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Background: The Alcohol Use Disorders Identification Test (AUDIT) has been extensively researched to determine its capability to accurately and practically screen for alcohol problems. Methods: During the 5 years since our previous review of the literature, a large number of additional studies have been published on the AUDIT, abbreviated versions of it, its psychometric properties, and the applicability of the AUDIT for a diverse array of populations. The current article summarizes new findings and integrates them with results of previous research. It also suggests some issues that we believe are particularly in need of further study. Results: A growing body of research evidence supports the criterion validity of English version of the AUDIT as a screen for alcohol dependence as well as for less severe alcohol problems. Nevertheless, the cut-points for effective detection of hazardous drinking as well as identification of alcohol dependence or harmful use in women need to be lowered from the originally recommended value of 8 points. The AUDIT-C, the most popular short version of the AUDIT consisting solely of its 3 consumption items, is approximately equal in accuracy to the full AUDIT. Psychometric properties of the AUDIT, such as test–retest reliability and internal consistency, are quite favorable. Continued research is urged to establish the psychometric properties of non-English versions of the AUDIT, use of the AUDIT with adolescents and with older adults, and selective inclusion of alcohol biomarkers with the AUDIT in some instances. Conclusions: Research continues to support use of the AUDIT as a means of screening for the spectrum of alcohol use disorders in various settings and with diverse populations.

Background Ethyl sulphate (EtS), a direct ethanol metabolite, appears to offer potential as a biomarker for recent alcohol consumption. Although its window of assessment is similar to that of ethyl glucuronide (EtG), there are differences between the two markers in their pathways for formation and degradation. Aims (a) To assess the excretion of EtS compared to EtG and ethanol in drinking experiments with healthy volunteers, and (b) to elucidate the possibility of using the two metabolites for monitoring abstinence in substance use disorder patients during rehabilitation treatment. Design, setting, participants (a) Nine drinking experiments were performed by six healthy volunteers (two females, four males), with a mean age of 34.1 years (20–62), average oral intake of 0.2 g/kg ethanol (0.1–0.61), and having 74 spot urine samples. (b) Thirty-six substance abuse patients (mean age 41.9 years, 20–59; 22 males, 14 females) in a rehabilitation programme after withdrawal, producing 98 urine samples. Ethyl glucuronide and ethyl sulphate were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) using d5-EtG and d5-EtS, respectively, as an internal standard. Findings (a) Volunteers: EtG and EtS were detectable for up to 36 hours and reached the limits of determination in urine at 20.6 hours and 21.2 hours (median), respectively, after ethanol intake. EtG-100 (standardized to a creatinine of 100 mg/dl) reached its maximum level at 2.8 hours and EtS-100 at 2.1 hours (median) after the beginning of the experiment. Of the ethanol ingested, 0.022% was excreted as EtS in one volunteer. Eight samples were positive for EtS only and six for EtG only. Spearman's rank correlation coefficients of 0.84 (P

As, for ethical reasons, it is difficult to investigate by an experiment the effect of acute intoxication on leptin levels in alcoholics, we tested the hypothesis of lowered levels as an effect of acute ethanol intake inhealthy volunteers. The subjects comprised (1) 17 healthy male participants, recruited via newspaper advertisements [age 29 + 3.75 years, body mass index (BMI) 24.3 + 3.5, leptin at baseline 3.3 + 3.1 ng/ml]; (2) for comparison, leptin levels of 16 male alcoholic patients at day I of withdrawal were used. They were characterized as follows: (mean, median, standard deviation and range) age in years (41.1, 40.5, 10.2, 24, 57), BMI (23.3, 21.7, 5.4, 16.6, 37.5), 1032g of ethanol (median) consumed within the last 7 days, leptin levels 2.3mglml. A placebo-controlled double-blind trial teas performed. Leptin levels of blood samples were taken at baseline (t 1 ), before ethanol intake (t 2 ), when blood alcohol had reached its maximum (t 3 ) and the morning after (t 4 ). The oral dose of ethanol administered was 0.6 g/kg ethanol. (1) Volunteers: (a) the ethanol and placebo group exhibited leptin levels corresponding closely with levels measured at baseline (t 1 ) (rs = 0.85, p < 0.0001) and follow-up (t 4 ) (r s = 0.768, p < 0.0001). (b) Leptin levels for the placebo and the alcohol-consuming (verum) group did not differ significantly at baseline, after ethanol intake or on the morning after [Mann - Whitney U-test (p = 0.669, p = 1.0 and p = 0.887, respectively)]. (2) Leptin levels in relation to BMI did not significantly differ at any measurement time in either group. (3) Leptin levels/BMI of the healthy volunteers at t 1 and t 4 were not significantly different from those of 16 alcoholics. The data do not support the hypothesis of a significant effect of acute moderate alcohol intake on leptin levels in healthy volunteers.

