Folic acid improves arterial endothelial function in adults with hyperhomocystinemia.

OBJECTIVES: To evaluate whether oral folic acid supplementation might improve endothelial function in the arteries of asymptomatic adults with hyperhomocystinemia. BACKGROUND: Hyperhomocystinemia is an independent risk factor for endothelial dysfunction and occlusive vascular disease. Folic acid supplementation can lower homocystine levels in subjects with hyperhomocystinemia; however, the effect of this on arterial physiology is not known. METHODS: Adults subjects were recruited from a community-based atherosclerosis study on healthy volunteers aged 40 to 70 years who had no history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease or family history of premature atherosclerosis (n = 89). Seventeen subjects (aged 54 +/- 10 years, 15 male) with fasting total homocystine levels above 75th percentile (mean, 9.8 +/- 2.8 micromol/liter) consented to participate in a double-blind, randomized, placebo-controlled and crossover trial; each subject received oral folic acid (10 mg/day) and placebo for 8 weeks, each separated by a washout period of four weeks. Flow-mediated endothelium-dependent dilation (percent increase in diameter) of the brachial artery was assessed by high resolution ultrasound, before and after folic acid or placebo supplementation. RESULTS: Compared with placebo, folic acid supplementation resulted in higher serum folate levels (66.2 +/- 7.0 vs. 29.7 +/- 14.8 nmol/liter; p < 0.001), lower total plasma homocystine levels (8.1 +/- 3.1 vs. 9.5 +/- 2.5 micromol/liter, p = 0.03) and significant improvement in endothelium-dependent dilation (8.2 +/- 1.6% vs. 6 +/- 1.3%, p < 0.001). Endothelium-independent responses to nitroglycerin were unchanged. No adverse events were observed. CONCLUSION: Folic acid supplementation improves arterial endothelial function in adults with relative hyperhomocystinemia, with potentially beneficial effects on the atherosclerotic process.

Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans.

BACKGROUND: Hyperhomocyst(e)inemia is associated with premature peripheral vascular, cerebrovascular, and coronary artery disease. Because homocysteine has been found to be damaging to endothelial cells in animal and cell culture studies, we evaluated the association between hyperhomocysteinemia and arterial endothelial dysfunction (a marker of early atherosclerosis) in asymptomatic adult subjects. METHODS AND RESULTS: Using high-resolution ultrasound, we measured endothelium-dependent flow-mediated dilation (EDD) and endothelium-independent nitroglycerin-induced dilation (GTN) of the brachial artery in 14 prospectively defined hyperhomocysteinemic (mean plasma homocysteine, 34.8+/-8.5 micromol/L), nonsmoking, healthy subjects aged 53+/-9 years and 14 control subjects with low plasma homocysteine levels (9.9+/-3.2 micromol/L). The two groups were well matched for age; sex; body mass index; blood pressure, blood cholesterol, folate, and vitamin B12 levels; and vessel diameter. EDD was significantly lower in hyperhomocysteinemic subjects (6.5+/-1.7%) than in subjects with low homocysteine levels (10.8+/-1.7%) (P<.001). GTN responses were similar in the two subject groups (P=.90). Multivariate analysis confirmed homocysteine level as the strongest predictor for impaired EDD, independent of age, sex, body mass index, or blood pressure, folate, vitamin B12, and cholesterol levels. CONCLUSIONS: Hyperhomocysteinemia is an independent risk factor for arterial endothelial dysfunction in healthy middle-aged adults.

Monoclonal gammopathy of unknown significance and malignant paraproteinemia in Hong Kong.

The incidence of multiple myeloma is lower in Southeast Asia than in the West. However, there are few reports on the overall incidence of paraproteinemia and its disease-associations in the Chinese. Therefore, the authors have correlated the laboratory features with the eventual clinical diagnosis in patients with paraproteinemia in a Hong Kong general/teaching hospital. Over 18 months, 1,600 patients were investigated for the presence of paraproteinemia. Paraproteinemia was detected in 157 (10%) patients. In 11 patients, investigations could not be completed. The remaining 146 patients were subjected to detailed clinical, radiologic, and laboratory investigations. Eighty-seven (59.6%) had monoclonal gammopathy of unknown significance (MGUS), 44 (30.1%) myeloma and 15 (10.3%) other lymphoproliferative disorder (LPD). There was no significant difference in the paraprotein concentration, frequency of hypogammaglobulinemia of Bence Jones proteinuria (BJP) or concentration of nonparaprotein immunoglobulin (Ig) between the myeloma and LPD groups. The overall kappa:lambda light chains ratios were 2.9, 1.6 and 3.3 in the MGUS, MM and LPD groups, respectively. Polyclonal Ig elevation was rare with myeloma (4.5%) but was detected in 33% of patients with LPD (P < .02) and 40% of those with MGUS (P < .0001). Biclonal (and one triclonal) gammopathy was detected in 11.5% of patients with MGUS, 11% with LPD and 4.5% with myeloma. In the MGUS group, infection was the commonest associated clinical disorder (29.3%). Moreover, 70% of patients with biclonal gammopathy and MGUS had an infection. Five of 15 patients with LPD had a T-cell malignancy, including 3 lymphomas and 2 large granular cell leukemias. Only one patient had primary systemic amyloidosis. It is concluded that the high frequency of biclonality and its association with infection, of paraproteinemia in association with T-cell malignancy and of kappa light chains in the MGUS and LPD groups are at variance with reports from the West and probably reflect local differences.

