Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy.

We examined the phenotypic characteristics, molecular genetics and optimal pharmacological treatment of cerebrotendinous xanthomatosis (CTX) in an English family with combined hyperlipidaemia. The proband presented in adulthood with classical clinical characteristics of CTX, a greater than tenfold elevation in plasma cholestanol and combined hyperlipidaemia. His brother also had typical features of CTX without the presence of dyslipidaemia. Genotyping revealed that the two brothers were compound heterozygotes for a novel missense mutation in exon 2 (R94Q) and for a recently described nonsense mutation in exon 5, of the sterol 27-hydroxylase gene (CYP27). Analysis of all available family members revealed that hyperlipidaemia did not co-segregate with the presence of a CYP27 mutant allele. Trial of therapy showed that the lowest plasma sterol and triglyceride concentrations and cholestanol:cholesterol ratio were achieved with the combination of chenodeoxycholic acid (CDCA) 750 mg/day, a primary bile acid, and simvastatin 40 mg/day, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. CDCA alone and simvastatin alone significantly lowered plasma cholestanol concentration, but the decrease was greater with the former. After 1 year there was significant improvement in both cognitive and motor function with regression of tendon xanthomata on computerized tomography. We conclude that CTX in this English pedigree is probably due to compound mutant alleles in CYP27, that combined hyperlipidaemia in this family is unrelated to CTX, and that this complicated condition responds optimally to the combination of CDCA and simvastatin.

Automated spectrophotometric method for determining oxidized and reduced glutathione in liver.

An enzymatic recycling method has been applied to the measurement of total and oxidized glutathione with a centrifugal analyzer. When the reduced form of glutathione (GSH) was masked with 2-vinylpyridine to measure the oxidized glutathione (GSSG), the time to ensure full derivatization was three times longer than has been reported. The method is quick, simple, accurate, and precise (1.27% for GSH, 3.3% for GSSG intraassay CV; 2.15% for GSH, 5% for GSSG interassay CV), and the automation allows large numbers of samples to be conveniently assayed.

Ethanol-induced inhibition of ventricular protein synthesis in vivo and the possible role of acetaldehyde.

We have determined the extent to which acute ethanol administration perturbs the synthesis of ventricular contractile and non-contractile proteins in vivo. Male Wistar rats were treated with a standard dose of ethanol (75 mmol kg-1 body weight; i.p.). Controls were treated with isovolumetric amounts of saline (0.15 mol l-1 NaCl). Two metabolic inhibitors of ethanol metabolism were also used namely 4-methylpyrazole (alcohol dehydrogenase inhibitor) and cyanamide (acetaldehyde dehydrogenase inhibitor) which in ethanol-dosed rats have been shown to either decrease or increase acetaldehyde formation, respectively. After 2.5 h, fractional rates of protein synthesis (i.e. the percentage of tissue protein renewed each day) were measured with a large (i.e. 'flooding') dose of L-[4-3H]phenylalanine (150 mumol (100 g)-1 body weight into a lateral vein). This dose of phenylalanine effectively floods all endogenous free amino acid pools so that the specific radioactivity of the free amino acid at the site of protein synthesis (i.e. the amino acyl tRNA) is reflected by the specific radioactivity of the free amino acid in acid-soluble portions of cardiac homogenates. The results showed that ethanol alone and ethanol plus 4-methylpyrazole decreased the fractional rates of mixed, myofibrillar (contractile) and sarcoplasmic (non-contractile) protein synthesis to the same extent (by approx. 25 per cent). Profound inhibition (i.e. 80 per cent) in the fractional rates of mixed, myofibrillar and sarcoplasmic protein synthesis occurred when cyanamide was used to increase acetaldehyde formation. There was also a significant decrease in cardiac DNA content. The results suggest that acute ethanol-induced cardiac injury in the rat may be mediated by both acetaldehyde and ethanol.

Lack of efficacy of hydergine in patients with Alzheimer's disease.

BACKGROUND: There is no effective pharmacologic treatment for Alzheimer's disease, the most common dementing illness in the United States. Hydergine, a combination of ergoloid mesylates, is the only approved medication for Alzheimer's disease, but despite widespread use its efficacy remains to be established. We conducted a clinical trial of Hydergine-LC, a newer preparation of ergoloid mesylates in the form of a liquid in a capsule (LC) that may have greater bioavailability, to determine its value in patients with Alzheimer's disease. METHODS AND RESULTS: Eighty older adults with probable Alzheimer's disease participated in this double-blind, placebo-controlled trial of Hydergine-LC for 24 weeks. The recommended dose of 1 mg orally three times daily was used. Cognition and behavior were evaluated before and after the trial, and the patients were monitored for adverse effects. The medication was safe and well tolerated. The Hydergine-LC group did not perform better after treatment than the placebo group on any test, and its performance was worse (P less than 0.01 and P less than 0.02, respectively) on one cognitive measure (Wechsler Adult Intelligence Scale Digit Symbol Substitution Task) and on one behavioral scale (the Geriatric Evaluation by Relatives Rating Instrument). CONCLUSIONS: Hydergine-LC appears to be ineffective as a treatment for Alzheimer's disease.

