Dopaminergic modulation of cortical function in patients with Parkinson's disease

Patients with idiopathic Parkinson's disease suffer not only from classic motor symptoms, but from deficits in cognitive function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in patients with Parkinson's disease. Ten patients with stage I and II Parkinson's disease were studied with functional magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively correlated with errors in task performance, and the increased activation in the cortical motor regions during the dopamine-replete state was positively correlated with improvement in motor function. These results support evidence from basic research that dopamine modulates cortical networks subserving working memory and motor function via two distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency of this region.     

No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.     

Selective enhancement of spatial learning under chronic psychosocial stress

The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic-hypothalamus-pituitary-adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal-dependent and hippocampal-independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal-dependent task, whereas no stress-induced effect was found in the hippocampal-independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.     

Subjective experiences in schizophrenia and bipolar disorders

Studies comparing 'subjective experiences' in schizophrenic and affective disorders have reached inconclusive results. We investigated the pattern of 'subjective perceived cognitive disturbances' in a group of 55 schizophrenic patients and 39 bipolar patients hospitalized for an index psychotic episode. The assessment of the subjective experiences was made using the Frankfurter Beschwerde-Fragebogen (FBF). Comparing the two groups on the four FBF factors, schizophrenic patients showed significantly higher scores in the areas of 'central cognitive disturbances', 'perception and motility' other than a significantly higher FBF total score. Our results suggest that cognitive, perception and motility disturbances are the most characteristic subjective experiences of schizophrenic patients in comparison with bipolar patients. This finding need to be further explored in light of the issue of cognitive dysfunction in schizophrenia.     

Effects of dark rearing on phosphorylation of neurotrophin Trk receptors

Total lack of visual experience (dark rearing, DR) is known to affect development of mammalian visual cortex (VC) and to prolong the critical period of visual cortical plasticity. Neurotrophins (NTs) have been proposed to play a relevant role in activity dependent processes important for the final shaping of cortical visual connections. Neurotrophin supply or antagonism of endogenous NT action profoundly affect visual cortical development and plasticity; in particular, exogenous supply of NTs counteracts DR effects on VC development. However, the effects of DR on NT expression are still debated and mounting evidence reports a mismatch between BDNF mRNA and protein expression in DR animals. To gain insight into the effects of DR on expression of nerve growth factor (NGF) and the functional state of NT signalling pathways, we assessed the phosphorylation state of Trk receptors in light-reared animals (LR), in dark-reared animals (DR), in DR animals briefly exposed to light and in DR animals with exogenous supply of NTs [NGF, brain-derived neurotrophic factor (BDNF) and NT-4] in the VC. We report that DR increases the expression of NGF but reduces the phosphorylation of TrkA and TrkB receptors with respect to LR; normal phosphorylation is rapidly rescued by a brief exposure to light. Exogenous supply of NGF, BDNF or NT4 in DR animals also rescues the phosphorylation of their receptors.     

External and internal dose in subjects occupationally exposed to ochratoxin A

OBJECTIVES: Ochratoxin A (OA) is a ubiquitous mycotoxin that can contaminate foods, drinks, and animal feeds worldwide. Humans and animals can therefore absorb this toxin via the gastrointestinal tract after ingestion of contaminated products. OA is known to exert toxic effects, particularly on the renal system, and the International Agency for Research on Cancer (IARC) classified it as a "possible human carcinogen" (Group 2B). The measurement of OA serum levels is an effective method of evaluating internal doses. Inhalation of airborne OA can represent a source of additional exposure. We determined the levels of serum OA in workers exposed to airborne dust originating from the handling or processing of contaminated foods. METHODS: We carried out area and personal sampling for airborne OA determination in three industries where coffee, cocoa beans, and spices, foods highly susceptible to contamination, were being processed. OA levels in the serum of six healthy workers employed in these factories were measured in samples collected at the end of the work shift. RESULTS: Airborne OA measured in the three industries, both by personal and area sampling, ranged from < 0.003 to 8.15 ng/m(3), while the levels measured in the breathing zone of the six workers who agreed to biological monitoring varied from 0.006 to 0.087 ng/m(3). OA serum levels ranged from 0.94 to 3.28 ng/ml, the latter values rather largely exceeding those of the control group (0.03 to 0.95 ng/ml). CONCLUSIONS: Our findings suggest that occupational exposure to this mycotoxin may represent a health risk for workers, especially if preventive and protection measures are not adopted in the workplaces. Airborne exposure levels can result in an increase of OA levels in serum, and this finding suggest that environmental and biological monitoring should be undertaken in workplaces where OA-contaminated products are handled or processed.     

Neurochemical mechanisms for cancer anorexia

Under normal conditions, the homeostasis of energy intake is maintained in the hypothalamus by 1) transducing metabolic and sensorial inputs arising from the periphery into neuronal response, 2) integrating the information originating from different tissues, and 3) triggering the appropriate feeding responses. If cancer anorexia is considered a disruption of the physiologic mechanisms controlling energy intake, it is conceivable that its pathogenesis may lie in an abnormal input of information to the hypothalamus, its defective transduction and integration, or the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of cancer anorexia is multifactorial and involves most of the neuronal signaling pathways modulating energy intake. Thus, a number of factors has been proposed as putative mediators of cancer anorexia, including hormones (e.g., leptin), neuropeptides (e.g., neuropeptide Y), cytokines (e.g., interleukin-1, interleukin-6, tumor necrosis factor), and neurotransmitters (e.g., serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms; rather, it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that hypothalamic monoaminergic neurotransmission and serotonergic activity in particular may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity has been tested as a therapeutic strategy in anorectic cancer patients with encouraging results. However, more clinical options will be available by revealing the complex interactions between the many factors participating in controlling energy intake under normal and pathologic conditions. Further, modulation of hypothalamic activity also might result in reduced catabolic signals to skeletal muscles, thus improving the cachexia associated with cancer.     

Expression of CD154 on renal cell carcinomas and effect on cell proliferation,motility and platelet-activating factor synthesis

CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Furthermore, the renal carcinoma cell lines expressed PAF-R. Blockade of PAF-R by WEB-2170, a PAF-R antagonist, abolished the CD154-dependent motility, indicating a role for PAF synthesized after CD154 stimulation in renal carcinoma cell motility. In conclusion, this study identifies new functional properties for CD154, which are potentially relevant for the growth and dissemination of renal carcinoma cells.     

New Approach to Tumor Therapy for Inoperable Areas of the Brain: Chronic Intraparenchymal Drug Delivery

Because the brainstem has little functional redundancy, diffuse lesions have been regarded as inoperable. To determine whether local drug therapy can prolong survival in a rodent model of a tumor in such eloquent tissue, lethal doses of F98 and 9L tumor cells were injected into the brainstems of Fischer 344 rats. Five days after inoculations, 0.5 mg/ml solutions of carboplatin were infused at 1 l/h for 7 days. Compared to control groups that survived 13–17 days with F98 tumors and 22–23 days with 9L tumors, animals locally infused with 0.1 mg of carboplatin survived 27–30 days (Prob > Chi Sq = 0.0003), and 32 days (Prob > Chi Sq = 0.01), respectively. Measurements of tissue platinum levels at autopsy suggested that infusions distributed pharmacologically relevant levels of carbo-platin through a volume of tissue at least 0.5 cm in diameter. The results suggest that chronic low-flow infusions provide a promising approach to therapy for CNS lesions in tissues considered to be inoperable.