Motoneuron activity is required for enhancements in functional recovery after peripheral nerve injury in exercised female mice

Inhibitory luminopsins (iLMO2) integrate opto- and chemo-genetic approaches and allow for cell-type specific inhibition of neuronal activity. When exposed to a Renilla luciferase substrate, Coelenterazine (CTZ), iLMO2 generates bioluminescence-mediated activation of its amino-terminal halorhodopsin, resulting in neuronal inhibition. Moderate daily exercise in the form of interval treadmill-training (IT) applied following a peripheral nerve injury results in enhanced motor axon regeneration and muscle fiber reinnervation in female mice. We hypothesized that iLMO2 mediated inhibition of motoneuron activity during IT would block this enhancement. Unilateral intramuscular injections of Cre-dependent AAV2/9-EF1a-DIO-iLMO2 (∼8.5 x 10¹³ vg/ml) were made into the gastrocnemius and tibialis anterior muscles of young female ChAT-IRES-Cre mice, thereby limiting iLMO2 expression specifically to their motoneurons. Four to six weeks were allowed for retrograde viral transduction after which a unilateral sciatic nerve transection (Tx) and repair was performed. Animals were randomized into four groups: IT only, IT + CTZ, CTZ only, and untreated (UT). Three weeks post Tx-repair, the maximal amplitude direct muscle responses (M-max) in both muscles in the IT only group were significantly greater than in UT mice, consistent with the enhancing effects of this exercise regimen. Inhibiting motoneuron activity during exercise by a single injection of CTZ, administered 30 minutes prior to exercise, completely blocked the enhancing effect of exercise. Similar treatments with CTZ in mice without iLMO2 had no effect on regeneration. Neuronal activity is required for successful enhancement of motor axon regeneration by exercise.     

Interventional radiologic procedures in liver transplantation

Postoperative biliary and vascular complications contribute significantly to morbidity and mortality in liver transplantation. Interventional radiologists are an integral part of the multidisciplinary team necessary for optimizing the management of these complications. During a 15-year period, 39 cadaveric and 25 living related liver transplantations were performed at the Chang Gung Memorial hospital, Taiwan. Of 64 liver transplant recipients, 9 (3 adult and 6 pediatric) underwent 13 interventional radiological procedures for the treatment of biliary sludge-casts (n = 2), bile duct occlusion or stenosis (n = 2), hepatic veins thrombosis (n = 1), hepatic veins stenosis (n = 1), portal vein stenosis with splenorenal shunting (n = 1), biloma (n = 1), and infected fluid collection or ascites (n = 4). Antegrade or retrograde interventional approach was used to successfully treat all biliary complications, and all percutaneous drainage procedures were effective in the control of intra-abdominal fluid collections. Portal vein stenosis was treated by balloon dilatation, and the associated splenorenal shunt was closed by metallic coil embolization via transhepatic catheterization of the portal vein. Hepatic vein stenosis was effectively treated by balloon dilatation and expandable metallic stent deployment via transfemoral and jugular venous approaches, respectively. Hepatic vein thrombosis was only partially lysed by transvenous streptokinase administration, and surgical thrombectomy was needed to achieve complete recanalization. The total success rate of the interventional procedures was 92 % with no procedure-related complications. The overall survival rate in this series is 89 %, and all patients who underwent living related liver transplantation maintain to date a 100 % survival rate. We can conclude that interventional radiological procedures are very useful for managing biliary and vascular complications after liver transplantation. These techniques provide a cure in most situations, thus obviating the need for further surgical intervention or re-transplantation. Received: 6 March 2000 Accepted: 5 May 2001     

Bioisosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.     

Primary cutaneous coccidioidomycosis

Primary cutaneous coccidioidomycosis is usually secondary to laboratory or autopsy inoculation, but can result from trauma in endemic areas. We describe an unusual case of primary inoculation cutaneous coccidioidomycosis occurring in an immunocompetent woman in a nonendemic area. The clinical features, diagnostic tests, and therapy of this extremely rare disease are reviewed.