The tyrosine kinase inhibitor genistein directly inhibits GABAA receptors

The protein tyrosine kinase (PTK) inhibitor genistein has been widely used to examine potential effects of tyrosine phosphorylation on neurotransmitter function. We report here that genistein inhibits GABAA receptors through a direct effect. Extracellular application of genistein and GABA reversibly inhibited GABA-activated currents recorded from HEK293 cells expressing rat alpha1beta2gamma2S or alpha1beta2 receptors, even when genistein was preequilibrated in the intracellular solution. Daidzein, an analog of genistein that does not block PTK, also inhibited GABA-activated current. Coapplication of lavendustin A, a specific inhibitor of PTK, had no effect on the GABA response. Our results demonstrate that genistein has a direct inhibitory effect on GABAA receptors that is not mediated via inhibition of tyrosine kinase.     

Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia

OBJECTIVE: Tracer constants (Ki) for blood-to-brain diffusion of sucrose were measured in the rat to profile the time course of blood-brain barrier injury after temporary focal ischemia, and to determine the influence of post-ischemic hypothermia. METHODS: Spontaneously hypertensive rats were subjected to transient (2 hours) clip occlusion of the right middle cerebral artery. Reperfusion times ranged from 1.5 min to 46 hours, and i.v. 3H-sucrose was circulated for 30 min prior to each time point (1 h, 4 h, 22 h, and 46 h; n = 5-7 per time point). Ki was calculated from the ratio of parenchymal tracer uptake and the time-integrated plasma concentration. Additional groups of rats (n = 7-8) were maintained either normothermic (37.5 degrees C) or hypothermic (32.5 degrees C or 28.5 degrees C) for the first 6 hours of reperfusion, and Ki was measured at 46 hours. RESULTS: Rats injected after 1.5-2 min exhibited a 10-fold increase in Ki for cortical regions supplied by the right middle cerebral artery (p < 0.01). This barrier opening had closed within 1 to 4 hours post-reperfusion. By 22 hours, the blood-brain barrier had re-opened, with further opening 22 and 46 hours (p < 0.01), resulting in edema. Whole body hypothermia (28 degrees C-29 degrees C) during the first six hours of reperfusion prevented opening, reducing Ki by over 50% (p < 0.05). CONCLUSIONS: Transient middle cerebral artery occlusion evokes a marked biphasic opening of the cortical blood-brain barrier, the second phase of which causes vasogenic edema. Hypothermic treatment reduced infarct volume and the late opening of the blood-brain barrier. This opening of the blood-brain barrier may enhance delivery of low permeability neuroprotective agents.     

Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.     

Diaschisis in chronic viral encephalitis with Koshevnikov syndrome.

The authors report a 61-year-old man with chronic viral encephalitis and Koshevnikov syndrome occurring 42 months after initial symptom of right hemiparesis. Serial computed tomography of the brain showed changes in the attenuation of the left temporal lobe lesion over time. Magnetic resonance images of the brain showed enlargement of left temporoparietooccipital lobes with cortical gyral enhancement on T1-weighted images following intravenous administration of gadolinium-DTPA. 99mTc-HMPAO single-photon emission computerized tomography showed increased radioactivity and hyperperfusion in the left temporoparietal region with paradoxically decreased local tissue perfusion at the contralateral right hemisphere. Follow-up magnetic resonance images of the brain 4 years later showed atrophy of bilateral cerebral hemispheres. We postulate that a "transcallosal diaschisis" with subsequent degeneration is a possible mechanism. A brain biopsy from the left temporal lobe lesion showed pictures compatible with viral encephalitis probably herpes simplex encephalitis.     

Intra-arterial infusion chemotherapy for penile carcinoma with deep inguinal lymph node metastasis

From July 1994 to January 1999, three patients with penile squamous cell carcinoma with deep inguinal lymph node metastases without distant metastases were treated with multimodality treatment including intra-arterial infusion chemotherapy mainly with monthly courses of cisplatin, methotrexate and bleomycin. One patient achieved a complete response and 2 achieved a partial response. It appears to be reasonable to presume that intra-arterial chemotherapy has a beneficial effect in the management of penile cancer with fixed metastatic inguinal lymph nodes, but a larger number of patients and longer follow-up are required to confirm these results.     

The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi: a midterm followup study

PURPOSE: We examined the efficacy of potassium citrate based medical prophylaxis for preventing upper urinary calculous recurrence, and compared it with the stone recurrence rate in patients who only received intermittent or no medical prophylaxis. MATERIALS AND METHODS: We retrospectively reviewed the records of 493 patients with upper urinary calculi, of whom 237 men and 76 women with a mean age of 56.1 and 51.4 years, respectively, were enrolled in the study. Of the 313 participants 64 (group 1, 20.4%) received regular medical prophylaxis for 24 to 42 months (mean 27.8), 80 (group 2, 25.6%) received intermittent medical prophylaxis for 1.5 to 19 months (mean 7.9) and 169 (group 3, 54%) did not receive any medical prophylaxis. RESULTS: At midterm followup of 24 to 60 months 107 patients (34.2%) had stone recurrence. In group 1 the stone recurrence rate was 7.8%, which was significantly less (p <0.001) than in groups 2 (30%) and 3 (46.2%). Similarly new calculous events in patients with a history of multiple stone recurrence were less frequent in group 1 than in groups 2 and 3 (9.7, 47.4 and 52.2%, respectively, p <0.001). Multiple stone recurrence history, hypercalciuria, hyperuricosuria and calcium oxalate dihydrate calculi were independent risk factors for stone recurrence. CONCLUSIONS: Regular medical prophylaxis may effectively prevent stone recurrence regardless of previous treatment modalities, stone composition, metabolic abnormalities and stone-free status. Cost effectiveness, patient compliance and gastrointestinal upset may limit patient acceptability and clinical use of medical prophylaxis. However, patients with a history of multiple stone recurrence, calcium oxalate dihydrate stones, hypercalciuria and hyperuricosuria benefit from regular medical prophylaxis.