Psychiatric distress in systemic lupus erythematosus outpatients.

A belief exists that systemic lupus erythematosus (SLE) patients have more psychiatric symptoms than patients with most other medical illnesses and that they often are as psychiatrically disturbed as psychiatric patient groups. These beliefs did not prove to be true for SLE outpatients. Twenty-two outpatients with SLE, 81 general medical outpatients, and 40 psychiatric outpatients were screened with psychometrically validated self-report instruments designed to assess psychiatric symptoms and stress. The SLE outpatients' psychiatric symptoms and stresses were much more similar to those reported by general medical outpatients, rather than by psychiatric outpatients, except in a few areas, and SLE patients were significantly less distressed than psychiatric patients in all areas except those relating directly to their SLE.

The natural history of medication compliance in a drug trial: limitations of pill counts.

To assess medication compliance over time, we prospectively performed pill counts among 121 ambulatory hypertensive subjects for less than or equal to 12 months. Prescribed regimens consisted of pinacidil or hydralazine administered four times a day and of secondary drugs administered up to twice daily. Surreptitious pill counts occurred every 1 to 12 weeks. Among a middle-aged subject group that had been selected for high rates of compliance, we observed mean compliance rates that approximated 100%. We noted marked intrasubject and intersubject variability for any one medication, between medications, and over time. From baseline blood pressures (+/- SE) of 155.5 +/- 1.9/97.3 +/- 1.0 mm Hg, subsequent mean blood pressures varied by compliance subgroup: "hypocompliers" (less than 80%), 151.3/91.0 mm Hg; "hypercompliers" (greater than or equal to 120%), 147.6/91.4 mm Hg; and "eucompliers" (80% to 119%), 143.3/88.5 mm Hg (systolic blood pressure: F1,52 = -220.9, NS; diastolic blood pressure: F1,52 = -121.4, NS). We concluded that weekly pill counts indicated marked intersubject and intrasubject variability, obscured by long-term averages; that compliance lapses appeared to be random; and that excessive medication-taking was the most consistent with "pill dumping."

Geriatric psychiatry patients' care by primary care physicians.

Primary care physicians were surveyed regarding their perceptions from recall of psychiatric disorders in, and their use of treatment approaches for, their geriatric patients. Affective disorders, organic mental syndrome, and generalized anxiety disorders were the three most common problems reported, and they were felt to be among the three most common problems by 89%, 56%, and 39% of the physicians, respectively. The three most common disorders for which they sought psychiatric consultation or referral were affective disorders, "psychosis," and organic mental syndrome, by 61%, 22%, and 18% of the respondents. The use of various psychiatric treatments and various sources of consultation and referral are analyzed and reported by age, primary care specialty, and practice setting of responding physicians.

Effect of changing dietary sodium on the airway response to histamine.

The airway response to histamine has been shown to be related to the 24 hour urinary excretion of sodium. To assess whether this relation is likely to represent a direct causal association a randomised double blind crossover trial of slow sodium (80 mmol/day) was compared with placebo in 36 subjects having a low sodium diet. The dose of histamine causing a 20% fall in FEV1 (PD20) was 1.51 doubling doses lower when the men were taking sodium than when they were taking placebo (p less than 0.05). On the basis of PD10 values, the difference in men was 1.66 doubling doses of histamine (p less than 0.05). There was no corresponding effect in women. Regressing PD10 against urinary excretion of electrolytes with data from the two occasions during the trial and the measurements made before the trial showed a significant association with sodium excretion after allowance had been made for any effect associated with potassium or creatinine excretion, the latter being a marker of the completeness of the urine collection. Again there was no corresponding effect among women. These findings are compatible with the differences in regional mortality data for England and Wales, which show a relation between asthma mortality and regional per person purchases of table salt for men but not for women.

Is alcohol hepatotoxic in the baboon?

The baboon is the only animal in which alcoholic fibrosis and cirrhosis of the liver has been produced with a nutritionally adequate diet. Zinc deficiency is associated with alcoholic liver disease and may contribute to liver damage. We have therefore investigated whether zinc supplementation would reduce liver damage in ten baboons receiving ethanol and an adequate diet. Eight received ethanol at up to 25 g/kg/day (70% of calories) for up to 60 months (four were supplemented with 50 mg zinc/day). All animals gained weight, and blood concentrations of ethanol were 63-342 mg/dl. Changes in liver blood tests were slight. Liver histology only showed fatty change in six animals, severe in two, and minor inflammatory changes but no significant fibrosis or cirrhosis. In one of the animals with severe fatty change there were also degenerative changes in parenchymal cells. There was thus no significant hepatic fibrosis or cirrhosis in baboons given large amounts of ethanol and an adequate diet for up to 5 years.

Pill count measures of compliance in a drug trial: variability and suitability.