Objective Surveys assessing alcohol use among physicians have most commonly employed the Alcohol Use Disorders Identification Test (AUDIT) or the AUDIT-C, the most common short version of the AUDIT. As with other screeners, prevalence estimation is dependent on the accuracy of the test as well as choice of the cutoff value. The aim of the current study is to derive more precise prevalence estimates of alcohol problems in physicians by correcting for false-positive and false-negative results. Method In the context of a survey, the AUDIT was sent out via email or standard postal service to all 2484 physicians in Salzburg, Austria. A total of 456 physicians participated. A published correction formula was used to estimate the real prevalence of alcohol use problems. Results Applying a cutoff of 5 points for the AUDIT-C, 15.7% of female and 37.7% of male physicians screened positive. Use of a correction based on general population data and the sensitivity and specificity of the AUDIT-C resulted in much lower prevalence rates: 4.0% for female and 9.5% for male physicians. Using the full AUDIT, 19.6% of the female physicians and 48% of the male physicians were screened positive. Using the correction, the estimated prevalence rates for females and males were 6.3% and 15.5%, respectively. Conclusions Our findings demonstrate that uncorrected screening results may markedly overestimate the prevalence of physicians drinking problems.

Current trends in conceptions of alcohol problems and provision of health care put increased emphasis on identifying individuals whose alcohol use and problems cover a range of severity. The purpose of this study is to begin to provide information on the relative utility of self-report measures designed to identify (screen for) individuals with alcohol problems. To achieve this goal, the empirical literature on contrasts of self-report screening measures was reviewed, and 13 relevant studies across diverse settings and subject populations were identified. The review showed that the CAGE, the Michigan Alcoholism Screening Test (MAST), and the short MAST (sMAST) have been the most widely studied self-report instruments to screen for alcohol problems. Direct comparisons show the MAST to be more sensitive than the CAGE, but with elderly patients the CAGE may perform better than the MAST. Furthermore, available data suggest that the CAGE and the sMAST perform comparably. Finally, the CAGE, MAST, and sMAST all perform best when predicting criteria most similar to those the instruments were designed to reflect. The study concludes with a discussion of priorities for research on screening instruments.

Using items from the Composite International Diagnostic Interview, dimensionality of the alcohol dependence syndrome was assessed in clinical samples in the United States and Russia. In both groups, a single-factor model provided a high degree of goodness of fit thus demonstrating cross-cultural coherence of the construct. The item dealing with narrowing of the drinking repertoire is most disparate in each sample. Severity of alcohol consequences was moderately related to alcohol dependence in both samples. Demographic variables, however, correlated less with severity of consequences. After the effects of severity of dependence and demographics were removed, quantity/frequency of recent alcohol consumption did not contribute to severity of consequences. Country, however, remained a significant, but small, predictor of severity of alcohol consequences.

While extensive research has been conducted to determine internal and external stimuli for drinking by alcoholics, the topic of how demographic, diagnostic, and personality variables may relate to these precipitants is largely unexplored. This study suggests that stimuli to use alcohol or drugs differ partly as a function of diagnosis (alcohol dependence vs. concurrent alcohol and drug dependence). Age, education, and gender do not appear related to the stimuli in either diagnostic group. Personality characteristics of cognitive reflectiveness, impulse control, sociability, and intrapunitiveness, however, seem to be associated with certain classes of high risk stimuli.

