Dexamethasone suppression testing of alcoholics.

Fourteen (33%) of 43 men hospitalized for alcohol abuse showed abnormal cortisol levels at 4 pm, 17 hours after administration of 1 mg of dexamethasone (median, five days after admission). Most (but not all) of these nonsuppressors showed multiple signs of alcoholic physical deterioration; there may be more than one mechanism by which alcohol abuse can lead to an abnormal result of this test. Suppressors and nonsuppressors reported similar alcohol consumption, symptoms of depression, and occurrence of depression among close relatives. Only two patients (5%) showed abnormal cortisol levels at 8 am, nine hours after administration of dexamethasone. These results suggest that, as a screen for primary depressive illness among recently abstinent alcohol abusers, the 4 pm cortisol level is not specific enough, but the 8 am level might be useful in patients who have no alcoholic relatives.

Characterization and prediction of lithium blood levels and clearances.

Mathematical simulations and nonlinear numerical methods for characterizing the serum elimination half-life, volume of distribution, and renal clearance of lithium after multiple oral doses of lithium carbonate and two or more blood level determinations were constructed and adapted for clinical use. These characteristics were measured for 24 inpatients; predictions were made with the simulation and compared with actual succeeding blood levels. The average elimination half-life of 25.9 hours was compared with half-lives reported after single oral doses. Average and median errors of prediction were negligible; the root mean square error was 0.12 mEq/L, near the coefficient of variation of 0.082 mEq/L. The correlation between predicted and observed levels (r) was .82; a small systematic effect of weight was found.

Antidepressant effects of high-dose right unilateral electroconvulsive therapy.

In a random-assignment, double-blind, controlled comparison in 38 melancholic men, overall antidepressant potency of high-dose electroconvulsive therapy (378-mC charge) given with right unilateral electrode placement was not significantly different from that with bilateral placement, although there was a trend for faster improvement with bilateral ECT. The suprathreshold character of the stimulus, about 2.5 times the expected seizure threshold, may have contributed to the high efficacy of brief-pulse right unilateral electroconvulsive therapy found in this study.

Decreased epinephrine in familial alcoholism. Initial findings.

Stress-induced epinephrine release, measured in urine, was less in a group of 17 nonalcoholic adoptee probands, aged 18 to 36 years, with alcoholic biologic relatives than in 12 similar controls with no alcoholic relatives. This result is similar to previous observations of small stress-induced epinephrine release in humans with aggressive or hyperactive character traits. Resting epinephrine levels and epinephrine released by alcohol in soft drink were also lower in our probands than in controls. Familial alcoholism might be associated with a trait of globally decreased epinephrine responsiveness.

Clinically occult diffuse proliferative lupus nephritis. An age-related phenomenon.

Thirteen patients with systemic lupus erythematosus (SLE) who had normal results of urinalysis, absence of proteinuria, and normal serum creatinine values underwent renal biopsy. Three of 13 patients had diffuse proliferative glomerulonephritis (group 1). Biopsy specimens showed segmental fibrinoid necrosis, diffuse mesangial hypercellularity, and substantial immunoglobulin deposition. Group 2 comprised those patients whose histologic findings did not portend a poor prognosis. Four had mesangial proliferative glomerulonephritis, three had focal proliferative glomerulonephritis, and three had minimal mesangial widening. The values of inulin clearance in group 1 did not differ significantly from those in group 2. Patients in group 1 had a mean age of 19 years, a value significantly lower than in group 2 (41.8 years). Review of previous reports also supports the thesis that this phenomenon is age related. Our study underscores the importance of renal biopsy in patients with SLE despite the absence of clinical evidence of renal involvement, particularly in patients under 30 years of age.

The interrelation of renin and iron binding capacity.

When rats are subjected to hypoxia, an increase in serum angiotensinogen concentration occurs which is accompanied by the appearance of serum erythropoietin (EP) during the first 24 h. Subsequent increases in EP reach maximum values 24 to 48 h after increases in packed cell volume (PCV) and serum renin levels. The current experiments were designed to determine if a decrease in iron stores is the stimulus for renin production when rats are rapidly expanding their red cell volume in a hypoxic environment. Young rats fed McCall's low iron diet were paired with rats fed the same diet supplemented with ferric citrate (6 g/kg diet). After two weeks at ambient pressure, they were subjected to hypoxia (0.48 atm) for 1 to 10 days. After 5 days at the reduced pressure, a fraction of the rats on the low iron diet were fed the iron-supplemented diet. At the time of sacrifice, serum was assayed for total iron binding capacity (TIBC) and renin. Rats that were fed the low iron diet showed an increase in TIBC, an increase in serum renin and a positive correlation between serum renin and TIBC. Rats that were fed a normal iron diet under the same conditions had lower TIBC, lower serum renin and no correlation between serum renin and TIBC. When low iron diet rats were supplemented with iron, TIBC and serum renin decreased. These experiments may have a clinical counterpart. The total iron binding capacity, renin and angiotensinogen were measured in the serum of women during the first 19 weeks of pregnancy. Women during early pregnancy showed an increase in TIBC, an increase of renin and angiotensinogen in the serum and a positive correlation between TIBC and renin concentration. It is suggested that the increased concentration of renin in the serum of women during the first 19 weeks of pregnancy and in the serum of rats that are rapidly expanding their red cell volume are related to a decrease in iron stores.

