Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine

 We examined the effect of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, on the development and expression of behavioral sensitization to amphetamine and cocaine in rats. A single injection of NBQX (12.5 mg/kg) administered 30 min prior to cocaine during the induction phase (days 1–5) prevented the development of cocaine sensitization, assessed by responsiveness to cocaine challenge on day 8. This NBQX regimen did not affect development of amphetamine sensitization. Two pretreatment injections of NBQX, one 20 min before and one 70 min after amphetamine on each day of the induction phase (days 1–6), did not affect sensitization of stereotypy but prevented sensitization of post-stereotypy ambulatory hyperactivity (both assessed by responsiveness to amphetamine challenge on day 8). The effect of NBQX on ambulatory sensitization was dose-dependent (attenuation with 12.5 mg/kg, complete prevention with 25 mg/kg). In contrast to its effects on development, NBQX (25 mg/kg) did not prevent expression of sensitization to cocaine or amphetamine. NBQX itself exerted no significant effects on locomotor activity in either drug-naive rats or rats that had received either NBQX or amphetamine repeatedly. These findings support a requirement for AMPA receptor stimulation in the development of locomotor sensitization to cocaine and amphetamine, but suggest a different mechanism for sensitization of amphetamine stereotypy. Received: 14 January 1997 / Final version: 24 June 1997     

Interobserver and interstudy variability of myocardial blood flow and flow-reserve measurements with nitrogen 13 ammonia-labeled positron emission tomography

Background  

Experimental studies have shown that positron emission tomography (PET) with ¹³N-labeled ammonia provides accurate quantification of regional myocardial blood flow (MBF) under rest and stress conditions. To establish the clinical utility of this method, the interobserver variability and the temporal variability of serial measurements of blood flow and coronary flow reserve (CFR) must be known. This study investigated the interobserver and temporal reproducibility of ¹³N-labeled PET for measurement of MBF and CFR.     

Increased prevalence of undernutrition in Parkinson's disease and its relationship to clinical disease parameters

Summary An anthropometric study was performed in 95 subjects (53 male, 42 female) with Parkinson's disease. Weight, height, triceps and biceps skin-fold thicknesses, and mid-arm circumference were recorded. A high incidence of undernutrition was found (23.6% of males and 22.5% of females, as defined by recent British guidelines). A subgroup of severely disabled patients with Parkinson's disease had a significantly lower mean body mass index than a similarly disabled control group with chronic pyramidal upper motor neuron lesions (males 20.6v 23.2 kg/m² p<0.05; females 20.6v 26.6 kg/m² p<0.01), suggesting that the undernutrition is not due to chronic illness or immobility alone. Correlation between anthropometric indices and clinical features of disease demonstrated that the presence of moderate or severe dyskinetic movements was the clinical parameter most strongly related to undernutrition. The reduction in anthropometric indices was most marked for skin fold thickness (related to percentage body fat) and least for arm muscle circumference (related to lean body mass); therefore the weight loss seen in Parkinson's disease is primarily due to fat loss rather than muscle loss.     

Origins of heterogeneous ovarian carcinomas. A molecular cytogenetic analysis of histologically benign, low malignant potential, and fully malignant components.

It is unclear whether ovarian carcinomas develop from malignant transformation of benign precursors or whether they arise de novo. Thus, histologically benign or low malignant potential components found in heterogeneous ovarian carcinomas may be remnants of pre-existing lesions that progressed to malignancy or, alternatively, elements that arose independently (de novo). In a third possible interpretation, they represent areas of malignant epithelium that matured. We evaluated clonal relationships of histological components in 10 heterogeneous ovarian carcinomas using fluorescence in situ hybridization and confocal microscopy. Detailed analysis of aneuploidy for chromosomes 8, 12, and 17 on intact paraffin sections revealed that two tumors were aneuploid in all components, two lacked abnormalities in benign-appearing components, and one lacked aneuploidy in both histologically benign and low malignant potential components. Histological appearance was significantly related to aneuploidy (P < 0.05). The distribution of aneuploidy among tumor components strongly supports the tumor progression theory and demonstrates that the de novo hypothesis is highly unlikely (P < 0.001). Results also indicate that benign-appearing components in heterogeneous ovarian carcinomas do not represent maturation of malignant tissue and suggest that some benign tumors that become cancerous may have genetic aberrations that predispose them to malignant transformation.     

Graduating medical students' ratings of stresses, pleasures, and coping strategies

The authors' objective in the study reported here was to gather data on the stress and coping of medical students in order to design a health promotion and wellness program. A retrospective questionnaire was completed by 71 of 157 graduating seniors. Examinations, classwork, and financial responsibilities were considered the three most stressful aspects of medical education. The most uplifting items (that is, pleasant, happy, or satisfying experiences) were recreation and social interaction, although good examination performance was rated second highest. Planful problem-solving (that is, deliberate problem-focused efforts to alter a situation) was the most frequently used form of coping, although four of the eight forms of coping assessed were used at least moderately often and all eight were used to some extent.     

