The shell region of the nucleus ovoidalis: a subdivision of the avian auditory thalamus.

The connectivity of a region surrounding the established thalamic auditory nuclei, n. ovoidalis (Ov) and n. semilunaris parovoidalis (SPO), was explored in the ring dove by using the anterograde tracers, Phaseolus vulgaris leucoagglutinin (PHAL) and biocytin, and the retrograde tracer, fluorogold. The Ov-SPO surround received a projection from a cell group along the interface of the auditory midbrain and the n. intercollicularis, as revealed with PHAL and biocytin, and was composed of neurons exhibiting a common morphology. These features and the presence of overlapping projections from different portions of the Ov-SPO surround suggest that this region comprises a functionally discrete area, which we term the Ov shell. Single unit recording within the shell established the existence of acoustically responsive units. Both PHAL and fluorogold labeling revealed a robust projection from the Ov shell to the caudomedial hypothalamus. Major telencephalic projections of the shell terminated within the ventral paleostriatal complex, "end-zones" of the field L, the caudomedial hyperstriatum ventrale, and regions immediately dorsal and lateral to the auditory neostriatum. Except for a portion of the shell bordering medial ovoidalis, PHAL injections into the shell also labeled fibers within the caudolateral neostriatum and along the lateral neostriatal rim. The connectivity of the Ov shell suggests that this region may integrate auditory pathways with brain regions associated with endocrine mediated behavior. In addition, the shell may constitute a source of converging input to several levels of central auditory pathways.     

Extreme hypogammaglobulinemia disclosing large granular lymphocytes with hepatosplenorenal infiltration

We report a case of large granular lymphocytosis, or chronic "natural killer" lymphocytosis, a newly described entity. We were able to demonstrate the proliferative character of the disease by the finding of karyotype abnormalities. This case was remarkable for the pre-existence, for at least three years, of severe hypogammaglobulinaemia, for the very slow course of the proliferative process and for the progressive and tumoral infiltration of the spleen and liver, then kidney.     

Mapping location of excitation during magnetic stimulation: Effects of coil position

We determined the location of excitation for different positions of a round and butterfly coil duringin vitro magnetic stimulation of cut peripheral nerves. We analyzed the conditions under which excitation occurs, either at the termination or at the peak of the field gradients (first spatial derivative of the electric field). These results were then compared to predictions about the location of excitation sites from a theoretical model of magnetic stimulation of finite neuronal structures. Excitation along a straight nerve occurred at terminations when 1) a coil was positioned close to the end of a nerve (at least one diameter length from the end), 2) a nerve ended in a finite terminating impedance much greater than the axial resistance of the nerve, 3) the induced electric field was of sufficient magnitude, pointing in a direction away from the axis of a nerve. Excitation occurred at the negative peak of the field gradients along a nerve when 1) a coil was positioned far away from the ends of a nerve, 2) there were no geometric or volume conductor inhomogeneities around a nerve, and 3) it was of sufficient magnitude. Threshold strengths for excitation at terminations were significantly lower than that for field gradient excitation and comparable to that due to geometric and volume conductor inhomogeneities.     

Evaluation of stromal metalloproteinases and vascular endothelial growth factors in a spontaneous metastasis model

This study aims to investigate MMP2 and MT1-MMP protein as well as VEGF-C and VEGF-D mRNA expression in tumor cells and distant organs considered to be targets for metastasis in a tumor spontaneous metastasis model previously described. Cultured tumor cells, able to express pro-MMP2, MMP2, pro-MMP9, and MT1-MMP, develop tumor growth and metastasis, mainly in the liver and spleen, when they are injected in the mammary pad gland of Wistar rats. Immunohistochemical studies of tumor masses showed small groups of tumor cells staining for MT1-MMP but not for MMP2. In the liver, tumor metastatic foci and a stromal positive staining for both MMP2 and MT1-MMP were shown. The spleen and lymph nodes, with only scattered metastatic cells, did not show MMPs immunostaining. Using RT-PCR, a significantly higher VEGF-C and VEGF-D gene expression was shown in the liver of tumor-bearing rats respect to normal rats, whereas spleen and lymph nodes did not show significant differences in mRNA VEGF-C/D levels. Taken together, our results suggest that the stroma microenvironment of target organs for metastasis has the ability to produce MMPs and VEGFs that facilitate the anchorage of tumor cells and promote tumor cell growth and angiogenesis.     

Intrahepatic cytokine profile in renal-transplant patients infected by hepatitis C virus

