Differences in the liability to self-administer intravenous cocaine between C57BL/6 x SJL and BALB/cByJ mice

Application of animal models of psychostimulant abuse for experimentation in mice is becoming increasingly important for studying the contribution of genetic differences, as well as the roles of selected (targeted) genes, in specific behaviors. The purpose of this study was to investigate strain differences in cocaine self-administration behavior between C57BL/6 x SJL hybrid mice and BALB/cByJ mice. These two strains were chosen because BALB/cByJ mice have a well-developed behavioral pharmacological profile, and hybrid strains on a C57BL/6 background are commonly used for generating transgenic expressing and knockout mutant mice. C57BL/6 x SJL mice dose-dependently acquired cocaine self-administration (1.0 mg/kg/injection but not 0.25 mg/kg/injection) by responding selectively in the active nose-poke hole and maintaining stable levels of daily drug intake; they also exhibited a characteristic inverted-U-shaped cocaine dose-effect function. BALB/cByJ mice failed to acquire cocaine self-administration at either dose under the same test conditions. The strain differences observed in self-administration did not seem to be attributed to other behavioral differences because the two strains exhibited similar amounts of spontaneous nose-poking in the absence of reinforcers, and BALB/cByJ mice responded more than C57BL/6 x SJL mice in a food-reinforced nose-poke operant task. Importantly, the dose-effect function for the motor stimulating effects of cocaine (3.8-30 mg/kg intraperitoneally) suggests enhanced sensitivity but reduced efficacy of cocaine in stimulating motor activity in BALB/cByJ mice relative to the C57BL/6 x SJL hybrid mice. These results indicate that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is not the result of differences in spontaneous activity or performance, but may reflect different sensitivities to the reinforcing, or rate-disrupting, properties of cocaine. The data support an influence of genetic background in the liability to self-administer cocaine. Thus, a hypothesis is proposed that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is related to differences in brain monoamine systems linked to the high "emotionality" profile of BALB/c mice in novel or fearful situations, including perhaps cocaine administration.     

Management of bowel obstruction in patients with abdominal cancer

OBJECTIVE: To determine the value of operation in patients with bowel obstruction caused by recurrent abdominal cancer. DESIGN: Retrospective case review. SETTING: The University of Connecticut Health Center, Farmington. PATIENTS: Ninety-eight patients admitted with a diagnosis of bowel obstruction and malignant neoplasm between November 1, 1987, and June 30, 1995. RESULTS: Data for 75 patients who developed a bowel obstruction within 5 years of a malignant diagnosis were analyzed. Forty-six patients (61%) were treated operatively and 29 (39%) were treated nonoperatively. The operative group included 32 patients (70%) whose obstruction was caused by carcinomatosis; 6 (19%) of these 32 patients had had at least 1 episode of previous obstruction requiring hospitalization. They had a 22% in-hospital mortality, stayed an average of 21 days in the hospital, and survived 7 +/- 6 months (mean +/- SD) after discharge; 5 (16%) had at least 1 episode of postoperative obstruction that required hospitalization. After discharge from the hospital, 53% had an excellent or good quality of life (assessed retrospectively). Of the 29 patients in the nonoperative group, 16 (55%) had carcinomatosis. These 16 patients had a 38% in-hospital mortality (6 of 16), stayed an average of 10 days in the hospital, and survived a mean of 13 +/- 9 months; 3 (19%) had at least 1 episode of recurrent obstruction requiring hospitalization. After discharge from the hospital, 6 (37%) had an excellent or good quality of life. CONCLUSION: The value of operative intervention for bowel obstruction in patients with cancer is derived from the possibility of a benign cause, not alleviation of the consequences of carcinomatosis.     

Magnetoencephalographic evidence for non-geniculostriate visual input to human cortical area V5