Phase II evaluation of merbarone in renal cell carcinoma

Summary The Southwest Oncology Group (SWOG) studied the response rate and toxicity of merbarone (1,000 mg/m² IV continuous infusion days 1–5, q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 36 eligible patients, there was one partial response for a response rate of 3% (95% C.I. 0.1–15%). There were no mixed responses. There were no treatment related deaths or adverse drug reactions. Significant anemia, diarrhea, and hypercalcemia were observed. Mild to moderate degrees of malaise/fatigue/lethargy, dizziness/vertigo, hyperglycemia, creatinine increase, nausea, vomiting, weight loss, pedal edema, dyspnea, and granulocytopenia were noted. Merbarone does not have significant activity as a single agent in advanced renal cell carcinoma.     

Ischemic monomelic neuropathy: An under-recognized complication of hemodialysis access

During the past 3 years six episodes of ischemic monomelic neuropathy (IMN) have been identified in five patients as a complication of upper extremity dialysis grafts. All patients had long-standing insulin-dependent diabetes, peripheral neuropathy, and brachial artery graft origins, whereas 60% had peripheral vascular disease. Five episodes occurred immediately after graft placement, whereas one was due to a graft-related thromboembolus. Diagnostic delay was common with initial findings attributed to anesthesia, positioning, or surgical trauma. Electrophysiologic studies showed underlying diabetic neuropathy with severe multifocal neuropathy distal to the grafts. Digital pressure indices were reduced but there was no critical ischemia. In three cases ischemia was completely corrected with improvement in one. One patient had proximal balloon angioplasty with no improvement and of the two untreated patients, one improved slightly. Ischemic monomelic neuropathy is a rare but disabling complication of dialysis access in diabetic uremic patients. Its occurrence is unpredictable and diagnostic delay is common. Correction of ischemia is indicated but usually does not improve the neuropathy. Prevention requires further research to more accurately characterize the patients at risk.Presented at the Twelfth Annual Meeting of the Southern California Vascular Surgical Society, Coronado, Calif., September 17–19, 1993.     

Ultrastructural distribution of NADPH-diaphorase in the normal hippocampus and after long-term potentiation

Summary The distribution of the enzyme nitric oxide synthase (NOS) was investigated at the ultrastructural level in synaptic structures of the hippocampal formation in relation to long-term potentiation (LTP), based on the histochemical NADPH-diaphorase (NADPH-d) staining with the tetrazolium salt BSPT. BSPT-formazan, the osmiophilic reaction product, was found to be selectively distributed and predominantly attached to membranes of the endoplasmic reticulum. In synaptic regions mainly the presynaptic sides showed labeling. Although several groups have demonstrated a principal involvement of NO in the LTP-mechanism, we found only a low, statistically insignificant increase in NADPH-d stained presynaptic areas of the dentate gyrus, where LTP was evoked. Postsynaptic elements also did not show any noticeable differences. Based on the present results, the predominantly presynaptic localization of NOS should be preferably considered in models describing a functional role of NO in LTP formation, despite the fact that we failed to reveal any indications for an LTP-related change in synaptically located NADPH-d.     

Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients.

(18)F-Galacto-RGD has been developed for PET of alpha(v)beta(3) integrin expression, a receptor involved in, for example, angiogenesis and metastasis. Our aim was to study the kinetics and biodistribution of (18)F-Galacto-RGD in cancer patients. METHODS: Nineteen patients with metastases of malignant melanoma (n = 7), sarcomas (n = 10), or osseous metastases (n = 2) were examined. After injection of 133-200 MBq (18)F-Galacto-RGD, 3 consecutive emission scans from the pelvis to the thorax or dynamic emission scans of the tumor over 60 min, followed by 1 static emission scan of the body, were acquired. Time-activity curves and standardized uptake values (SUVs) were derived by image region-of-interest analysis with image-based arterial input functions. Compartmental modeling was used to derive the distribution volume for muscle tissue and tumors. RESULTS: (18)F-Galacto-RGD showed rapid blood clearance and primarily renal excretion. SUVs in tumors ranged from 1.2 to 9.0. Tumor-to-blood and tumor-to-muscle ratios increased over time, with peak ratios of 3.1 +/- 2.0 and 7.7 +/- 4.3, respectively, at 72 min. The tumor kinetics were consistent with a 2-tissue compartment model with reversible specific binding. Distribution volume values were, on average, 4 times higher for tumor tissue (1.5 +/- 0.8) than those for muscle tissue (0.4 +/- 0.1). The data suggest that there was only minimal free and bound (specific or nonspecific) tracer in muscle tissue. CONCLUSION: (18)F-Galacto-RGD demonstrates a highly favorable biodistribution in humans with specific receptor binding. Most important, this study shows that (18)F-Galacto-RGD allows visualization of alpha(v)beta(3) expression in tumors with high contrast. Consequently, this tracer offers a new strategy for noninvasive monitoring of molecular processes and may supply helpful information for planning and controlling of therapeutic approaches targeting the alpha(v)beta(3) integrin.