Hyperhomocysteinaemia and premature coronary artery disease in the Chinese.

OBJECTIVES: To examine the prevalence of hyperhomocysteinaemia and compare it with the classic risk factors and vitamin status in Hong Kong Chinese patients with premature atherosclerotic coronary artery disease. DESIGN: Case-control study. SETTING: General hospital and community. SUBJECTS: Forty five patients (39 males) with significant coronary artery disease confirmed by angiography (32 post myocardial infarction) and 23 healthy volunteers (17 male), all aged less than 55 years. INTERVENTION: Standardised methionine-loading test. MAIN OUTCOME MEASURES: Coronary artery disease, risk factors. RESULTS: More patients than controls had fasting hyperhomocysteinaemia (10/45 v 2/23, P = 0.122), post-methionine hyperhomocysteinaemia (17/45 v 1/23, P = 0.008), and an abnormal response to methionine (15/45 v 1/23, P = 0.015). A history of smoking was more frequent in patients (3/23 v 25/45, P = 0.002). Sixteen of 17 patients with hyperhomocysteinaemia but only nine of 28 with normohomocysteinaemia were smokers (P = 0.0002). Fasting plasma cholesterol concentrations (mean (SD)) were higher in hyperhomocysteinaemic patients (6.41 (1.58) mmol/l) than in controls (5.53 (0.90) mmol/l) (P = 0.042). Serum vitamin B-12 was not reduced and serum folate was higher in hyperhomocysteinaemic patients (35 (4) nmol/l) than normohomocysteinaemic patients (26 (9) nmol/l) (P = 0.009). CONCLUSIONS: Although the prevalence of hyperhomocysteinaemia in Hong Kong Chinese is similar to that in white subjects, hyperhomocysteinaemia is not an independent risk factor for coronary artery disease and is associated with smoking. This may be of some consequence in view of the change to a more Western diet with more animal protein, and therefore methionine, coupled with a high frequency of cigarette smokers in this region. The causes of the hyperhomocysteinaemia are multifactorial but in this pilot study a deficiency of folate and/or vitamin B-12 did not seem to be one of them.

Fatal acute hepatorenal failure following potassium permanganate ingestion.

Potassium permanganate (KMnO4), a powerful oxidizing agent, is readily available without prescription. Tissue contact produces coagulation necrosis and the lethal consequences of oral ingestion are well described, with most deaths because of airway oedema and obstruction or circulatory collapse. Whilst systemic toxicity is reported, its mechanism is unclear. We describe a case of suicidal ingestion of KMnO4 followed by acute hepatorenal toxicity resulting in the death of the patient. The clinical course bore close resemblance to that of severe paracetamol overdose. We discuss the pathogenesis of the systemic toxicity of KMnO4 and postulate that it is due to oxidative injury from free radicals generated by the absorbed permanganate ion. We recommend that N-acetyl cysteine be given within the first few hours to all patients with potassium permanganate poisoning.

Water and sodium disorders following surgical excision of pituitary region tumours.

A prospective observational study of the pathophysiology of sodium and water disorders in patients with pituitary region tumours after surgical excision was carried out in 20 patients. Serial pre-operative and post-operative fluid and sodium balance, plasma and urine elctrolyte biochemistry and their derived parameters, and circulating hormones associated with fluid balance, atrial natriureic peptide (ANP) and antidiuretic hormone (ADH) were documented to correlate with the patients' clinical conditions. Ten out of these twenty cases developed diabetes insipidus (DI) requiring ADH replacement therapy, although in the majority (6 cases), this way only a transient event. Of the nine patients who developed hyponatraemia, six had symptoms such as impaired consciousness and convulsions. Four patients developed alternating hypoatraemia and hypernatraemia, which constituted a difficult group, where appropriate sodium and fluid management, and ADH replacement therapy were based upon twice daily plasma and urine biochemistry and their derived parameters. Whilst DI in this group of patients was the result of a low circulating ADH level, hyponatraemia was not associated with an exaggerated ADH activity (6.0 +/- 2.3 vs 7.4 +/- 2.3 pmol/ml, mean +/- SEM). Rather, hyponatraemia was strongly associated with an elevated circulating ANP concentration (82.4 +/- 10.5 vs 30.0 +/- 3.1 pmol/ml, mean +/- SEM, p < 0.001), resulting in salt wasting and hypovolaemia.