No single treatment has emerged as effective for all persons diagnosed as alcoholics. "Patient-treatment matching" is a method of choosing between alternative treatment options based on particular patient characteristics that interact differentially with interventions to produce more beneficial results than if "matching" had not been done. This review distinguishes three models for interactions between patient characteristics and interventions in terms of their clinical implications. Supporting empirical evidence for matching is also summarized. Requirements for the future research agenda are discussed and the pros and cons of implementing patient treatment matching in the clinical setting are addressed.

Aims: Physicians recovering from substance-related disorders are usually allowed to return to practice if they agree to remain abstinent from drugs, including alcohol, and to undergo random urine testing. Over 9000 physicians are currently involved in such monitoring programs in the US. To date, it has been difficult to adequately monitor abstinence from alcohol due to the short half- life of alcohol and no other highly specific marker. Ethyl glucuronide (EtG), a direct metabolite of alcohol, offers an extended window for assessment of drinking status (up to 5 days). Our aim was to assess the potential value of EtG testing in abstinence-based monitoring programs. Patients and methods: Urine samples were obtained from 100 participants in a physician monitoring program and additional samples were subsequently obtained 'for cause', 'to verify positive urine alcohol, when drinking was denied' and 'in high risk individuals'. All participants had signed contracts agreeing to remain abstinent from mood-altering drugs, including alcohol, and had agreed to random urine testing. EtG was determined using LC/MS-MS in addition to standard testing. The main outcome measure were urine specimens positive for EtG versus those positive based on standard testing for alcohol and other drugs. Results: Among the initial 100 random samples collected, no sample was positive for alcohol using standard testing; however, seven were positive for EtG (0.5-196 mg/l), suggesting recent alcohol use. Subsequent EtG testing was performed clinically during the course of monitoring. Of the 18 tests performed to date, eight of eight tests performed 'for cause' were positive for EtG but negative for all other drugs including urine alcohol. All eight were confirmed positive by self reported drinking by the patient when confronted regarding the positive test result. Of six tests performed to 'confirm a positive urine alcohol' two were positive for EtG and confirmed positive by self reported drinking. For the other four samples, especially as two are from a diabetic, in vitro fermentation of ethanol is discussed. Conclusions: These data suggest that physicians in monitoring programs have a higher rate of unrecognized alcohol use than previously reported. Incorporation of EtG testing into alcohol abstinence monitoring can strengthen these programs.

Aims: In a variety of clinical and forensic situations long term use of alcohol must be monitored. In this project we explore the utility of fatty acid ethyl esters (FAEE) in this regard. Additionally, we propose a cut-off value of FAEE to distinguish teetotallers/moderate/social drinkers from alcoholics or individuals drinking at harmful levels. Patients and methods: FAEE levels from 18 alcohol-dependent patients in detoxification were contrasted with those of 10 social drinkers and 10 teetotallers. FAEE in hair were determined, using headspace solid phase microextraction and gas chromatography mass spectrometry. C FAEE , as sum of the concentrations of four esters, was compared to a major FAEE, ethyl palmitate. PEth was measured in heparinized whole blood with a high pressure liquid chromatography (HPLC) method. Drinking validation criteria include self reports, phosphatidyl ethanol (PEth) in whole blood as well as the traditional markers of heavy drinking, gamma glutamyl transpeptidase (GGT), mean corpuscular volume (MCV) and carbohydrate deficient transferrin (CDT). Results: Receiver-operating characteristic (ROC) curve analysis for C FAEE , indicated a sensitivity of 100% and a specificity of 90% for a cut-off of 0.29 ng/mg. By using a cut-off of 0.4 ng/mg, CFAEE identified 94.4% correctly. C FAEE and ethyl palmitate were significantly associated (r = 0.945; P < 0.001) as were C FAEE and PEth (r = 0.527; P = 0.025). No significant correlation was found between CFAEE and total grams of ethanol consumed last month, blood-alcohol concentration at admission to the hospital, CDT, MCV, or GGT. Among the serum and blood markers, %CDT identified 47.1%, MCV 38.8% and GGT 72.2% of patients with chronic intake of higher amounts of ethanol correctly, whereas PEth achieved 100% accuracy. Conclusions: The data suggest that C FAEE is a potentially valuable marker of chronic intake of high quantities of ethanol. Furthermore, the results indicate that a reasonable and provisional FAEE cut-off to distinguish between social/moderate and heavy drinking/alcoholism in hair is 0.4 ng/mg.

