Within-subject behavioral analysis of recent memory in aging mice

Two experiments addressed the utility of a T-maze, delayed reversal paradigm for assessment of recent memory impairment in aging C57BL/6NNia mice. This paradigm involved acquisition of a learning set for identification of the correct arm choice in a daily multiple-trial discriminated avoidance session. During each session, the correct arm was always opposite that entered on an initial "information trial" and maximal performance thus required a reversal (or "lose-shift") strategy. Once the learning set had been acquired, retention performance was examined following delays of varying length which were introduced following the information trial during each session. In the first experiment, acquisition and retention components of delayed reversal were considered in a cross-sectional study involving separate groups of mice aged 7, 10, 15, or 27 months. Analysis of acquisition components suggested that relative to young mice, the old mice were slower to acquire both the first reversal and the learning set. Analysis of the retention phase suggested that memory decay gradients for goal arm discrimination became more pronounced with increasing age, whereas decay gradients for the avoidance response were similar among the age groups. Correlational analysis of data for the old mice suggested independence of age-related deficits in the acquisition and recent memory components of the delayed reversal paradigm. In the second experiment, survivors from the previous 7- and 10-month-old groups were retested when 27 months of age. The cross-sectional and longitudinal data led to the same conclusions with regard to the effect of age on recent memory function. Overall, these results suggest that the delayed reversal paradigm will be a valuable tool in the analysis and evaluation of interventions potentially affecting age-related cognitive impairment.     

Neurobehavioral biomarkers of aging: influence of genotype and dietary restriction

Because of the importance of central nervous system (CNS) functions to productive capacity and quality of life, biomarkers of these functions will play a key role in evaluating the success of interventions targeting aging processes. The CNS biomarkers may also be useful for predicting aging in other systems and in the organism as a whole. Age-related behavioral changes, the products of CNS aging, have content and predictive validity with respect to human functional capacities and may, therefore, represent important "neurobehavioral" markers of functional aging. This article presents a discussion of some behavioral paradigms which are currently being considered as neurobehavioral biomarkers of aging in mice and the experimental approaches being employed in the assessment of their validity. Studies conducted in the authors' laboratory using dietary restriction and genetic comparisons to evaluate the validity of neurobehavioral biomarkers have revealed several methodological concerns, and hypothetical and empirical examples of these pitfalls are described and discussed. In spite of those concerns, it is concluded that approaches to validity using genetic comparisons and dietary restriction can be successfully implemented and should ultimately lead to identification of valid and useful neurobehavioral biomarkers of aging.     

Primary angiitis of CNS : neuropathological study of three autopsied cases with brief review of literature

Primary angiitis of CNS(PACNS) or granulomatous angiitis of CNS is a rare inflammatory disease of small blood vessels mostly confined to the CNS. The clinical and pathological features of 3 autopsied cases are described. Clinically all the three PACNS patients were young males, age ranging from 19 to 31 years. All presented with varied neurological manifestations. There was no evidence of systemic disease in any of the cases. The ESR was normal and CSF analysis showed chronic meningitic pattern. The cerebral angiogram in one case was normal and the CT scan done in another case showed multiple intracerebral haematoma due to vasculitis. Brain biopsy was not done. Diagnosis was made at post-mortem examination. Histology showed characteristic but variable degree of granulomatous and non-granulomatous angiitis of small vessels. Venulitis with parenchymal haemorrhages was the predominant feature and in one case phlebitis with thrombosis was noted. Since the disease responds to steroids and immunosuppressive therapy, establishing antemortem diagnosis is important. In view of the association of angiitis of CNS with bacteria and viral infections, their role in the evolution of the disease needs to be investigated.     

Type 1 diabetic mice are protected from acetaminophen hepatotoxicity.

Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.     

Parathyroid hormone-related protein is expressed by transformed and fetal human astrocytes and inhibits cell proliferation

Parathyroid hormone-related protein (PTHrP) and the PTH/PTHrP receptor are expressed in most normal tissues, including brain, where PTHrP is though to act locally in an autocrine or paracrine fashion. Previous in situ localization studies in adult rodents have documented CNS PTHrP expression in neurons but not in glial cells. However, a recent report describing immunoreactive PTHrP in human astrocytomas suggests that PTHrP expression may be a marker of dedifferentiation and/or malignant transformation in glial cells. To begin to test this hypothesis, constitutive and regulated PTHrP expression were examined in cultured fetal and transformed (U-373 MG) human astrocytes. PTHrP was expressed in untreated fetal astrocytes and U-373 MG cells, as determined by Northern analysis, immunocytochemical staining, and detection of PTHrP(1-84) protein in conditioned media. Epidermal growth factor and tumor necrosis factor, important growth factors in astrocyte development and malignant transformation, stimulated PTHrP expression in both cell types. Treatment of U-373 MG cells or fetal astrocytes with PTHrP(1-34) consistently inhibited cellular proliferation, as measured by [(3)H]-thymidine incorporation. These findings suggest that PTHrP, a peptide whose expression is induced by mitogens in both immature and transformed human astrocytes, may feedback inhibit cellular proliferation, an effect that may be of importance during malignant transformation as well as CNS development. Furthermore, when combined with previous evidence of PTHrP expression by PTH/PTHrP receptor-positive neurons, our demonstration of regulated PTHrP expression by receptor-positive astrocytes identifies PTHrP as a potential peptide mediator of cross-talk between glial cells and neurons.     

Development and implementation of an appropriateness guideline for use of CT in cases of suspected intraabdominal abscess

RATIONALE AND OBJECTIVES: The purpose of this study was to develop an evidence-based guideline for use of computed tomography (CT) in the evaluation of suspected abdominal abscess. The goal of the guidelines was to decrease the absolute number of CT examinations performed for suspected abdominal abscess and to increase the rate of positive CT examinations while not missing clinically relevant abscesses. MATERIALS AND METHODS: A multidisciplinary team developed an evidence-based guideline regarding use of CT to evaluate for suspected abscess. A control group consisted of patients scanned for suspected abscess during a 6-month period. The intervention group consisted of patients scanned in the 6 months after guideline implementation. Focal fluid collections depicted on CT scans were reviewed for both patient groups to determine if these collections were abscesses. The number and proportion of abscesses in each group were then compared. RESULTS: During the control period, 263 CT examinations for suspected abscess were performed, 75 of which (28.5%; 90% confidence interval [CI], 24%, 33%) depicted focal fluid and 25 of which (9.5%; 90% CI, 7%, 12%) depicted abscess. During the intervention period, 238 CT examinations were performed, 54 of which (22.7%; 90% CI, 18%, 27%) depicted fluid and 41 of which (17.2%; 90% CI, 13%, 21%) depicted abscess. CONCLUSION: A guideline was successful at decreasing the number of CT examinations and increasing the proportion of positive CT results for abdominal abscess. As with other inpatient utilization interventions, each practice must assess the cost-benefit trade-off of guideline implementation in complex clinical situations.     

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.