To evaluate pill counts as a compliance measure for drug trials, we followed 121 ambulatory hypertensives selected for good compliance over less than or equal to 12 months. The medication regimens consisted of either pinacidil or hydralazine as monotherapy or with propranolol and/or hydrochlorothiazide. Pill counts for the two primary drugs were obtained at each of the 20 return visits. The population was characterized by chronic uncomplicated hypertension and sociodemographic diversity; mean age was 53 years. Despite excellent average weekly pill counts (overall mean compliance rate [+/- SD] = 96.0 +/- 13.2%), we observed large intersubject and intrasubject variance in weekly pill count assessment: individuals' mean standard deviation = 13.7% (range = 0%-86%) and mean coefficient of variation = 0.138 (range = 0.001-0.410). By pill count, 35% of individuals exhibited greater than 110% compliance on at least 1 visit. We conclude that (a) pill count variability is large, even among highly selected subjects, (b) traditional reports of overall pill counts are suboptimal, and (c) pill counts may unreliably measure medication-taking behavior because "supranormal" compliance by this method is improbable but common.

A double-blind, randomized, controlled trial comparing pinacidil to hydralazine in essential hypertension.

Pinacidil is a direct vasodilator with good absorption, a half-life of 2 to 4 hours, and side effects similar to those of other vasodilators. We hypothesized that controlled-release pinacidil would be comparable to or better than hydralazine for blood pressure control and side effects. A double-blind, randomized trial comparing pinacidil with hydralazine when combined with hydrochlorothiazide or propranolol to control side effects or the diastolic blood pressure was performed. Pinacidil decreased systolic and diastolic blood pressure from 156/100 mm Hg to 132/81 mm Hg. The increase in heart rate and weight with both drugs was controlled with the additional drugs. There was 1/17 successes on monotherapy with both drugs. When combined with other drugs there were 15/18 successes with hydralazine and 16/20 successes with pinacidil. Side effects were typical of vasodilators. Both drugs acutely increased plasma norepinephrine and epinephrine during chronic therapy.

Effect of a sustained-release formulation of trimazosin in mild to moderate hypertension.

A single-blind study was conducted to evaluate the blood pressure (BP) reduction and side effects of a sustained-release (SR) formulation of trimazosin in patients with mild to moderate hypertension. Eighteen individuals (age, 21-65 yr; mean diastolic BP, greater than 95 mm Hg) with essential hypertension were enrolled into the study. Each patient's dose was titrated to a range of 150-900 mg/d, with polythiazide added as necessary to achieve BP control. Four hours following the maximum titrated dose of trimazosin, mean standing and supine diastolic BPs were significantly lower than baseline readings. Supine systolic BP and supine and standing heart rate were not significantly lower than baseline. At 24 hours after administration of the maximum dose, there were no significant differences in heart rate of BP compared with baseline readings. Five of 16 patients responded to trimazosin therapy alone. Of the 11 treatment failures with trimazosin alone, five were therapeutic failures and six discontinued because of side effects. Only two of these 11 patients achieved satisfactory results with the combination therapy. Trimazosin SR acutely lowers BP three to six hours after administration. It appears to have a duration of action longer than six hours, but it is not sustained for 24 hours. The proportion of patients failing to respond in this sample was very high and suggests that for similar patients, the drug does not appear to be a very useful antihypertensive agent.

Rod mediated retinal dysfunction in cats with zinc depletion: comparison with taurine depletion.

Cats fed for 4 months with a diet with less than 7 p.p.m. zinc developed tissue zinc depletion, as judged by reduced muscle zinc content. Dark adapted electroretinogram (ERG) thresholds became elevated in zinc depleted cats. Electroretinograms and muscle zinc levels were reversed by zinc supplementation. Rod ERG to suprathreshold stimuli became reduced in b-wave amplitude in cats with zinc depletion, but suprathreshold cone ERG were unchanged. The ERG changes in zinc depleted cats were unlike those in cats fed on a taurine depleted diet.

Research problems for consultation-liaison psychiatry in the DRG era.

Psychiatry needs to conduct more rigorously designed empirical research studies to demonstrate its cost-effectiveness, especially since the DRG era is becoming more firmly established. The effectiveness of psychiatric intervention can be evaluated on its abilities to improve physical functioning as well as its improvement of psychosocial symptoms and cost savings. Some of the problems in consultation-liaison research are discussed, including the potentially confounding influences of demographic variables, type and severity of somatic disease, time since diagnosis, level of psychosocial stress, and initial level of physical functioning. Several types of research measures used in assessing physical and psychosocial functioning are discussed, and some of the dilemmas for psychiatry in utilizing individual versus standardized research interventions are explored.

Some methodological issues in consultation-liaison psychiatry research.

This is a research methodologic design model that may be useful to consultation-liaison psychiatrists. It is intended to facilitate such researchers in setting up and executing carefully controlled studies of the effectiveness (in psychiatric, medical, surgical, functional, cost, or other areas) of consultation-liaison interventions. The specific variables discussed are areas of particular interest to the authors, but many other variables may be readily substituted into this basic model. The design may be expanded or contracted relatively easily as would be appropriate for particular projects. The overall purpose of this paper is, hopefully, to serve as a catalyst for consultation-liaison psychiatrists to consider such research in their academic settings and to foster increased discussion and critical thinking regarding such research. The authors consider such research efforts important for the future regarding the scientific basis, proven effectiveness, and funding of consultation-liaison and general hospital psychiatry.