Several biochemical tests are available to screen for heavy drinking in patients. Most of these (e.g., liver function tests and macrocytic volume) rise due to adverse effects of alcohol on organs or the organ's functions. Carbohydrate-deficient transferrin, however, seems to elevate because of the direct action of alcohol or one of its metabolites. A second valuable contribution of biomarkers is identification of relapse events in recovering alcoholics that either would not be voluntarily reported or reported only much later. Finally, providing feedback to patients in treatment based on their biomarker values and changes in them during the course of treatment can enhance motivation, a key component in recovery from alcohol problems. The current article offers a clinical rationale for routine use of biomarkers of heavy drinking in health care practice and proposes recommendations on how they might be best used.

An isocratic HPLC procedure for the assessment of thiamine (T), thiamine monophosphate (TMP) and thiamine diphosphate (TDP) in human erythrocytes is described. Several aspects of the procedure make it suitable for both clinical and research purposes: limits of detection and quantification of 1 and 2.5 nmol/l, respectively, recovery of 102% on average (range 93-112%), intra- and inter-day precisions within 5 and 9%, respectively, total elution time 15 min. This analytical methodology was applied to a case-control study on erythrocyte samples from 103 healthy subjects and 36 alcohol-dependent patients at risk of thiamine deficiency. Mean control values obtained were: T=89.6+/-22.7 nmol/l, TMP=4.4+/-6.6 nmol/l and TDP=222.23+/-56.3 nmol/l. T and TDP mean values of alcoholics were significantly lower than those of control cases: T=69.4+/-35.9 nmol/l (P

Background. Misuse of alcohol is associated with a range of medical problems. Fortunately, a simple pencil-and-paper measure, the Alcohol Use Disorders Identification Test, can effectively and efficiently screen for early-stage alcohol abuse as well as provide the physician information that can assist in brief intervention. Objective. The objective of this article is to briefly summarize research published on the Alcohol Use Disorders Identification Test and suggest its potential role in brief intervention in primary care settings. Methods. Scientific literature on the Alcohol Use Disorders Identification Test though 2000 was reviewed and synthesized to address issues relevant to use of the test in primary health care settings. Results. The Alcohol Use Disorders Identification Test is quite sensitive and specific and compares favorably with alternative self-report screens for alcohol problems.

The relationships of carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT) and their mathematical combination (gamma-CDT) with self-reported diseases were evaluated in a large cross-sectional risk factor survey. Significant gender effects were observed in associations of the markers with several medical conditions as well as with general health care utilization. In men, CDT was associated with rheumatoid arthritis. In both genders, GGT was positively associated with hypertension and diabetes. gamma-CDT was positively associated with hypertension in males and with asthma in females. This general population study demonstrates that these markers, although most commonly used to assess alcohol misuse, might also serve as health risk indicators.

The dose response to alcohol use of carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and their combination (gamma-CDT) was studied in an age- and gender-stratified, random sample from Finland in 1997. A linear association with a threshold between alcohol consumption and the three markers was observed. Body mass index was negatively associated with CDT and positively with GGT Age was positively associated with GGT and gamma-CDT In conclusion, CDT appears to be an early phase marker of alcohol consumption. The combined marker, gamma-CDT, was less associated with factors such as body mass index but more strongly correlated with alcohol consumption than were the two markers separately.

Whereas heavy alcohol consumption is known to elevate serum carbohydrate-deficient transferrin (CDT) and gamma-glutamyl transferase (GGT) levels, the contribution of drinking pattern to these effects is not completely understood. We present data on 423 men and 146 women evaluated 1 year after treatment in a large-scale alcoholism treatment study (Project MATCH). Relationships between drinking frequency (number of days drinking), intensity (drinks per drinking day), and blood levels of CDT and GGT were analyzed by using response surface regression models and thin-plate spline-smoothing techniques. Both models indicated differences between CDT- and GGT-drinking pattern relationships in men and, also, a difference between men and women in CDT drinking-pattern relationships. For men, CDT levels appeared to respond primarily to frequency of drinking, whereas GGT was influenced primarily by drinking intensity. For women, both CDT and GGT were influenced more by drinks per drinking day (intensity) than by number of days drinking (frequency). The data confirm both the independent nature of these biological markers of alcohol consumption and gender differences in alcohol-induced CDT response reported previously.