The aim of this study was to establish whether there is non-geniculostriate input to the extrastriate motion-sensitive area V5 in humans. Responses were measured with a SQUID neuro-magnetometer to motion stimuli presented within the blind hemifield of GY, a well-documented subject with a complete absence of the left primary visual cortical area V1. The motion stimulus was a 0.5c/deg, rapidly drifting (16Hz) achromatic sinusoidal grating. With this stimulus, the magnetic responses recorded over the temporo-parieto-occipital region in normals are well modelled by localized current sources in areas V1 and V5 (Anderson, S. J. et al., Proceedings of the Royal Society, London, Series B, 1996, 263, 423-431). As a control, evoked responses were measured to a 1.0 c/deg, stationary, photometrically isoluminant red/green sinusoidal grating. With the chromatic stimulus, the principal component of the magnetic responses recorded over the occipital pole in normals is well modelled by a current source in area V1 (Fylan, F. et al., Investigative Ophthalmology and Visual Science, 1995, 36, s1053). Both stimuli subtended 4 deg vertically by 6 deg horizontally, positioned such that the stimulus extended beyond the area of macular sparing into the lower field quadrant of the blind (or sighted) hemifield. Chromatic stimuli failed to evoked responses from GY's blind (contralateral) hemifield, consistent with there being no V1 activity in his left cortical hemisphere. However, motion stimuli did evoke responses from GY's blind hemifield, originating from a location consistent with activity in area V5. We further observed that both colour and motion stimuli evoked responses from GY's sighted (ipsilateral) hemifield. We conclude that there is non-geniculostriate input to extrastriate motion-sensitive areas in the human visual system, and that this pathway subserves the residual visual sensitivity to motion in the blind hemifield that has been demonstrated psychophysically in observer GY.     

Congenital chylothorax in siblings

We describe two cases of congenital chylothorax in siblings with important differences from previously described familial cases. Our findings support the likelihood of an autosomal recessive inheritance in some cases of this condition, rather than X-linked recessive inheritance, which has also been suggested. Autopsy findings from one of these cases and others previously described suggest that the pathophysiological mechanisms involved may be variable.     

A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock

Circadian clocks are complex biochemical systems that cycle with a period of approximately 24 hours. They integrate temporal information regarding phasing of the solar cycle, and adjust their phase so as to synchronize an organism's internal state to the local environmental day and night. Nocturnal light is the dominant regulator of this entrainment. In mammals, information about nocturnal light is transmitted by glutamate released from retinal projections to the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Clock resetting requires the activation of ionotropic glutamate receptors, which mediate Ca2+ influx. The response induced by such activation depends on the clock's temporal state: during early night it delays the clock phase, whereas in late night the clock phase is advanced. To investigate this differential response, we sought signalling elements that contribute solely to phase delay. We analysed intracellular calcium-channel ryanodine receptors, which mediate coupled Ca2+ signalling. Depletion of intracellular Ca2+ stores during early night blocked the effects of glutamate. Activators of ryanodine receptors induced phase resetting only in early night; inhibitors selectively blocked delays induced by light and glutamate. These findings implicate the release of intracellular Ca2+ through ryanodine receptors in the light-induced phase delay of the circadian clock restricted to the early night.     

Thoracoscopic pleural tent

Lung volume reduction has been performed in patients with advanced emphysema to relieve dyspnea and improve exercise tolerance. Median sternotomy and video-assisted thoracoscopy have been proposed as equally adequate approaches; however, prolonged postoperative air leakage is the most prevalent complication in all series. For this reason, on the basis of the experience achieved with the median sternotomy approach, buttressing of the suture line with different materials and techniques for space reduction have been proposed. We describe a technique to create a pleural tent after thoracoscopic volume reduction. The thoracoscopic creation of a pleural tent is feasible and results in a duration of postoperative air leaks and hospital stays similar to that achieved with stapler line buttressing.     

Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer

PURPOSE: This multicenter phase II trial investigated the efficacy and safety of a combination of paclitaxel and topotecan in patients with pretreated metastatic breast cancer. Plasma levels of paclitaxel and topotecan were obtained during cycle 1 to correlate pharmacokinetic parameters with toxicity. PATIENTS AND METHODS: Paclitaxel was administered intravenously (i.v.) at 230 mg/m2 over 3 hours on day 1 followed by topotecan 1.0 mg/m2 i.v. over 30 minutes on days 1 to 5. Patients received an abbreviated premedication regimen that consisted of ranitidine 50 mg, diphenhydramine 50 mg, and a single 20-mg dose of dexamethasone, all administered i.v. 30 minutes before paclitaxel. Granulocyte colony-stimulating factor (GCSF) was administered at 5 micrograms/kg/d subcutaneously starting on day 6 and continuing until the absolute granulocyte count (AGC) was greater than 10,000/microL. Plasma paclitaxel and topotecan concentrations were assessed during the first cycle using limited-sampling strategies. RESULTS: Seventeen patients were treated. The majority had visceral metastases. Four patients experienced neutropenic fever and one had mild bronchospasm. Only one partial response (PR) was observed. Nadir AGC correlated strongly with both duration of paclitaxel levels greater than 0.05 mumol/L and maximum concentration (Cmax) of paclitaxel. CONCLUSION: This regimen does not produce a response rate superior to that expected with single-agent paclitaxel at doses that do not require growth factor support.