).q RSNA, 2014 Purpose:To evaluate the diagnostic accuracy of unenhanced and quantitative contrast-enhanced ultrasonography (US) in the differential diagnosis of small nonpalpable testicular lesions. Materials andMethods:The local review board approved the protocol, and all patients provided written informed consent. One hundred fifteen patients (median age, 34 years; age range, 14-61 years) with nonpalpable testicular lesions were consecutively enrolled between 2006 and 2012 and underwent unenhanced scrotal US, contrast-enhanced US, surgical enucleation, and at least 18 months of follow-up. Clinical and histologic features were recorded, and qualitative and quantitative analysis of contrast-enhanced US time-intensity curves were performed. Logistic regression analysis was performed to explore features of malignancy. Receiver operating characteristic (ROC) curves were developed for cumulative unenhanced and contrast-enhanced US scores. Results:All lesions were 1.5 cm or smaller. Forty-four of the 115 patients (38%) had malignant tumors, 42 had benign tumors (37%), and 29 (25%) had nonneoplastic lesions. Conclusion:Benign testicular tumors are frequent incidental findings. Quantitative scrotal contrast-enhanced US is a noninvasive diagnostic tool that could improve the differential diagnosis and individualized management of small testicular lesions.q RSNA, 2014
Cure of H. pylori infection is associated with reversal of iron dependence and recovery from iron deficiency anemia.
Activation of initiator and effector caspases, mitochondrial changes involving a reduction in its membrane potential and release of cytochrome c (cyt c) into the cytosol, are characteristic features of apoptosis. These changes are associated with cell acidification in some models of apoptosis. The hierarchical relationship between these events has, however, not been deciphered. We have shown that somatostatin (SST), acting via the Src homology 2 bearing tyrosine phosphatase SHP-1, exerts cytotoxic action in MCF-7 cells, and triggers cell acidification and apoptosis. We investigated the temporal sequence of apoptotic events linking caspase activation, acidification, and mitochondrial dysfunction in this system and report here that (i) SHP-1-mediated caspase-8 activation is required for SST-induced decrease in pH i . (ii) Effector caspases are induced only when there is concomitant acidification. (iii) Decrease in pH i is necessary to induce reduction in mitochondrial membrane potential, cyt c release and caspase-9 activation and (iv) depletion of ATP ablates SST-induced cyt c release and caspase-9 activation, but not its ability to induce effector caspases and apoptosis. These data reveal that SHP-1-/caspase-8-mediated acidification occurs at a site other than the mitochondrion and that SST-induced apoptosis is not dependent on disruption of mitochondrial function and caspase-9 activation.Apoptosis is a physiological process of cell death indispensable for the maintenance of multicellular organisms. This process drives the cell into self-destruction via a common execution pathway. The cellular machinery utilized for this process creates distinct apoptotic features of cell shrinkage, cytoplasmic and nuclear condensation, membrane blebbing, chromatin compaction, and fragmentation of chromosomal DNA into 180-base pair multimers. A central event in the process of apoptosis is the activation of cysteine aspartate proteases (caspases) (1). Active caspases consist of dimeric complexes of ϳ20-and 10-kDa fragments derived from the procaspases that exist as inactive zymogens by internal proteolytic cleavage at cysteineaspartate sites (2). Mammalian caspases can be divided into initiator (e.g. caspases 2, 8, 9, 10) and effector (caspases 3, 4, 5, 6, 7, 11, 12, and 13) enzymes. A feature of apoptosis that impinges on caspases is altered mitochondrial function characterized by a reduction in the electrochemical gradient across the mitochondrial membrane (⌬ m ) 1 and release of mitochondrial cyt c into the cytoplasm (3-15). Cyt c is necessary for caspase-9 activation (16, 17). Caspase-9 can function as an initiator caspase when mitochondrial dysfunction is the primary event in apoptosis, whereas it serves to amplify the apoptotic signaling of other initiator caspases under conditions in which disruption of mitochondria is a late event (16 -19).In some models of apoptosis activation of caspases is associated with intracellular acidification (20 -23). The question of whether intracellular acidification is necessary for inducing ...
Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.
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