This project explores the cross-national construct validity of the Alcohol Dependence Syndrome. The investigation also examines basic psychometric properties of the Alcohol Dependence Scale (ADS), an instrument commonly employed to measure dependence. Subjects consisted of inpatients and outpatients in American and Russian alcoholism treatment programs. Despite some variations, an orthogonal four factor structure of the ADS appears similar across the two cultural samples, thus lending support to the alcohol dependence construct. Analyses of psychometric properties of the Scale generally support its value in future cross-cultural research on alcohol dependence.

Sensitivities, specificities, and odds ratios for hazardous drinking for various cut scores on the CAGE are computed for a large sample active duty Army personnel. Contrasts on these properties are made between the standard CAGE and a "modified CAGE" consisting of standard CAGE items and two other items dealing with problematic drinking. The role of demographic variables--gender, ethnicity, marital status, rank category, and age in mediating relationships of both versions of the screening test to hazardous drinking--is also explored. At a cutoff score of one endorsed item, odds ratios were highest for female personnel and commissioned officers. Language: en

✓ The pituitary function of two patients with acromegaly was monitored before, during, and after selective transnasal pituitary adenomectomy. The purpose of the study was to verify the efficacy of this technique, and to see if there was normal function in the residual pituitary tissue. Following surgery, both patients showed clinical improvement with no evidence of significant anterior or posterior pituitary dysfunction. Concentrations of plasma growth hormone obtained serially during surgery were elevated prior to tumor removal but fell precipitously after adenomectomy. The half-life for immunoreactive growth hormone in these patients was less than 35 minutes. We conclude that selective transnasal pituitary adenomectomy is an effective treatment for pituitary tumors. Furthermore, our data suggest that the pituitary tumor in these patients did not arise because of excessive stimulation by hypothalamic growth hormone-releasing factor.

Melatonin levels exhibited a day-night rhythm with highest levels at night. Nocturnal plasma melatonin concentrations were unrelated to sleep stages, whereas secretion of GH was temporally related to slow wave sleep. Levels of corticotropin rose in the later sleep cycles. We found no relationship between endogenous nocturnal melatonin and adenohypophyseal hormone levels. The results indicate that in young men nocturnal levels of melatonin are controlled separately from those of LH, PRL, corticotropin, and GH.

SUMMARY In order to define nyctohemeral plasma ACTH secretory patterns, frequent plasma ACTH samples were obtained in seven patients with untreated Cushing's disease (i.e. pituitary-dependent Cushing's syndrome), five Cushing's patients treated by bilateral adrenalectomy, four of whom had Nelson's syndrome, and one patient with 21-hydroxylase deficiency (congenital adrenal hyperplasia). A nyctohemeral rhythm of plasma ACTH concentration was apparent in the one patient with the adrenogenital syndrome but not in those with Nelson's syndrome or Cushing's disease. The effect of graded doses of dexamethasone, 2, 8 or 32 mg per 24 h period, on plasma ACTH concentrations was studied in patients with untreated or treated Cushing's disease or Nelson's syndrome. In all of these hypercorticotrophic states, the mean plasma ACTH concentration was not significantly affected by the smallest dose of dexamethasone, was partially suppressed by the intermediate dose, and further suppressed by the largest dose. In contrast, the patient with congenital adrenal hyperplasia and elevated plasma ACTH concentrations showed complete suppression of plasma ACTH levels following the smallest dose of dexamethasone. These findings indicate that there is resistance to ACTH suppression by dexamethasone in all stages of Cushing's disease and suggest that negative feedback of glucocorticoids may be involved in the pathogenesis of this disease.