In order to examine the immunopathogenesis of hepatitis C virus (HCV)-related liver injury in renal-transplant patients, intra-hepatic cytokine profiles were examined in 38 liver biopsies from 38 patients by measuring messenger RNA (mRNA) concentrations by a real-time PCR method of a Th1 cytokine (i.e., interferon (IFN)-gamma), a Th2 cytokines (i.e., interleukine (IL)-10), a proinflammatory cytokine (i.e., IL-8), and a potent fibrogenic factor (transforming growth factor [TGF]-beta). There was no significant difference in TGF-beta, IFN-gamma, IL-10, or IL-8 levels of expression according to liver-activity grade, liver-fibrosis stage, the concentration of HCV RNA at liver biopsies, or the HCV genotype. However, IFN-gamma/beta-actin mRNA concentration was higher than the IL-10/beta-actin mRNA concentration in patients with F3 Metavir score. Median IFN-gamma/beta-actin mRNA concentration tended to be higher in patients with A3 and A4 Metavir activity grades compared with those with A0 and A1 activity grades. There was a significant correlation between the duration of HCV infection and both TGF-beta/beta-actin (r(2)=0.19, P=0.04) and IL-8/beta-actin mRNA concentrations (r(2)=0.19, P=0.03). IFN-gamma/beta-actin mRNA concentration also increased according to the duration of HCV (r(2)=0.19, P=0.07). Finally, there was a significant correlation between the duration of HCV infection and liver fibrosis stage (r(2)=0.17, P=0.045). Intrahepatic Th1 cytokine profile seems to be predominant in patients with extensive fibrosis and activity scores, suggesting that it might be responsible for liver injury in renal transplant patients.     

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

alpha4 integrins and L-selectin differently orchestrate T-cell activity during diabetes prevention following oral administration of CTB-insulin

Oral administration of insulin conjugated to the B chain of cholera toxin (CTB-insulin) in non-obese diabetic (NOD) mice results in diabetes prevention. We investigated the respective contributions of L-selectin (CD62L) and alpha4-integrin pathways during CTB-driven tolerance. Purified CD62L+CD4+ cells from CTB-insulin fed mice significantly reduced the capacity of diabetogenic T cells to transfer diabetes in syngeneic recipients. In vivo antibody blockade of fed animals during adoptive co-transfer experiments indicated that both CD62L and alpha4-integrins pathways were necessary to develop a protective response after oral tolerance induction. In contrast, when antibodies were given to recipient mice, only CD62L was critical for the protection. In vitro stimulated CD62L+CD4+ cells from the spleen of fed animals secreted lower amounts of IL-4 and IL-10 but comparable levels of TGFbeta than CD62L-cells. A reduced IFN-gamma production between the two cell subsets was specifically observed in CTB-insulin fed mice. Furthermore, antibody treatments induced changes in T-cell migration to the spleen, mesenteric and pancreatic lymph nodes. The protective effect was also associated with migration of regulatory T cells into pancreatic islets. Taken together, our results suggest that L-selectin and alpha4-integrin have distinct but complementary roles in the generation and function of regulatory CD4+ T cells following CTB-insulin administration.     

Amantadine therapy in renal transplant patients with hepatitis C virus infection.

BACKGROUND: To date, there is no safe and efficient treatment of hepatitis C virus (HCV) infection after renal transplantation. Recently, there were encouraging reports after using amantadine in HCV-positive immunocompetent patients. OBJECTIVES: In an open pilot study, we evaluated the efficacy and the safety of amantadine monotherapy in 8 HCV positive renal-transplant patients with chronic active hepatitis and increased alanine aminotransferase (ALT) levels. RESULTS: After 6 months of amantadine therapy (200 mg per day), there were no decrease in HCV viremia (5.87 +/- 0.37 log copies/ml at M6 versus 5.71 +/- 0.5 log copies/ml at baseline; P > 0.05). However, we found a significant decrease in ALT activity (71 +/- 17 IU/l at M6 versus 100 +/- 9 IU/l at baseline; P = 0.04), whereas the decrease in aspartate aminotransferase activity did not reach statistical significance. There were no significant changes in liver histology. The clinical and biological tolerance was very good. Finally, there were a significant decrease in cyclosporine A whole blood trough levels during therapy. CONCLUSIONS: Our study is the first one to demonstrate that amantadine monotherapy lack of efficacy in HCV renal-transplant patients. It is able to improve liver enzymes but it has no impact neither upon HCV viremia nor upon liver histology.     

Effects of long-term lamivudine therapy in renal-transplant patients.

BACKGROUND: Following renal transplantation (RT), chronic immunosuppression is associated in hepatitis B virus (HBV) (+) patients with a flare-up of the disease, which might be harmful in the long term. OBJECTIVES: We report on the effect of long-term lamivudine therapy given at an initial daily dose of 100mg in 18 HBV (+) RT patients. RESULTS: When lamivudine therapy was commenced, 14 patients (77%) had an increase in their aspartate (AST) and alanine (ALT) aminotransferase levels. During a mean follow-up, under treatment, of 36.5 +/- 3.5 months (up to 66 months), 10 patients (55%) had a sustained partial (HBV DNA < 4 x 10(5)copies/ml) (n = 4) or complete (HBV DNA < 400 copies/ml) (n = 6) virological response. Overall, 12 virological breakthroughs were observed. Of those who were HBe Ag(+) prior to lamivudine therapy (n = 4), one seroconverted to HBe Ab during therapy. At the last follow-up, AST and ALT levels were normal in 13 patients. When liver biopsy was repeated during treatment (n = 15), the virological responders showed a significant decrease in total Knodell score from 10 +/- 0.6 to 7 +/- 1 (P = 0.04), but no significant change in the stage of fibrosis. Conversely, in those patients with high HBV DNA titers, there were no significant changes in the total Knodell score or in the grade of fibrosis. CONCLUSION: In conclusion, lamivudine therapy is safe in HBV(+)ve renal-transplant patients. However, even if the full and partial virological response rates are still high (55%) in the long term, relapse or primary non-responses occur. The implementation of alternative efficient strategies is warranted.