Anti-interleukin-6 antibodies attenuate inflammation in a rat meningitis model.

OBJECTIVES: Interleukin-6 (IL-6) is elevated in the cerebrospinal fluid (CSF) of humans and animals with bacterial meningitis. This study's hypothesis was that anti-IL-6 antibodies will attenuate meningeal inflammation in a rat model of bacterial meningitis. METHODS: 14 male Sprague-Dawley rats were inoculated intracisternally (IC) with 0.1 mL of heat-killed pneumococci. At one hour post-inoculation, the rats received intraperitoneal doses of either 1.0 mL phosphate-buffered saline (PBS treatment group, n = 7) or 70 microg anti-IL-6 antibodies in 1.0 mL PBS (anti-IL-6 antibody treatment group, n = 7). Nine rats (normal group, n = 9) had no inoculation, and four rats (surgical sham group, n = 4) had IC inoculations of saline. At six hours post-inoculation, all the animals had CSF removed via IC tap. The CSF protein and white blood cell (WBC) count measures were compared using a t-test. RESULTS: Mean CSF WBC for the anti-IL-6 treatment group was 2,458/microL, versus the PBS controls' mean of 9,697/microL (p = 0.007). Mean CSF protein for the anti-IL-6 group was 180 mg/dL, versus 296 mg/dL for the controls (p = 0.032). The surgical sham and normal animals had normal CSF WBC and protein values. CONCLUSIONS: In this rat meningitis model, systemic treatment with anti-IL-6 antibodies after the induction of meningitis suppressed both CSF WBC count and CSF protein level, two important indices of meningeal inflammation.

Polysymptomatic syndromes and autonomic reactivity to nonfood stressors in individuals with self-reported adverse food reactions.

This study compared symptom reports and cardiovascular reactivity of a group of 24 individuals recruited from the community who reported a cognitive or emotional symptom caused by at least one food (food-sensitivity reporters, FSR) vs those of 15 controls (C) without a history of food, chemical, drug, or inhalant sensitivities. The main findings were: 1) FSR indicated sensitivities not only to foods, but also to environmental chemicals, drugs, and natural inhalants, as well as significantly more symptoms than C in multiple systems; 2) more FSR than C noted recent state depression and anxiety, as well as higher trait anxiety on the Bendig form of the Taylor Manifest Anxiety Scale; 3) however, on multiple regression analysis, not only depression, but also the number of sensitivities (foods, chemicals, drugs, inhalants), accounted for part of the variance in total number of symptoms (38 and 17%, respectively), whereas none of the affective measures accounted for any of the variance in total number of sensitivities over all subjects; 4) after controlling for depression and anxiety, FSR still showed a trend toward poorer performance on a timed mental arithmetic task (p = 0.16); and 5) FSR and C showed opposite patterns of heart rate change to two different stressful tasks (mental arithmetic and isometric exercise) (group by task interaction, p < 0.05). The data are discussed in terms of a time-dependent sensitization (TDS) process that predicts a cross-sensitizing and cross-reactive role for xenobiotic agents (e.g., foods, chemicals, drugs, and inhalants) and for salient psychological stress in the expression of psychophysiological dysfunctions of FSR. As in other chronically ill populations, negative affect in food-sensitive individuals may explain greater symptom reporting, but not necessarily account for the illness itself. For either a food or a psychological stimulus to begin to elicit sensitized responses, e.g., marked physiological differences from C, FSR may require multiple, intermittent exposures spaced over 5-28 days rather than on only 1 day.

Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and their regulation by chronic morphine in the mesolimbic dopamine system.

