Lack of metallothionein-I and -II exacerbates the immunosuppressive effect of ultraviolet B radiation and cis-urocanic acid in mice

The effect of a null mutation for the metallothionein (MT)-I and -II isoforms in mice on the immunosuppressive action of ultraviolet B (UVB; 280-320 nm) radiation has been examined. Mice were exposed to a series of increasing daily UVB doses, each dose administered to the dorsum on 3 consecutive days. Erythema was assessed, and measured as its oedema component by the post-irradiation dorsal skinfold thickness, but there was no effect of the null mutation (MT-/-) observed after 3 x 3.4 kJ/m2 of UVB radiation. Immune function was assessed by the contact hypersensitivity (CHS) response, which was initiated by sensitization on unirradiated abdominal skin, and thus demonstrated the systemic effects of dorsal treatments. In comparison with the wild-type MT+/+ mouse, the MT-/- mouse was significantly more immunosuppressed by moderate daily UVB doses (1. 75-5.9 kJ/m2). When topically applied cis-urocanic acid (cis-UCA) replaced UVB radiation as the immunosuppressive agent, contact hypersensitivity in MT-/- mice was again markedly more suppressed than in MT+/+ mice, in a dose-responsive manner. The results infer that MT, which was shown immunohistochemically to be strongly induced in the epidermis of MT+/+ mice, but to be absent in MT-/- epidermis, has the potential to protect from photoimmunosuppression, and that the mechanism of action may be via the inactivation of the epidermal UVB-photoproduct, cis-UCA.     

6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists

Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.     

1,3-Dinitrobenzene metabolism and GSH depletion

Previous work demonstrated that the mitochondrial fraction of rat seminiferous tubules is capable of metabolizing 1,3-dinitrobenzene, using NADPH as a cofactor. Moreover, 1,3-dinitrobenzene treatment of rat tubules caused a decrease in mitochondrial GSH levels. In situ mitochondrial metabolism of 1,3-dinitrobenzene may have caused this depletion through the production of reactive oxygen intermediates, generating oxidative stress and/or one or more metabolites of 1,3-dinitrobenzene which reacted nonenzymatically with GSH. The goal of this study is to investigate which of these two potential mechanisms may have caused the observed GSH depletion. Liver microsomes, known to rapidly metabolize 1,3-dinitrobenzene, generated the superoxide anion radical when incubated with 1,3-dinitrobenzene and NADPH. However, with the seminiferous tubule mitochondria, no oxygen radicals were detected. Hence, the aforementioned GSH depletion is unlikely due to the production of reactive oxygen intermediates from in situ mitochondrial metabolism of 1,3-dinitrobenzene. To investigate the ability of 1,3-dinitrobenzene metabolites to deplete seminiferous tubule mitochondrial GSH, mitochondria were incubated with 1,3-dinitrobenzene and NADPH. Loss of GSH correlated with the appearance of the 1,3-dinitrobenzene metabolites, nitrophenylhydroxylamine and nitroaniline. Subsequent investigation demonstrated that the metabolites, nitrosonitrobenzene, known to react nonenzymatically with nonprotein sulfhydryls, and nitrophenylhydroxylamine both oxidized seminiferous tubule mitochondrial GSH. Further studies suggested that nitrophenylhydroxylamine could deplete GSH via a free radical mechanism. In aqueous solution, this metabolite was shown to exist in equilibrium with a radical form, thought to be the hydronitroxide radical. The addition of GSH eliminated the signal, implying that the radical reacted nonenzymatically with GSH. In conclusion, the data in this study suggest that the decrease in mitochondrial GSH observed in DNB-treated seminiferous tubules is due to the formation of NPHA and NNB and not reactive oxygen intermediates.     

Impact of timing on completion thyroidectomy for thyroid cancer

BACKGROUND: It has been stated that completion thyroidectomy for thyroid malignancy should be performed either within 10 days of the primary operation or after 3 months, to reduce the incidence of complications. The aim of this study was to review the impact of timing on the rate of complications following completion thyroidectomy. METHODS: Data were obtained retrospectively from the Endocrine Surgery Thyroid Data Base, to which the records of all patients have been entered since 1957. The patients who had the last 100 consecutive completion thyroidectomies for thyroid cancer comprised the study group. RESULTS: Sixty-three patients had the second operation performed within 10 days or more than 90 days after the initial operation (group 1). Thirty-seven patients had reoperation between 10 and 90 days after the first procedure (group 2). One patient (2 per cent) in group 1 and one patient (3 per cent) in group 2 suffered a permanent complication (P not significant). CONCLUSION: There was no definite impact of the timing of surgery on the rate of complications after completion thyroidectomy.     

Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association

This report reviews the state of the literature and opportunities for research related to "executive control function" (ECF). ECF has recently been separated from the specific cognitive domains (memory, language, and praxis) traditionally used to assess patients. ECF impairment has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. No single putative ECF measure can yet serve as a "gold standard." This and other obstacles to assessment of ECF are reviewed. ECF impairment and related frontal system lesions and metabolic disturbances have been detected in many psychiatric and medical disorders and are strongly associated with functional outcomes, disability, and specific problem behaviors. The prevalence and severity of ECF deficits in many disorders remain to be determined, and treatment has been attempted in only a few disorders. Much more research in these areas is necessary.     

Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters

BACKGROUND: The T1 and T2 classifications of the International Union Against Cancer TNM classification system for renal cell carcinoma are based on primary tumor size, and in various editions of the classification, the cut points between T1 and T2 have been amended to provide clinical utility. In the current edition, the T1/T2 cut point is less than or equal to and greater than 7 cm. and more recently a subdivision of the T1 classification (less than or equal to and < 4 cm) has been proposed to identify patients suitable for partial nephrectomy. This study investigates the prognostic significance of tumor size in a series of organ-confined clear cell renal cell carcinomas. METHODS: One hundred thirty cases of organ-confined clear cell renal cell carcinomas, with a minimum of 5 years' follow-up, were identified from the New South Wales Cancer Registry. Tumor size was compared with survival using the method of Kaplan and Meier for TNM size categories, and proportional hazards regression was used for assessing size as a continuous variable. Proportional hazards regression also was used for multivariable comparisons of size and other prognostic parameters (Fuhrman grade, AgNOR score, and Ki-67 index) against survival. RESULTS: Of 116 cases for which tumor dimension was recorded, 25 patients had died of cancer-related causes. Primary tumor size ranged from 12 to 140 mm (mean, 57.3 mm). The association between survival and size was significant irrespective of the TNM classification and was also significant when size was modeled continuously (P = 0.000125, hazard of death increased by 3.51 times for each doubling of tumor size). On univariate analysis, Fuhrman grade (P = 0.04) and AgNOR score (P = 0.015) were associated with survival; however, on multivariate analysis only tumor size retained significance. CONCLUSIONS: Although the cut point of T1 and T2 TNM categories and the proposed T1 subdivision cut point correlate with survival, our finding that size is a continuous variable indicates that as a prognostic parameter for clear cell renal cell carcinoma, primary tumor size is relative rather than indicative.