Motor cortex stimulation for neuropathic facial pain

Facial neuralgia is the last common pathway for a variety of pathological conditions with different etiology. Neuropathic facial pain is often refractory to routine medical or surgical treatments. We present here a long-term follow-up of two patients with unilateral facial neuropathic pain due to idiopathic trigeminal neuropathy or to surgical trauma to the glossopharyngeal nerve, respectively. These patients have been treated by other modalities for several years without obtaining satisfactory pain relief. Electrical stimulation of the motor cortex (MCS) with a quadripolar electrode contralateral to the painful area of the face was attempted in both cases for control of the facial pain, and resulted in immediate analgesia with more than 50% pain reduction. During a follow-up period of 72 months, a sufficient (> 50%) and stable analgesic effect of MCS was observed. These cases are discussed and the recent literature on MCS is reviewed in an attempt to identify indications for MCS as well as key structures in the brain for mediating the MCS effect.     

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine)

CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC(50) = 0.10 microM) with an average cytotoxic IC(50) of 15.2 microM in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs.     

C-Jun N-terminal kinase is required for phorbol ester- and thapsigargin-induced apoptosis in the androgen responsive prostate cancer cell line LNCaP

In early, androgen dependent stages of prostate cancer, androgen withdrawal, the major course of therapy in prostate cancer, leads to a rapid regression of the tumor as a result of apoptosis. However, prostate cancer invariably progresses to an androgen independent and apoptosis resistant stage for which no curative treatment is available. The molecular details of regression upon androgen withdrawal and progression to a resistant state are largely unknown. Here we show that c-Jun N-terminal Kinase (JNK) is activated strongly and in a sustained fashion by 12-O-tetradecanoylphorbol 13-acetate (TPA) and thapsigargin (TG), two agents which were previously shown to lead to apoptosis in the androgen responsive prostate cancer cell line LNCaP. The time course of JNK induction by both compounds correlated very well with the onset and progression of apoptosis in LNCaP cells. Inhibition of either ERK or p38 pathways did not affect TPA-induced cell death. In the androgen-independent prostate cancer cell lines DU-145 and PC-3, and in the cervical carcinoma cell line HeLaS3, TPA did not lead to apoptosis and there were no significant changes in JNK activity upon TPA treatment. The failure of TPA to induce JNK activity in PC-3, DU-145, and HelaS3 cells was not due to a general defect in JNK signaling since ultraviolet (UV) irradiation dramatically increased JNK activity in all four cell lines. Specific inhibition of JNK by expression of the JNK Inhibitory Protein (JIP) dramatically inhibited both TPA- and TG-induced apoptosis. Furthermore, apoptosis induced by both agents was completely blocked by ectopic expression of the baculovirus caspase-inhibitor P35. Surprisingly, ZVAD-fmk, a cell-permeable fluoromethylketone inhibitor of caspases, had no effect on TPA-induced apoptosis, whereas it completely inhibited TG-induced cell death; JNK activity was not affected in either case. This indicates that ZVAD-fmk does not inhibit some of the caspases involved in TPA-induced apoptosis, and that despite the common requirement of JNK activation, TPA- and TG-induced cell death are mechanistically different. Furthermore, it also suggests that JNK is either upstream or independent of caspases in LNCaP cells. Collectively, these results indicate that apoptosis in LNCaP cells requires a sustained increase in JNK activity and caspase activation; components of these signaling pathways may be defective in the androgen independent prostate cancer cell lines.     

Macroinvertebrate community response to pulse exposure with the insecticide lambda-cyhalothrin using in-stream mesocosms

Pesticides are constantly being applied to agricultural catchments, but little is known about their impact on aquatic biota during natural exposure. In the present study, the impact of the pyrethroid lambda-cyhalothrin was studied in an in-stream mesocosm setup. Twice during the summer of 2002, the natural macroinvertebrate community was exposed in situ to a 30-min pulse of lambda-cyhalothrin. Pyrethroid doses were released through a modified drip set with nominal concentrations of 0.10, 1.00, and 10.0 microg L(-1) during the first exposure and 0.05, 0.50, and 5.00 microg L(-1) in the second exposure. Before, during, and after exposure, drifting macroinvertebrates were caught in nets. Quantitative benthic samples were taken both before and on two occasions after exposure. Macroinvertebrate drift increased immediately after the pulse exposure, with total drift being significantly higher at all concentrations. Gammarus pulex, various Ephemeroptera, Leuctra sp., and Simuliidae were some of the taxa showing the most pronounced drift response. Structural change in the community was found only at 5.00 and 10.0 microg L(-1), and recovery occurred within approximately two weeks. The present study may be valuable in assessing extrapolations based on laboratory results as well as in evaluating pyrethroid impact on natural freshwater environments.     

