Synaptic Depression Via Mglur1 Positive Allosteric Modulation Suppresses Cue-Induced Cocaine Craving

Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc preceded and enabled CP-AMPAR accumulation. Thus, restoring mGluR1 transmission by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results suggest a strategy in which recovering addicts could use a systemically active compound to protect against cue-induced relapse

Noninvasive imaging of the biliary tree before or after laparoscopic cholecystectomy: use of three-dimensional spiral CT cholangiography.

OBJECTIVE: The purpose of this study was to determine the feasibility of using three-dimensional spiral CT after IV administration of a cholangiographic agent for noninvasive detection of anatomic variations of the bile ducts and common bile duct stones before or after laparoscopic cholecystectomy. SUBJECTS AND METHODS: Three-dimensional spiral CT cholangiography was performed before laparoscopic cholecystectomy in 24 patients and after surgery in two patients who had recurrent symptoms. After slow infusion of 250 ml of iodipamide, spiral CT was performed. Three-dimensional images of the bile ducts and a secondary reformation through the long axis of the common bile duct were obtained. Visualization of the biliary tract was evaluated by two observers. Detection of anatomic variations and common bile duct stones was assessed in 19 patients for whom a gold standard (operative or retrograde cholangiogram) was available. RESULTS: In all 26 patients, the common bile duct and the confluence of the hepatic ducts were seen on three-dimensional spiral CT cholangiograms, and in 21 patients second- or higher-order branches were also seen. Seven patients had anatomic variations and two had common bile duct stones. These anomalies were proved by operative cholangiography in each case, except for a low junction of the cystic duct and a common bile duct stone, which were shown by retrograde cholangiography. Six of the seven anatomic variations were adequately detected with spiral CT cholangiography, as were the two cases of common bile duct stones. CONCLUSION: Three-dimensional spiral CT cholangiography is a feasible method for noninvasive detection of biliary anatomic variations and common bile duct stones before or after laparoscopic cholecystectomy

Generation of a Patient-Derived Brain Metastasis Breast Cancer Cell Line via Novel Orthotopic Injection Placement and Serial Mouse Transplantation to Develop PDX Mouse Model

Background: The incidence of brain metastasis appears to be increasing, potentially due to advanced technology that aids early diagnosis. Patient-derived xenografts (PDX) have high translational value, as these models retain key functional characteristics of the patient tumor. PDX models are useful to understand the molecular basis of tumorigenesis and to identify new treatment targets. However, generating a first-line PDX model is challenging as engraftment failure is high. Serial transplanting tumor tissue via mouse-to-mouse propagation increases engraftment rates and decreases PDX development time. Herein we report methods to generate a PDX cell line from patient-derived tumor tissue that includes the cerebral aqueduct as a novel intracranial orthotopic implantation site. Purpose: Develop human tumors in mouse models for therapeutic purpose. Methods: Patient-derived brain metastasis tumor tissue was enzymatically dissociated into a single cell suspension and maintained in neurocult media supplemented with human recombinant bFGF and EGF (20 ng/ml). The cells were seeded at a density of 1.0 × 104/cm2 on ultra-low attachment plates and maintained at 37°C with 5% CO2. PDX models were generated via orthotopic stereotactic surgeries. Athymic nude mice were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg). The cerebral aqueduct was located using these coordinates from bregma: A: -5; L: +0.2; V: -2.4. Mice were injected with 5.0 × 104 cells in 2 μl of media at a rate of 0.4 ul/min. Mice were monitored daily for symptoms of tumor formation. Upon becoming symptomatic, mice were euthanized and tumor tissue was harvested for both culture and H&E stain for tumor verification. Results: Mice injected with primary patient cells (first-generation mice) developed tumors at 7 weeks (average: 6.77 weeks), second-generation mice yielded tumors at 2 weeks (average: 13.5 days), and third-generation mice replicated results from second-generation mice (average: 13 days). H&E stain revealed invasive tumor masses in the ventricular system that extended from the cerebral aqueduct to the lateral ventricles. Immunohistochemistry analysis confirmed the third-generation cell line retained key characteristics of the patient tumor. Conclusion: These methods successfully generated a PDX cell line from patient-derived brain metastasis that demonstrates reliable tumor formation and phenotypic stability. Importantly, our unique intracranial implantation site revealed several distinct masses, a hallmark of brain metastasis in patients

Is a lung perfusion scan obtained by using single photon emission computed tomography able to improve the radionuclide diagnosis of pulmonary embolism?

Planar pulmonary scintigraphy is still regularly performed for the evaluation of pulmonary embolism (PE). However, only about 50-80% of cases can be resolved by this approach. This study evaluates the ability of tomographic acquisition (single photon emission computed tomography, SPECT) of the perfusion scan to improve the radionuclide diagnosis of PE. One hundred and fourteen consecutive patients with a suspicion of PE underwent planar and SPECT lung perfusion scans as well as planar ventilation scans. The final diagnosis was obtained by using an algorithm, including D-dimer measurement, leg ultrasonography, a V/Q scan and chest spiral computed tomography, as well as the patient outcome. A planar perfusion scan was considered positive for PE in the presence of one or more wedge shaped defect, while SPECT was considered positive with one or more wedge shaped defect with sharp borders, three-plane visualization, whatever the photopenia. A definite diagnosis was achieved in 70 patients. After exclusion of four 'non-diagnostic' SPECT images, the prevalence of PE was 23% (n =15). Intraobserver and interobserver reproducibilities were 91%/94% and 79%/88% for planar/SPECT images, respectively. The sensitivities for PE diagnosis were similar for planar and SPECT perfusion scans (80%), whereas SPECT had a higher specificity (96% vs 78%; P =0.01). SPECT correctly classified 8/9 intermediate and 31/32 low probability V/Q scans as negative. It is concluded that lung perfusion SPECT is readily performed and reproducible. A negative study eliminates the need for a combined V/Q study and most of the 'non-diagnostic' V/Q probabilities can be solved with a perfusion image obtained by using tomography