Alpha-1-antitrypsin phenotypes and associated disease patterns in neurological patients.

INTRODUCTION: Alpha-1-antitrypsin (AAT) deficiency is usually associated with lung or liver disease. It is often detected as a qualitative reduction of the alpha-1 band on the serum protein electrophoretic pattern. MATERIAL AND METHODS: We examined the protein electrophoretic pattern in sera of 22980 unselected consecutive patients with neurological disorders and noted a reduced alpha-1 band in 88. Their phenotypes were compared with the clinical disease. RESULTS: 75 patients had a deficient or non-M and 13 the usual MM phenotype. Contrary to in the general population, PiMZ was four times more common than PiMS. Vascular disease was more common in patients with PiMZ while multiple sclerosis significantly more frequent in patients with PiMS than with other phenotypes, including PiMM. CONCLUSIONS: Other genetic abnormalities have previously been found in AAT associated with multiple sclerosis, but not PiMS. Since PIMS leads to modest reduction of AAT activity, the association may be through other mechanisms than reduced protease activity.

Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: phenytoin.

The temporal pharmacokinetic (blood) and neuropharmacokinetic (cerebrospinal fluid, CSF) interrelationship of phenytoin was studied after acute and during chronic (up to 5 days) intraperitoneal administration of phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat model. After administration, phenytoin rapidly appeared in both serum (Tmax mean range 0.15-0.38 h) and CSF (Tmax mean range 0.9-1.4 h), suggesting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phenytoin concentrations rose dose dependently in serum, CSF concentrations did not. Further, the divergence between the blood and CSF compartments increased with chronic dosing. Cmax, AUC and t1/2 values for serum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essential if phenytoin entry into the brain is to be facilitated, and this may be important in studies of phenytoin in animal models of status epilepticus.

IgD multiple myeloma with thoracic spine compression due to epidural extra-osseous tumour spread.

On initial presentation of a patient with IgD multiple myeloma there were no features to suggest an unusual variant. Two months later she developed spinal cord compression due to an IgD plasmacytoma. This complication of IgD myeloma has rarely been reported. During the course of the disease and using the routine laboratory protocol for investigating and identifying paraproteins, including IgD, the patient's results became indistinguishable from those in Bence-Jones proteinuria myeloma.

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics (cerebrospinal fluid): hematological and biochemical characterization and kinetic evaluation using carbamazepine.

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics [cerebrospinal fluid (CSF)] is described. The blood (jugular vein) and CSF (cisterna magna) catheters employed are simple, reliable, and inexpensive. The blood catheter was made of soft and flexible Silastic tubing and sealed with heparin. The CSF catheter consisted of intersliding polythene tubing and interlocking Silastic tubing, which allowed maneuverability within the cisternal magna space and thus prolonging patency for chronic studies. Both catheters were well tolerated by the animals, and the postoperative success rate was 80%-100%; after 8 days 80%-85% of catheters were still patent. Using a sampling protocol considered suitable for kinetic studies, we determined numerous biochemical and hematological parameters and compared them with those values obtained postsurgically and in control rats. The parameter changes associated with the sampling protocol did not affect the kinetics of the commonly prescribed antiepileptic drug carbamazepine and its primary pharmacologically active metabolite carbamazepine-10, 11-epoxide. Therefore, the model can be used to study the interrelationship between drug kinetics at central and peripheral sampling sites and mechanism(s) of drug action.

Concurrent monitoring of central carbamazepine and transmitter amine metabolism and motor activity in individual unrestrained rats using repetitive withdrawal of cerebrospinal fluid.

A method for repeated withdrawal of cerebrospinal fluid (CSF) from the cisterna magna was used in a pharmacokinetic and behavioural study of conscious, freely-moving rats, given the antiepileptic drug carbamazepine (35 mg/kg i.p.). Pharmacokinetic constants (i.e. time to peak concentration, peak concentration, area under the curve and t 1/2) for the drug and its primary metabolite carbamazepine-10,11-epoxide and also concentrations of acidic metabolites of 5-hydroxytryptamine and dopamine were obtained for the CSF of individual rats. A pharmacodynamic constant, the effective concentration of drug in CSF for 50% inhibition of motor activity was also determined for each animal. The above data provides good indices of the corresponding values for carbamazepine and its metabolite in brain insofar as a separate experiment showed good correlations between CSF and brain for concentrations of both the drug and its metabolite. Carbamazepine appeared to be largely responsible for the depression of motor activity as the metabolite, at the levels attained, seemed to have little effect. The changes in motor activity were not associated with altered concentrations of the metabolites of 5-hydroxytryptamine or dopamine in the CSF. While the investigation did not reveal major advantages in monitoring the drug under study in CSF rather than in serum it illustrates the potential of the CSF method as a simple way to obtain neuropharmacokinetic and neuropharmacodynamic profiles of the action of drugs in individual rats.