Sequential hemodynamic changes in end-stage renal disease and the anephric state during volume expansion.

The sequence of hemodynamic events during periods of salt- and water-loading was studied in anephric patients and those with end-stage kidney disease. The 10 patients studied showed four different sequential hemodynamic patterns: 1) no significant increase in blood pressure (BP) in two patients; 2) increase in BP associated with an increase in cardiac output and without change in total peripheral resistance in two patients; 3) increase in BP associated with an increase in total peripheral resistance from the beginning without an increase in cardiac output in five patients; and 4) increase in BP associated with an initial increase in cardiac output followed by an increase in total peripheral resistance in one patient. There was a significant positive correlation between BP and blood volume and between BP and total exchangeable sodium in the patients in whom salt- and water-loading increased the BP. It is concluded that during salt- and water-loading an initial rise in cardiac output is not necessary to increase BP and that a sustained rise in cardiac output does not always increase the total peripheral resistance. Mechanisms other than whole-body autoregulation play a role in increasing BP during salt- and water-loading in patients deprived of renal excretory function.

Generalization, duration, and low-frequency electroencephalographic persistence of bilateral electroconvulsive therapy seizure.

Measurements were made at the beginning and end of a course of bifrontotemporal brief-pulse ECT for 28 males to both determine how well seizure generalization is maintained along the course of electroconvulsive therapy (ECT) and examine correspondence between low-frequency EEG activity and other seizure durations. Durations of spike electroencephalographic (EEG) paroxysmal activity, heart rate elevation, and Ionic-clonic activity decreased about 30% along the course, p < 0.0001, yet correlated highly at both times, I = 0.69 to 0.88, p < 0.0005, as did their changes: these correlations demonstrate high-seizure generalization and its maintenance. EEG low-frequency persistence, the difference between total and spike EEG paroxysmal durations, doubled along the course (p = 0.041), but showed no association with any other seizure duration measure. This absence of association suggests that low-frequency activity and other seizure duration measures describe separate phenomena and should be expressed separately, rather than combined as the (traditional) total EEG paroxysmal duration.

Timolol kinetics in chronic renal insufficiency.

A single-dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function--(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; C cr, 20 to 50 ml/min); (3) 4 patients with end-stage renal disease (ESRD)--to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (C max) was 84.3 +/- 44.8 ng/ml at 0.8 +/- 0.4 hr for N and 87.1 +/- 22.8 ng/ml at 1.7 +/- 1.2 hr (p, NS) for MCRI. N and MCRI mean half-lives (5.2 +/- 2.6 hr and 4.0 +/- 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 N and 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration of timolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.

Efficiency of the stimulus characteristics of ECT.

OBJECTIVE: Greater ECT stimulus efficiency allows for a lower stimulus dose and should diminish the side effects of ECT. METHOD: Four different ECT stimuli of identical charge (average mC=2.5 times age) with pulse widths of 0.5 msec and 1 msec and frequencies of 30 Hz and 60 Hz, respectively, were compared for efficiency. The stimuli were applied in a balanced order to each of 24 subjects. Asymmetric bilateral electrode placement was used. RESULTS: Peak heart rates were higher with the 0.5-msec pulse width than the 1-msec pulse width. Seizure induction was more successful with the 0. 5-msec pulse width than the 1-msec pulse width. Stimulus frequency had no effect on heart rate or seizure induction. CONCLUSIONS: The pulse width of 0.5 msec is more efficient than the 1-msec pulse width. The "half-age" dose for the first bilateral ECT treatment is usually successful for subsequent ECTs when the 0.5-msec pulse width is used.

Generalization of the effects of unilateral and bilateral ECT.

The correlation coefficients among four different measures of seizure duration (motor activity, EEG spikes, EEG total, tachycardia) were substantially lower with unilateral than bilateral ECT. This suggests that unilateral ECT is less well generalized through the brain than bilateral ECT.

Duration of ECT-induced tachycardia as a measure of seizure length.

