TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates

The neuroprotective efficacy of the propargylamine TCH346 was studied in the primate model of Parkinson's disease, the bilaterally MPTP-treated monkey. Male rhesus monkeys received 2.5 mg MPTP into the left carotid artery and, 8 weeks later, 1.25 mg MPTP into the right carotid artery. Starting 2 h after the second MPTP infusion, either 0.014 mg/kg TCH346 or its solvent was subcutaneously injected twice per day for 14 days. The first MPTP treatment induced mild Parkinson symptoms, reduced right limb movements, and reduced FDOPA uptake in the left striatum. The second MPTP treatment made Parkinson symptoms worse, reduced left limb movements, and reduced FDOPA uptake in the right striatum of solvent-treated monkeys. In contrast, the second MPTP treatment did not further worsen motor symptoms and did not decrease FDOPA uptake in the right striatum of TCH346-treated monkeys. Although the effects of the second MPTP treatment were largely prevented, the effects of the first MPTP treatment were not reversed by TCH346. Immunohistochemical examination confirmed the dramatic loss of dopamine cells in vehicle-treated monkeys and the preservation of these neurons in the right brain side of the TCH346-treated animals. In conclusion, systemic administration of TCH346 prevented motor symptoms and nigrostriatal degeneration induced by MPTP in primates.     

Seven-year trends in stroke rehabilitation: patient characteristics, medical complications, and functional outcomes

Studies of stroke trends have focused primarily on incidence, mortality, and hospitalization rates. There has been little evaluation of changes over time in the common patient characteristics, medical comorbidities, and functional outcomes of patients. The present study evaluated changes during a 7-year period. We found that while demographic variables, stroke severity, and most stroke characteristics remained relatively stable, disability levels at admission and discharge decreased and frequencies of both medical tube usage and many secondary medical complications increased over time. These changes have important implications for the clinical management of stroke patients in rehabilitation and for the organization and financing of stroke rehabilitation programs.     

Selective attention in anxiety: distraction and enhancement in visual search

According to cognitive models of anxiety, anxiety patients exhibit an attentional bias towards threat, manifested as greater distractibility by threat stimuli and enhanced detection of them. Both phenomena were studied in two experiments, using a modified visual search task, in which participants were asked to find single target words (GAD-related, speech-related, neutral, or positive) hidden in matrices made up of distractor words (also GAD-related, speech-related, neutral, or positive). Generalized anxiety disorder (GAD) patients, social phobia (SP) patients afraid of giving speeches, and healthy controls participated in the visual search task. GAD patients were slowed by GAD-related distractor words but did not show statistically reliable evidence of enhanced detection of GAD-related target words. SP patients showed neither distraction nor enhancement effects. These results extend previous findings of attentional biases observed with other experimental paradigms.     

Inhibition of alpha-ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death

Mitochondrial dysfunction has been implicated in cell death in many neurodegenerative diseases. Diminished activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme of the Krebs cycle, occurs in these disorders and may underlie decreased brain metabolism. The present studies used alpha-keto-beta-methyl-n-valeric acid (KMV), a structural analogue of alpha-ketoglutarate, to inhibit KGDHC activity to test effects of reduced KGDHC on mitochondrial function and cell death cascades in PC12 cells. KMV decreased in situ KGDHC activity by 52 +/- 7% (1 hr) or 65 +/- 4% (2 hr). Under the same conditions, KMV did not alter the mitochondrial membrane potential (MMP), as assessed with a method that detects changes as small as 5%. KMV also did not alter production of reactive oxygen species (ROS). However, KMV increased lactate dehydrogenase (LDH) release from cells by 100 +/- 4.7%, promoted translocation of mitochondrial cytochrome c to the cytosol, and activated caspase-3. Inhibition of the mitochondrial permeability transition pore (MPTP) by cyclosporin A (CsA) partially blocked this KMV-induced change in cytochrome c (-40%) and LDH (-15%) release, and prevented necrotic cell death. Thus, impairment of this key mitochondrial enzyme in PC12 cells may lead to cytochrome c release and caspase-3 activation by partial opening of the MPTP before the loss of mitochondrial membrane potentials.     

Ganser symptoms in a case of frontal-temporal lobe dementia: is there a common neural substrate?

Neuropsychological testing was completed in a patient who showed cognitive decline of mental functions, unusual answers to questions, and other characteristics of what has typically been described in the literature as the "Ganser Syndrome." Clear evidence of malingering on a memory test seemed to confirm that this patient was exaggerating deficits for psychiatric reasons or secondary gain, yet the patient showed evidence of mild organic impairment on MRI and continued to deteriorate in cognitive functions and basic self-care. Although an initial SPECT scan had suggested a pattern inconsistent with dementia, a second scan showed frontal-temporal perfusion deficits. Based on this scan and the clinical picture of progressive deterioration, a diagnosis of frontal-temporal lobe dementia was made. This case illustrates that the seemingly deliberate selection of incorrect responses may occur in the early stages of an organic dementia, and that a diagnosis of frontal-temporal lobe dementia should be considered in cases where symptoms appear to be psychiatric or nonorganic. The case further raises the question of whether the reported symptoms of Ganser Syndrome may be accounted for by frontal-temporal lobe dysfunction, since there appears to be some overlap between symptoms of Ganser Syndrome and frontal-temporal lobe dementia. It is also important to note that many reported cases of Ganser Syndrome had a history of head injury.     

Changes in rat hepatic gene expression in response to zinc deficiency as assessed by DNA arrays

Zinc deficiency affects hepatic functions and due to the central role of the liver in metabolism, this may contribute to metabolic alterations in other tissues in zinc deficiency. In addition to clinical manifestations of zinc deficiency, we used cDNA- and oligonucleotide-arrays to compare the expression of > 2500 different genes in liver of rats force-fed a zinc-adequate or a zinc-deficient diet for 11 d. Radio- or fluorescence-labeled cDNAs from liver of control and zinc-deficient rats were hybridized to arrays. Approximately 1550 mRNAs were detected above background levels; by comparing expression profiles of the two groups, the mRNA levels of 66 genes were found to be altered by zinc deficiency. Steady-state expression levels of 35 genes were reduced, whereas the mRNA-levels of 31 genes were elevated. Array data were verified by Northern blot analysis for 24 selected genes and 19 were confirmed to be up- or down-regulated. Among those, predominantly gene products that participate in growth (i.e., insulin-like growth factor binding proteins), lipid metabolism (long-chain acyl-CoA synthetase), xenobiotic metabolism (cytochrome P(450) isoenzymes), the stress response (glutathione transferase), nitrogen metabolism (cytosolic aspartate aminotransferase), intracellular trafficking (syntaxin isoforms) and signal transduction (G-protein-coupled receptors) were identified. Additionally, regulation of mRNA levels of genes important for porphyrin synthesis and collagen metabolism was observed. In conclusion, we have identified in vivo a number of mammalian genes from different cellular pathways whose expression changes in response to zinc depletion. The characterization of the identified genes and their products will allow a more comprehensive analysis of the role of zinc in metabolism; moreover, the mRNAs identified could be useful in establishing biomarkers for the determination of zinc status in mammals.