(1) The nocturnal rise in plasma melatonin concentration continued through two cycles with continuous light occlusion by blindfolds in normal subjects. A daytime nap did not disturb the rhythm. (2) The plasma melatonin rhythm was present in patients with pituitary-adrenal and pituitary-gonadal failure, but appeared diminished or absent in patients bearing lesions at different points in the pineal afferent pathway. (3) In other patients and subjects who showed normal response of cortisol, growth hormone or prolactin after stimuli including hypoglycemia, pneumoencephalography, exercise or administration of l -dopa during the daytime, there was no stimulation of plasma melatonin concentration. (4) Melatonin was not correlated with prolactin in blood or cerebrospinal fluid of patients with a wide range of plasma prolactin levels. (5) The adult human melatonin rhythm is relatively independent from pituitary, gonadal, and adrenal function, but may rely on a neural pathway similar to that controlling the rhythm in lower animals. The human melatonin rhythm may represent the output of a stable oscillator with a signal relatively free from acute perturbation by sleep, darkness, or stress sufficient to cause changes in other hormones.

The circadian secretion of ACTH and corticosterone was assessed by measuring immunoreactive ACTH concentration in the plasma and ACTH content in the anterior and posterior pituitary over a 30 h period in groups of both male and female rats and comparing these data to fluorometric corticosterone concentration in the plasma and corticosterone content in the adrenal. A circadian rhythm of plasma corticosterone levels and adrenal content was apparent in both males and females with the highest levels at the onset of darkness. In contrast, there was no significant circadian rhythm in plasma ACTH levels or anterior or posterior ACTH pituitary content. Because the ACTH and corticosterone rhythms were dissociated, rhythmic corticosterone secretion is not entirely dependent on ACTH secretion.

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis-Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady-state phenytoin serum concentrations resulting from different daily doses: The observed steady-state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p less than 0.02). The average deviation between observed and predicted levels was 0.04 mug/ml (range, +/- 3.2 mug/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r= 0.360, p less than 0.05). The average deviation was --3 mug/ml (range, 3.9 to --11.3 mug/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.

SummaryComplete or anterolateral, but not anterior, basal hypothalamic deafferen-tation prevented the increased basal secretion of ACTH in chronically adrenalecto-mized rats. ACTH secretion in response to ether stress was at least as great in the de-afferented, adrenalectomized rats as in intact controls. The data suggest that extra-hypothalamic influences which enter the lateral basal hypothalamus are necessary to achieve a high basal ACTH secretion when plasma ghicocorticoids are depressed.

Adaptation to a repeated stress in male rats was studied by measuring plasma ACTH by radioimmunoassay 2.5 min or plasma corticosterone by acid fluorescence 20 min alter initiation of the stress. No adaptation was seen in the secretion of ACTH in response to ether, tourniquet, or leg-break stresses repeated at 90 min intervals 1–3 times. A marked rise in plasma ACTH concentration was produced within 2.5 min after application of each stress. Plasma ACTH always returned to basal levels by 90 rain after application of stress. Ether stress repeated at 24-hr intervals for 3 days did not produce any decrease in either the plasna ACTH or corticosterone response by the third day. These data indicate that no adaptation in ACTH secretion in response to repeated stress occurs under the conditions of our experiments.

Various levels of lower body negative pressure (LBNP) were applied to human volunteers and plasma ACTH and Cortisol levels measured. There were no significant alterations in plasma ACTH and Cortisol concentrations suggesting that LBNP is a mild stressor.

• The optimal dosage of phenytoin can be accurately determined by a pharmacokinetic method. By plotting the rate of administration of phenytoin acid against the apparent plasma clearance rate, we estimated the maximum rate of metabolism and the serum concentration at which the rate of metabolism was one half the maximum rate for phenytoin and then applied the Michaelis-Menten equation to optimize the dosage of phenytoin in a 48-year-old man with uncontrolled idiopathic generalized seizures and increased metabolism of phenytoin. The patient became seizure free on a regimen of 650 mg of phenytoin daily and experienced no side effects of phenytoin over-dosage. The pharmacokinetic technique described is simple to use and can be applied in an outpatient clinic.

In a study of 36 men burned in a fire, based on sequential early morning samples, plasma cortisol concentration was elevated in proportion to burn size. Plasma corticotrophin (ACTH) was not correlated with burn size, suggesting that factors other than ACTH contribute to the elevated cortisol. Cortisol levels did not fall on the days preceding death in nonsurvivors. During 24-hour sampling, burned patients exhibited a fitted cortisol curve mean that was elevated in proportion to burn size, a rhythm amplitude that was significantly less than that in uninjured controls, and a normal peak time. Metabolic rate, rectal temperature, and urinary catecholamine excretion were also elevated in proportion to burn size. Although plasma cortisol was positively correlated with metabolic rate and with temperature, this appeared to result from a common relationship of these variables with burn size. On the other hand, urinary catecholamine values significantly reduced the residual variance of metabolic rate and temperature after accounting for variance related to burn size. Cortisol appears to be less prominent than catecholamines as a possible mediator of the elevated thermogenesis.