The duration of ECT-induced tachycardia in 203 seizures of 28 patients was measured. Tachycardia duration was easily determined; it correlated highly with both motor (cuffed arm) and EEG seizure estimates.

Antidepressant effects of right versus left unilateral ECT and the lateralization theory of ECT action.

In a random-assignment, double-blind, controlled comparison of right versus left unilateral ECT in 30 melancholic men, the two methods were not significantly different in overall antidepressant potency, although there was a significantly faster rate of improvement with left unilateral ECT. These results imply that the antidepressant effects of ECT cannot be attributed primarily to right hemisphere mechanisms, as others have postulated.

Serum prolactin levels during extended cocaine abstinence.

Following a report indicating almost a 100% risk for hyperprolactinemia in cocaine users after 1 month of abstinence, the authors determined the serum prolactin concentrations of 23 male inpatients who had abstained from cocaine for 2-43 weeks. None showed high prolactin levels; this places the incidence below 12.3% with 95% confidence. These results imply that persistent hyperprolactinemia requires a medical explanation other than cocaine abstinence itself.

Differential effects of right unilateral and bilateral ECT on heart rate.

In a series of 11 melancholic patients who received both right unilateral and bilateral ECT during a single course of treatment, mean and minimum postictal heart rates were greater after bilateral ECT. Greater catecholamine release during bilateral ECT is the most likely explanation for these effects. These differences complement other evidence that bilateral ECT has a more pronounced physiological impact than unilateral ECT.

Cell surface oligosaccharide modulation during differentiation: III. Lectin affinity class distributions.

In previous studies we showed that the onset of the morphological phenotype of cellular senescence (IMR-90) in vitro is preceded by complex cell surface changes. Using fluorescently conjugated lectins these studies showed: (1) quantitative PDL-dependent decreases in cell surface mannosyl, galactosyl, and N-acetyl-glucosamine residues; (2) these changes were correlated with changes in ligand/lectin membrane mobility, suggesting a functional relationship for the quantitative changes. To further investigate the biological significance of these observations we have developed a synthetic ligand competition assay to analyze the lectin binding event itself. The results of these analyses show that: (1) the number of binding affinity class distributions is highly restricted; (2) the PDL-dependent mannosyl change is due to the loss of a high-affinity class distribution without significant change in the low-affinity site; and (3) PDL-dependent changes in both galactosyl and N-acetyl glucosamine binding events are the result of changes in the affinity class distributions. These results are interpreted in terms of the potential available energy to act as the basis for signal transduction at the cell surface.

Cell surface oligosaccharide modulation during differentiation: IV. Normal and transformed cell growth control.

In previous studies it was shown that cell surface oligosaccharide affinity class distributions and binding capacities were down-regulated as normal cells approach senescence. Using a sensitive, amplified, lectin/specific-ligand competition analysis three other growth regulation states were compared to that of cellular senescence. Non-senescent and senescent low-density and contact-induced growth inhibition was compared with neoplastic cell growth control. Non-senescent human fetal lung fibroblasts (IMR-90) down-regulated their mannosyl and galactosyl specificities in response to both low-density and contact-induced growth inhibition. Senescent IMR-90 down-regulate their mannosyl residues in response to contact conditions while they up-regulate their galactosyl residues under the same conditions. Growth-transformed transplantable canine glioma cells did not show density-dependent regulation of their cell surface oligosaccharide structures. Modulation of the CG cells with a specific alpha-mannosidase II inhibitor, Ricinus communis a galactosyl specific lectin, and pokeweed mitogen a cellular differentiating agent resulted in an altered growth phenotype and up-regulation of the mannosyl and galactosyl surface oligosaccharides. These data indicate a controller function for the cell surface oligosaccharides and a general influence on growth control.

Cell surface oligosaccharide modulation during differentiation. II. Membrane mobility of oligosaccharide lectin conjugates.

The quantitative, population doubling level (PDL) dependent changes in cell surface oligosaccharides on IMR-90 cells, were investigated from the perspective of membrane mobility of the lectin-oligosaccharide conjugates. Concanavalin-A (CON-A), wheat germ agglutinin (WGA), Ricinus communis agglutinin (RCA-120), and Dolichos biflorus agglutinin (DBA) were all observed to cluster, cap, and endocytose in cultured human diploid fibroblasts (IMR-90). Quantitative photometry at 37 degrees C over defined periods of time indicated that as the IMR-90s approached cellular senescence a specific lectin-dependent inability to either endocytose or process the capped complex occurred. The development of a biotin/avidin/enzyme amplification assay permitted the assignment of the accumulating signal to the internal compartment. Kinetic data indicate that there are at least three separate (and separable) mechanisms for the PDL related changes in lectin binding. Data for the CON-A complex indicates that at least two classes of functional complexes are present. Regression analysis of the kinetic data for the RCA-120 complex indicates a similar membrane clearance for the IMR-90s at all population doubling levels (PDL), suggesting that the quantitative differences observed earlier were due to simple quantitative reductions in the RCA complexing molecules. Data for WGA mobility on the membrane indicates that they are both changes in the number and mobility status of the complexes. These results indicate that the quantitative changes in lectin binding observed previously as IMR-90 cells approach senescence are correlated with alterations in membrane mobility patterns of the lectin oligosaccharide conjugates.

Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3.

BACKGROUND: Benefits in patient health-related quality of life (HRQL) have not yet been demonstrated for combination antiretroviral therapy with protease inhibitors and nucleoside analogues. This double-blind study evaluated zalcitabine or saquinavir monotherapy and combination saquinavir plus zalcitabine therapy on HROL of human immunodeficiency virus (HIV)-infected adults. METHODS: 940 HIV-infected patients (CD4 counts 50-300 cells/mm3) who had discontinued zidovudine therapy (for intolerance or treatment failure) were randomized to one of three regimens: zalcitabine 0.75 mg every 8 h; saquinavir 600 mg every 8 h; or combination zalcitabine 0.75 mg plus saquinavir 600 mg every 8 hours. HRQL was measured at baseline, 24 and 48 weeks using the Medical Outcome Study HIV Health Survey (MOS-HIV). The primary endpoints were the physical and mental health summary scores (PHS; MHS) of the MOS-HIV as well as a global visual analogue scale (VAS) score. RESULTS: After 24 weeks, the zalcitabine-treated patients demonstrated significantly greater decreases in PHS scores (-4.4 +/- 0.6; saquinavir: -1.3 +/- 0.6; zalcitabine plus saquinavir: -1.7 +/- 0.6; P < 0.0001) and MHS scores (-2.2 +/- 0.5; saquinavir: -1.0 +/- 0.5; zalcitabine plus saquinavir: -0.5 +/- 0.5; P = 0.032) compared to saquinavir and zalcitabine plus saquinavir treated patients. No differences were observed on the VAS (P = 0.172). Nine of 10 MOS-HIV subscales demonstrated results consistent with the primary endpoints. After 48 weeks, a statistically significant difference between the saquinavir-treated groups and the zalcitabine monotherapy group was observed for PHS scores (zalcitabine: -5.8 +/- 0.6; saquinavir: -4.1 +/- 0.6; zalcitabine plus saquinavir: -3.5 +/- 0.6; P = 0.014). CONCLUSIONS: Saquinavir monotherapy and combination saquinavir plus zalcitabine demonstrated a benefit in HRQL relative to zalcitabine monotherapy in patients with prior zidovudine therapy. The HRQL findings are concordant with improved survival and reduced clinical progression of HIV infection found in this study.

Predicting success of intensive dialysis in the treatment of uremic pericarditis.

To identify predictors of the success or failure of daily intensive dialysis in uremic pericarditis, a retrospective examination was made of initial clinical, laboratory, and echocardiographic data in 97 patients using univariate and multivariate statistical analysis. In this group, 67 patients showed response to intensive dialysis, and 30 patients did not (22 required surgery and eight died). By univariate analysis, nine factors correlated with intensive dialysis failure (p less than 0.10): admission temperature over 102 degrees F, rales, admission blood pressure under 100 mm Hg, jugular venous distension, peritoneal dialysis treatment only because of severe hemodynamic instability, white blood cell count over 15,000/mm3, white blood cell count left shift, large effusion by echocardiography, and both anterior and posterior effusion by echocardiography. Echocardiographic left ventricular size and function were not useful predictors of success or failure; there was no difference in response to hemodialysis in patients with pericarditis before dialysis (69 percent) versus patients with pericarditis during a maintenance program (67 percent). By discriminant analysis, a seven-variable function was constructed that divided the patients into three groups: (1) those likely to show response to intensive dialysis (48 patients, predictive value of 98 percent), (2) those with an intermediate (38 percent) chance of showing response to intensive dialysis (30 patients), and (3) those unlikely to show response to intensive dialysis (14 patients, predictive value of 100 percent). When the function was applied prospectively to 12 patients (eight with success and four with failure), all were classified correctly. Thus, discriminant analysis of patients with uremic pericarditis allows improved selection of patients with uremic pericarditis likely to have response to daily intensive dialysis and early consideration of alternative forms of treatment in patients unlikely to show response to intensive dialysis. However, the model should be validated in the particular institution where it is to be used before its application.