Relative roles of ICAM-1 and VCAM-1 in the pathogenesis of experimental radiation-induced intestinal inflammation

PURPOSE: Cell adhesion molecules mediate leukocyte recruitment into the irradiated organs; modulation of this process may protect from radiation damage. Our objective was to characterize the requirement for intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in intestinal inflammatory response after abdominal irradiation. METHODS AND MATERIALS: Endothelial ICAM-1 and VCAM-1 expression was determined using radiolabeled antibodies in mice 24 h and 14 days after irradiation with 10 Gy, or sham radiation. Leukocyte-endothelial cell interactions in intestinal venules were assessed using intravital microscopy, and the function of ICAM-1 and VCAM-1 in this process by using blocking antibodies and ICAM-1(-/-) mice. RESULTS: The number of adherent leukocytes significantly increased 24 h after irradiation and remained elevated at 14 days. Treatment with anti-ICAM-1 antibodies and ICAM-1 genetic deficiency significantly reduced leukocyte adhesion 24 h after irradiation. At 14 days after irradiation, both wild-type and ICAM-1(-/-) mice had an upregulation of VCAM-1, expression, and VCAM-1 immunoneutralization, but not ICAM-1 immunoneutralization, significantly reduced leukocyte adhesion. In ICAM-1(-/-) mice, regeneration of the intestinal epithelium was enhanced relative to wild-type mice. CONCLUSIONS: ICAM-1 plays a key role in leukocyte recruitment at early time points after abdominal irradiation, whereas VCAM-1 is the main molecular determinant of leukocyte recruitment at late time points.     

VR1-positive primary afferents contact NK1-positive spinoparabrachial neurons

Neurons in rat superficial dorsal horn that express neurokinin receptor 1 (NK1), a receptor for substance P, play a critical role in the development of hyperalgesia. Thermal hyperalgesia is dramatically reduced after ablation of these neurons, but, paradoxically, not in mice that lack the NK1 receptor (Mantyh et al. [1997] Science 278:275-279). Because primary afferents that express vanilloid receptor 1 (VR1), a receptor for noxious heat, are essential for thermal nociception and hyperalgesia, we reasoned that VR1-positive fibers may terminate onto NK1-expressing dorsal horn neurons. We therefore combined immunofluorescent staining for VR1 and NK1 to show that NK1-positive neurons in lamina I are contacted by VR1-positive fibers. That these contacts represent synapses was verified by staining for the presynaptic marker synaptophysin and by electron microscopy. By combining retrograde tracing with immunocytochemistry, we also found that most NK1-positive cells contacted by VR1-positive fibers project to the lateral parabrachial nucleus. Because quantitative evaluation suggests a preferential targeting of NK1-positive lamina I neurons by fibers containing VR1, these results demonstrate a significant monosynaptic innervation of spinoparabrachial neurons by VR1-positive afferents.     

Afferent and efferent connections of the cerebellum of the chondrostean Acipenser baeri: a carbocyanine dye (DiI) tracing study

The afferent and efferent connections of the cerebellum of the primitive bony fish Acipenser baeri were studied in fixed brains with a fluorescent lipophylic carbocyanine (DiI). The three regions of the cerebellum (the auricles, valvula, and corpus) showed similar afferents, mostly originated from extensive precerebellar populations of the midbrain tegmentum and from the inferior olive. A pretectal nucleus was also labeled after DiI application to the three regions of the cerebellum. However, DiI application to the pretectal region revealed that the pretectocerebellar projection mainly targeted to the caudal region of the corpus cerebelli. Some precerebellar cells were observed in the torus semicircularis, isthmic central gray, and rhombencephalic reticular formation. Primary fibers of the anterior lateral line nerve and neurons of the octavolateral area also project to the auricle. After DiI application to the auricles, most ascending efferents coursed to the region of the nucleus of the medial longitudinal fascicle and thalamus, mostly contralaterally. Ipsilateral descending fibers were also labeled in the medullary octavolateral area. Application of DiI to the nucleus of the medial longitudinal fascicle revealed three clusters of cerebellar projection neurons located in the granular layers of the auricles, valvula, and corpus cerebelli, mostly contralateral to the application site. These cerebellar projection neurons did not exhibit a number of characteristics of teleost eurydendroid cells (i.e., the cerebellar efferent cells of teleosts), such as the presence of spiny dendrites ascending to the molecular layer. Comparison of the afferent and efferent projections of the sturgeon cerebellum with those reported in teleosts supports the hypothesis that some traits observed in the teleost cerebellar system represent recent evolutionary developments.     

Carcinoma epidermoide primario de mama

Primary squamous cell carcinoma of the breast is an infrequent tumour, that requires to rule out a tumor from other location to be diagnosed. Several characteristics as big size, and necrosis or cyst presence, have been associated rather than adenocarcinoma, although clinic and radiological squamous cell carcinoma non-specific characteristics are difficult to distinguish from adenocarcinomas. We present a woman with a 4-cm primary squamus cell carcinoma of the breast. Pathogenic, diagnostic, and therapeutic aspects in accordance with medical literature, are discussed.     

Biweekly gemcitabine plus vinorelbine in first-line metastatic breast cancer: efficacy and correlation with HER2 extracellular domain

Purpose To assess the toxicity and efficacy of biweekly gemcitabine plus vinorelbine in first-line advanced breast cancer, and to establish whether circulating HER2 ECD levels correlate with the efficacy of the combination. Patients and methods 52 patients were treated with gemcitabine 2500 mg/m² plus vinorelbine 30 mg/m², both on day 1 of 14-day cycles, for a maximum of 10 cycles. Baseline serum levels of HER2 ECD were assessed with an ELISA. Results All patients were evaluable for toxicity, and 50 for efficacy. Overall toxicity was moderate. Grade 3 neutropenia occurred in 35% of patients and grade 4 in 19%. Other grade 3 toxicities were observed in less than 6%. There was one episode of febrile neutropenia, and one death after cycle three. Overall response rate was 52% (95% CI: 38% to 66%), with 2 patients achieving a CR (4%). Response rate did not correlate with HER2 ECD, with 50% of HER2 ECD positive patients responding, vs 48.5% of the HER2 ECD negative. Median overall survival was 24.6 months. Conclusion Gemcitabine plus vinorelbine, given as an every-two-week schedule, is an active regimen in advanced breast carcinoma. This combination can be an option when anthracyclines and taxanes are not preferred. HER2 ECD has no predictive value in this non-taxane combination.     

Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study

Optimal treatment for HIV-related visceral leishmaniasis (VL) has still to be established. A pilot clinical trial was carried out in 57 HIV-VL coinfected patients to compare the efficacy and safety of amphotericin B lipid complex (ABLC) versus meglumine antimoniate. The patients were randomized to receive either ABLC 3 mg/kg/day for 5 days (ABLC-5, 18 patients), ABLC 3 mg/kg/day for 10 days (ABLC-10, 20 patients) or meglumine antimoniate 20 mg Sbv /kg/day for 28 days (19 patients). Treatment was considered successful if parasites were not detected in a bone marrow aspirate after treatment. Parasitological cure was attained in 33% (95% CI: 13%-59%) of the ABLC-5 group, in 42% (95% CI: 16%-62%) of the ABLC-10 group and in 37% (95% CI: 16%-62%) of the meglumine antimoniate group (P = 0.94). Eight out of 19 patients administered antimoniate discontinued treatment prematurely following serious adverse events, compared with one in the ABLC groups (P = 0.0006). The efficacy of ABLC is similar to meglumine antimoniate, but the severity of toxicity in the treatment of HIV-VL is lower with ABLC.