We studied levels of neurofilament (NF) proteins in the ventral tegmental area (VTA), and other regions of the central nervous system, of two genetically inbred rat strains, Lewis (LEW) and Fischer (F344) rats. These strains represent genetically divergent populations of rats that have been used to study possible genetic factors involved in a variety of biological processes, including drug addiction: compared to F344 rats, LEW rats show a much higher preference for several classes of drugs of abuse. We found 30-50% lower levels of three NF proteins, NF-200 (NF-H), NF-160 (NF-M), and NF-68 (NF-L), in the VTA of LEW compared to F344 rats by use of immunolabeling and Coomassie blue staining. These strain differences were highly specific to this brain region, with no differences observed elsewhere in brain or spinal cord. Interestingly, chronic treatment of F344 rats with morphine decreased levels of these three NF proteins in the VTA, as found previously in outbred Sprague-Dawley rats (Beitner-Johnson, D., Guitart, X., and Nestler, E.J.:J. Neurosci., 12:2165-2176, 1992), whereas morphine had no effect on NF levels in the VTA of LEW rats. A similar strain difference was observed in chronic morphine regulation of tyrosine hydroxylase, with morphine increasing enzyme immunoreactivity in the VTA of F344 rats (as has been observed previously in Sprague-Dawley rats [Beitner-Johnson, D., and Nestler, E.J.:J. Neurochem., 57:344-347, 1991]), but not in LEW rats. In view of the observations that LEW and F344 rats show different levels of preference for several types of drugs of abuse, and of the evidence supporting a central role of the mesolimbic dopamine system in drug reward mechanisms, the results of the current study suggest the possibility that levels of NFs and tyrosine hydroxylase may mediate some aspects of drug reinforcement and contribute to individual genetic differences in vulnerability to drug addiction.

Plasma homocysteine in vascular disease and in nonvascular dementia of depressed elderly people.

Depression among elderly people with reversible cognitive loss often manifests with concomitant vascular disease and can also precede the development of nonvascular degenerative dementia. Little is known about etiological factors for reversible or irreversible dementias in older depressed people. The amino acid homocysteine (HC), which is both a vascular disease risk factor and a precursor of the excitotoxic amino acids cysteine and homocysteic acid, could play a role in the pathophysiology of such individuals. Twenty-seven depressed elderly acute inpatients by DSM-III-R criteria had significantly higher plasma homocysteine levels and lower cognitive screening test scores than did 15 depressed young adult inpatients. HC was highest in the older patients who had concomitant vascular diseases (n = 14). HC was lowest in the older depressives who had neither vascular illnesses nor dementia (n = 8), comparable to the young adult depressives. Higher HC correlated significantly with poorer cognition only in the nonvascular geriatric patients (rs = -0.53). The findings extend earlier work showing higher HC in vascular patients from general medical populations, and also suggest a possible metabolic factor in certain dementias associated with late-life depression.

Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction.

This was a 4-week randomized placebo-controlled double-blind study to assess augmentation of open tricyclic antidepressant treatment with 10 mg each of vitamins B1, B2, and B6 in 14 geriatric inpatients with depression. The active vitamin group demonstrated significantly better B2 and B6 status on enzyme activity coefficients and trends toward greater improvement in scores on ratings of depression and congnitive function, as well as in serum nortriptyline levels compared with placebo-treated subjects (Ss). Without specific supplementation, B12 levels increased in Ss receiving B1/B2/B6 and decreased in placebo Ss. These findings offer preliminary support for further investigation of B complex vitamin augmentation in the treatment of geriatric depression.

Early dyskinesia--vulnerability.

Relative vulnerability to dyskinesia in terms of exposure to antipsychotic drugs prior to onset of dyskinesia was studied in a sample of 100 psychiatric patients with dyskinesia onset generally within a year or less of the point of study entry. Unipolar and bipolar patients were more vulnerable to dyskinesia than other diagnostic groups. In the total sample, lithium exposure did not appear to delay development of dyskinesia. Longer exposure to antiparkinson drugs was associated with delayed onset of dyskinesia. Past exposure to electroconvulsive therapy was related to decreased vulnerability to dyskinesia.

An assessment of time following trauma resuscitation: the transitional evaluation and monitoring phase.

