonstrated as well. Because all these alterations were observed in the absence of clinically overt disease, one might speculate whether these metabolic abnormalities could be involved in the pathogenesis of organic diseases associated to chronic alcoholism.

[Magnesium: physiological and clinical relevance. 1: homeostasis and alterations in the metabolism of magnesium]. / Magnésio: revelância na fisiologia e clínica. 1a Parte: Homeostasia e perturbações no metabolismo do magnésio.

Magnesium is the second most abundant cation in intracellular fluid and is an essential electrolyte. It has several critically important roles in the body, namely as a cofactor in numerous enzyme systems, and is involved in phosphate transfer, muscle contractility and neuronal transmission. The physiologic role, homeostasis, causes and clinical manifestations of hypo and hypermagnesemia and their therapy are briefly reviewed. Magnesium treatment is emerging as an important adjunct in the management of a few conditions: prevention and control of seizures in eclampsia, cardiovascular diseases, diabetes mellitus, asthma and others.

Non-alcoholic fatty liver: another feature of the metabolic syndrome?

BACKGROUND AND AIMS: Hepatic steatosis and nonalcoholic steatohepatitis (NASH) have been associated with obesity, non insulin-dependent diabetes mellitus and hyperlipidemia. The present study was designed in order to evaluate whether patients with steatosis/NASH presented common features with the metabolic syndrome. METHODS: In 30 patients with nonalcoholic fatty liver the prevalence of hypertension and diabetes; the glucose/insulin profile, lipid profile, and serum leptin were evaluated and correlated with body composition and energy expenditure, assessed by bioimpedance spectroscopy and indirect calorimetry, respectively. Results were compared with a group of eight controls. RESULTS: Obesity was present in 80% of patients, hypertension in 50% and non insulin dependent diabetes in 33%. Glucose metabolism was altered in 69%, with elevated insulin in 14 patients. Serum leptin, higher in women, was increased in patients: 33.9 +/- 38.9 vs 9.6 +/- 6.9 ng/ml, P< 0.05. There was a correlation between insulin and leptin, both of which correlated with body mass index, fat mass and percentage of body fat. Dyslipidaemia was found in 80% of patients: 45% presented low high density lipoproteins cholesterol, 58% high low density lipoproteins and 38% elevated very low density lipoproteins. CONCLUSIONS: There is a strong association between nonalcoholic fatty liver and features of the metabolic syndrome, suggesting a simultaneous insulin resistance and decreased sensitivity to leptin.

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.

Bioavailability of phylloquinone from an intravenous lipid emulsion.

This randomized, controlled study evaluated the bioavailability of phylloquinone from an intravenous lipid emulsion. A mild vitamin K deficiency was induced in 12 healthy adult men and women by dietary restriction of phylloquinone (40 microg/d, days 1-11) and by administration of warfarin (1.0 mg/d, days 5-11). On day 11, subjects received a 500-mL intravenous solution of either lipid or saline, both of which contained 154 microg phylloquinone. Bioavailability was assessed by serial measurements of plasma phylloquinone, vitamin K1-2,3-epoxide. PIVKA-II (proteins induced by vitamin K absence or antagonists-II), and percentage undercarboxylated osteocalcin. As a result of vitamin K deficiency and minidose warfarin, vitamin K1-2,3-epoxide, PIVKA-II, and percentage undercarboxylated osteocalcin increased significantly between days 1 and 11 (P = 0.05, 0.016, and 0.001, respectively). With the infusions, plasma phylloquinone increased in both groups (P = 0.001). After the infusions vitamin K,-2,3-epoxide decreased in both groups (P = 0.002). Changes in plasma phylloquinone and vitamin K1-2,3-epoxide were no different in the two groups (mean areas under the curves +/- SEM: 116+/-13 nmol x h/L for the saline group and 102+/-20 nmol x h/L for the lipid group for phylloquinone; 38.6+/-7.5 nmol x h/L for the saline group and 31.3+/-9.0 nmol x h/L for the lipid group for vitamin K1-2,3-epoxide). PIVKA-II decreased significantly from baseline values (P = 0.005) in both groups after the infusions. Intravenous lipid reversed the effects of minidose warfarin and of dietary restriction of phylloquinone on hemostasis and vitamin K nutritional status. This reversal was no different from that seen with the infusion of phylloquinone in a saline solution.