We have compared the capacity to secrete ACTH in response to stress or adrenalectomy in control rats and in those with total hypophysectomy (H), adenohypophysectomy (AH) with preservation of the intermediate and the neural lobes, neurohypophysectomy (NH) with removal of the pars nervosa and all or part of the pars intermedia with preservation of the adenohypophysis, or incomplete adenohypophysectomy (IAH) in which a portion of the adenohypophysis and all of the pars intermedia and pars nervosa were left intact. Plasma ACTH measured with an N-terminal antibody that reacts on an equimolar basis with ACTH and alpha-MSH but not with other known pituitary hormones was elevated after ether or tourniquet stress in all except the H group. Three weeks after adrenalectomy there was an elevated basal plasma ACTH and an augmented ACTH response to stress in intact and IAH but not in AH rats. When a more specific alpha11-24 ACTH antibody was used there was a high plasma ACTH after ether stress in the IAH, NH, and intact groups but not in the AH or H groups. Adrenal weight and plasma corticosterone after tourniquet or ether stress were indistinguishable in the AH and H groups and were much higher and nearly identical in the intact, NH and IAH groups. We conclude that only the adenohypophysis secretes functionally significant amounts of ACTH. Plasma ACTH detected by the N-terminal antibody in the AH group is probably related to alpha-MSH or similar peptides and is incapable of maintaining adrenal weight or stimulating corticosterone secretion.

Sensory deprivation produced by removing the eyes and olfactory bulbs in male rats allowed pinealectomy to markedly augment the post-adrenalectomy elevation of ACTH levels. Pineal removal or sensory deprivation separately did not have this effect. Thus, intact sensory input and an intact pineal gland are independently capable of restricting the post-adrenalectomy rise in ACTH levels.

Peripheral neuropathy and hypertension caused by lead intoxication are reported in two children with sickle cell anemia. One child had generalized weakness in the initial occurrence and distal paralysis during a relapse two years later. The second child had foot and wrist drop. Both had slow peripheral nerve conduction velocities during the episodes. Chelation therapy was successful and resulted in a return of strength (over a period of several months) and a normalization of the blood pressures. Children with sickle cell anemia who are subjected to lead intoxication appear to be predisposed to peripheral nerve damage.

Four male subjects were given phenytoin orally in single or twice-daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas-liquid chromatography, ranged from 1 to 18 micrograms/ml. Serum phenytoin concentration-time data were fit to a 1-compartment open model with zero-order input and Michaelis-Menten elimination. The resulting computer-generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/1; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis-Menten kinetic behavior.

Serial measurements of plasma adrenocorticotropic hormone (ACTH) and growth hormone (GH) concentrations did not change significantly during cerebral arteriography in 7 adults without evidence of hypothalamic or pituitary disease. No serious permanent complications were observed in 324 patients following cerebral arteriography. These facts indicate that selective cerebral arteriography should be the first contrast study performed when attempting to evaluate hypothalamic or pituitary disease.

The effect of pneumoencephalography on plasma and cerebrospinal fluid (CSF) adrenocorticotrophic (ACTH) and growth hormone concentrations was studied in patients with and without hypothalamicpituitary disorders. In those without hypothalamic-pituitary disease, basal plasma and CSF ACTH levels were approximately equal, whereas plasma growth hormone levels were higher than CSF levels. Associated with the stress of the procedure, both ACTH and growth hormone concentrations increased in the plasma without a corresponding change in CSF levels of these two hormones. In two patients with suprasellar extension of either an ACTH or growth hormone secreting pituitary tumor, basal CSF ACTH or growth hormone levels were higher than in those without suprasellar extension. In contrast, those patients with nonendocrine active pituitary tumors that extended above the sella turcica did not have elevation of CSF ACTH or growth hormone levels.