Trauma resuscitation for 431 major trauma patients averaged 24 +/- 0.61 minutes. Further analysis of the care of 350 of these patients documented a transitional evaluation and monitoring phase (TEMP), with a physician and nurse in attendance, for an additional 158 +/- 12 minutes until arrival at the operating room, surgical intensive care unit (SICU), hospital ward, or discharge. The duration of TEMP did not vary according to severity of injury (R2 = 0.02). Arrival time (days: 167 +/- 23 minutes; evenings: 142 +/- 13 minutes; and nights: 147 +/- 30 minutes) had minimal effect on TEMP duration. The TEMP for 67 patients undergoing an operation was significantly less than for patients admitted to the hospital ward or SICU (112 +/- 19 minutes vs. 171 +/- 20, p less than 0.05). These 350 patients underwent 582 activities during TEMP including radiologic evaluation (265), CT scan (173), and other activities (144). Extrapolating TEMP time for the 1,800 major trauma patients seen annually, this represents 4,740 hours each of nursing and physician time. A better understanding of TEMP is needed to provide appropriate support and organization during this critical period of trauma care.

B complex vitamin patterns in geriatric and young adult inpatients with major depression.

This study compared the B complex vitamin status at time of admission of 20 geriatric and 16 young adult non-alcoholic inpatients with major depression. Twenty-eight percent of all subjects were deficient in B2 (riboflavin), B6 (pyridoxine), and/or B12 (cobalamin), but none in B1 (thiamine) or folate. The geriatric sample had significantly higher serum folate levels. Psychotic depressives had lower B12 than did non-psychotic depressives. Poorer blood vitamin status was not associated with higher scores on the Hamilton Depression Rating Scale or lower scores on the Mini-Mental State Examination in either age group. The data support the hypothesis that poorer status in certain B vitamins is present in major depression, but blood measures may not reflect central nervous system vitamin function or severity of affective syndromes as measured by the assays and scales in the present study.

Cocaine conditioned place preference is attenuated by chronic buprenorphine treatment.

Previous research shows that buprenorphine (BUP), a mixed opioid agonist-antagonist, reduces cocaine use in humans and suppresses cocaine self-administration in monkeys. The present study found that BUP reduces cocaine's ability to condition a place preference in rats. Compared to vehicle treated rats, rats treated with BUP 2 times/day for 2 weeks spent significantly less time in the cocaine conditioned place compared to their respective saline trained controls. No conditioned place preference was shown for BUP alone. These results further implicate a role for the opioid system in cocaine use and stress the importance of differentiating chronic vs. acute opioid effects.

Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.

This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition.

Weight changes on fluoxetine as a function of baseline weight in depressed outpatients.

In order to test the hypothesis that weight changes on fluoxetine are a function of baseline weight, we divided a group of 39 depressed outpatients into 3 groups based on the Fogarty table: ideal, underweight, and overweight. Subjects were participants in an open label depression trial that was carried out over 3 years. Doses ranged from 20 mg to 80 mg depending on the patients' response and side effect profile. Demographic data, weights and Hamilton Rating Scale for Depression (HAM-D) scores were collected at baseline. Subsequent Hamilton scores and weights were obtained at monthly intervals until the subjects were terminated from the study. Only those subjects who remained in the study for at least 6 months were included in this analysis. Overweight subjects showed a significant weight loss of 3.3 lbs (p less than .001) in the first 2 months whereas ideal weight subjects gained 4.4 lbs (p = .02) over a 4-month period. All of these changes were maintained throughout the study. The underweight patients showed no consistent trends. All patients examined (those who completed 6 months or more in the trial) had significant decreases in their HAM-D scores (p less than .001).

The natural history of tardive dyskinesia.

Follow-up data from the first 100 patients with early dyskinesia are presented. After an average of 40.9 months, the cohort showed statistically significant decreases in tardive dyskinesia (TD) ratings. After TD onset, ratings decreased for 4 years, then plateaued and rose during the 7th year. Age was not a negative prognostic factor in this cohort. Improvement in TD correlated significantly with fewer neuroleptic-free periods before and more neuroleptic-free periods after TD onset. Neuroleptic dosage correlated negatively with improvement in trunk and dystonia ratings. Improvement in TD is the usual finding in longitudinal studies of TD cohorts. Follow-up studies of neuroleptic-treated groups with varying proportions of patients showing TD, by contrast, tend to show increased TD because new TD cases more than offset improvement. A naturalistic study with pharmacotherapy tailored to the underlying psychiatric disorder and conducted long-term from TD onset is the ideal design for investigating the natural history of TD.