Oncogenicity evaluation of resveratrol in p53(+/-) (p53 knockout) mice.

A six-month study was conducted in p53(+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53(+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53(+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

Altered hepatic mRNA expression of apoptotic genes during dimethylnitrosamine exposure.

The role of TNFalpha in regulating apoptotic signaling was investigated during subacute, low-dose (5.0 mg/kg) dimethylnitrosamine (DMN)-induced hepatotoxicity. In TNFalpha receptor (TNFR) intact (wild-type, WT) mice following 4 and 7 DMN exposures, hepatic transcripts for TNFalpha and TNFR-1 were elevated as compared to vehicle controls. DMN hepatotoxicity in WT and TNFR-1/TNFR-2 double knockout (DKO) mice were then compared over a 7-d exposure period. Liver RNA was isolated to measure hepatic expression of TNFalpha/Fas-related genes and the Bcl-2 family of genes that impact apoptosis. Hepatic mRNA levels for Fas, the apoptosis-promoting gene Bax, and the anti-apoptotic gene, Bcl-X(L), were up regulated following 4 and 7 DMN exposures in both WT and TNFR DKO mice as compared to vehicle controls. Notably, hepatic transcript levels for Bax were higher in TNFR DKO mice treated with DMN compared to identically treated WT mice. However, we detected approximately equal DMN-induced apoptotic degradation of liver DNA following 1, 4, and 7 exposures in WT and TNFR DKO mice. Taken together, these data show DMN-induced hepatic TNFalpha expression and suggest that TNFR-1 signaling may be up regulated following 4 and 7 daily DMN exposures. However, TNFalpha is not required for apoptotic signaling at the mRNA transcript level within the liver and instead may actually decrease Bax production.

Acute hepatotoxicant exposure induces TNFR-mediated hepatic injury and cytokine/apoptotic gene expression.

Tumor necrosis factor receptor knockout (TNFR KO) mice were used to examine the role of tumor necrosis factor-alpha (TNFalpha) signaling during acute hepatotoxicant exposure. Mice were exposed intraperitoneally (ip) to either vehicle, phosphate-buffered saline (PBS), or dimethylnitrosamine (DMN, 100 mg/kg) for 24 h. Histological evaluation showed that DMN-treated TNFR-2 KO mice had increased liver damage compared to wild type (WT), TNFR-1 KO, or TNFR double KO (DKO) mice. Also, 3 of 8 TNFR-2 KO mice died following DMN treatment, suggesting that hepatic TNFR-2 signaling produces protective responses that counteract TNFR-1-mediated damage. DMN-induced cellular infiltration was absent in TNFR-1-deficient mice, indicating that infiltrating cells do not exacerbate acute hepatotoxic events. In separate experiments, mice were exposed ip to either DMN (5.0 or 100 mg/kg), carbon tetrachloride (CCl4, 0.3 or 1.0 ml/kg), or corresponding PBS/corn oil controls for 6 or 24 h to compare the hepatic mRNA expression of cytokine- and apoptotic-associated genes. Following 24 h of DMN (100 mg/kg) or 6-24 h of CCl4 treatment, hepatic transcripts for TNFalpha, interferon (IFN)-gamma, IL (interleukin)-1RI, and transforming growth factor (TGF)-betaRII were induced. Hepatotoxicant-treated WT and TNFR DKO mice induced liver transcripts for the pro- and anti-apoptotic genes, Bax and Bcl-X(L), respectively, indicating TNF-independent gene activation. The anti-apoptotic gene, Bfl-1, was highly expressed in CCl4-treated, TNFR-positive strains, but minimally expressed in TNFR DKO mice, suggesting that hepatic Bfl-1 is TNF-regulated. Taken together, these data show that acute hepatotoxicant exposure is followed by upregulation of liver cytokine, cytokine receptor, and apoptotic transcripts, and that TNFalpha regulates various aspects of liver inflammation and injury in a TNFR-specific fashion.

Evaluation of depression in a general hospital: utility and limitations of the dexamethasone suppression test.

Use of the DST was studied in medically hospitalized, depressed patients. Although complicating medical factors necessarily excluded nearly 60% of referrals, post-dexamethasone plasma cortisol values were significantly higher in 14 major depressives appropriate for the DST as compared to 12 patients with milder, subsyndromal depressive conditions. Using a plasma cortisol criterion of greater than 7 micrograms/dl, the DST identified major depression with 57% sensitivity and 92% specificity in this subsample (p less than 0.005). While limited by a high exclusion rate, the DST may be useful for confirmation of major depression in carefully screened general hospital patients. Implications for research and practice are discussed.

Patterns of utilization of a neuropsychiatric assessment unit.

During a one-year period an inpatient psychiatric ward specializing in the evaluation of neuropsychiatric disorders admitted 306 patients for neurodiagnostic services and 119 general psychiatric patients for brief treatment. About half the neurodiagnostic patients were referred by sources not affiliated with the unit, and about a quarter came from outside the immediate area, indicating that a variety of community agencies relied on the unit as a referral facility. In nearly 60 per cent of the cases evaluated, suspected medical or neurologic abnormality was confirmed and the probable etiology determined, while in only a small percentage was a previously unsuspected abnormality detected; this combination of outcomes suggests that most referrals were appropriate and that the unit's main function was to clarify etiologic relationship and design treatment plans.

Psychotic pica, nicotinism, and complicated myocardial infarction.

The authors report a case of a schizophrenic patient who repeatedly consumed a wide variety of inedible materials, including significant quantities of tobacco. The phenomenology of this behavior, as well as its psychiatric and medical complications are discussed. It is probable that chronic nicotinism contributed to this patient's refractoriness to psychiatric treatment and to his eventual cardiovascular crisis. The occurrence of pica as a manifestation of severe psychopathology was vividly described by the early pioneers of neuropsychiatry, but has received little attention in recent psychiatric literature. This is in marked contrast to the syndrome of psychogenic water intoxication which continues to be reported frequently. The majority of descriptions of pica have dealt with its occurrence in children, in pregnant women, and as a societal practice in certain cultures studied from a medico-anthropologic point of view. The toxic organic brain syndrome caused by chronic ingestion of nicotine-containing products has also been neglected in psychiatric publications. Descriptions of the neuropsychiatric complications of subacute and chronic nicotinism have been restricted to textbooks of toxicology, where greater emphasis has been given to the acute effects of large quantities of nicotine, often in forms other than tobacco. The following case illustrates the near-fatal practice of tobacco pica in a psychotic patient and dramatically demonstrates the systemic and central nervous system effects of nicotinism.