Successful pregnancy in a liver transplant recipient treated with lamivudine for de novo hepatitis B in the graft

Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy. Liver transplant recipients with recurrent hepatitis C or hepatitis B nonetheless appear to be at risk of a worse graft function in the event of pregnancy, and antiviral drugs are generally contraindicated in pregnancy because of their teratogenic effects. A 33-year-old woman had undergone liver transplantation for Carolis disease 6 years previously. Two years later the patient experienced de novo HBV hepatitis. Lamivudine treatment (100 mg/day) was started and clearance of HBsAg was documented 1 year later. Four years after starting antiviral treatment the patient became pregnant, despite of the risk of teratogenic effects; lamivudine, cyclosporine and azathioprine were not discontinued for risk of break-through hepatitis and acute or chronic rejection. The course of gestation was uneventful and caesarean section was performed after 36 weeks. The newborn infant was a healthy male weighing 3,080 g and measuring 50 cm.     

Impaired water maze navigation of Wistar rats with retrosplenial cortex lesions: effect of nonspatial pretraining

Damage to the retrosplenial cortex (RC) impairs the performance of rodents on spatial learning and memory tasks, but the extent of these deficits was previously reported to be influenced by the lesion type, rat strain, and behavioral task used. The present study addressed the issue of whether or not cytotoxic damage to RC impairs place navigation of Wistar rats in the Morris water maze and, if so, whether this is merely attributable to spatial learning deficits or to impaired learning of general (nonspatial) behavioral strategies required to correctly perform this task or both. Behaviorally naive rats with bilateral lesions to RC were significantly impaired relative to sham-lesioned rats both during the period of initial learning of the task and during the later phases of training. In addition, these animals showed enhanced thigmotaxis, indicating that the lesion was associated with considerable abnormalities in nonspatial learning. In contrast, RC-lesioned animals that have been previously familiarized with general task rules in a series of shaping trials did not show more thigmotaxis than did their respective controls. Furthermore, although these rats were still impaired in the middle of the training process, their performance during the period of initial learning as well as by the end of training was found to now be normal. Our results confirm those of earlier studies indicating that RC is important for spatial navigation. The findings herein reported are also consistent with the notion that, in addition to spatial information processing, RC is involved in cognitive processes underlying the ability of subjects to properly respond to general task demands.     

Anatomical basis of glial cell line-derived neurotrophic factor expression in the striatum and related basal ganglia during postnatal development of the rat

There is increasing evidence that glial cell line-derived neurotrophic factor (GDNF) plays a role as a limiting, striatal target-derived neurotrophic factor for dopamine neurons of the substantia nigra pars compacta (SNpc) by regulating the magnitude of the first phase of postnatal natural cell death which occurs in these neurons. While it has been shown that GDNF mRNA is relatively abundant in postnatal striatum, the cellular basis of its expression has been unknown. We therefore used nonradioactive in situ hybridization and immunohistochemistry to examine the cellular basis of GDNF mRNA and protein expression, respectively, in postnatal striatum and related structures. We found that GDNF mRNA is expressed within medium-sized striatal neurons. Expression in glia was not observed. At the protein level, regionally, GDNF expression in striatum was observed in striosomal patches, as previously described. At a cellular level a few neurons were observed, but they do not account for the striosomal pattern. This pattern is predominantly due to GDNF-positive neuropil. Some of this neuropil arises from tyrosine hydroxylase-positive nigro-striatal dopaminergic afferents. Astrocytic processes do not appear to contribute to the striosomal pattern. GDNF-positive fibers are identified not only within intrinsic striatal neuropil, but also in fibers within the major striatal efferent targets: the globus pallidus, the entopeduncular nucleus, and the SN pars reticulata. We conclude that during normal postnatal development, medium-sized neurons are the principal source of GDNF within the striatum.