The male reproductive function in patients with spinal cord injury

Seminal findings and blood hormone levels were studied for evaluating the male reproductive function in patients with spinal cord injury. The patients were divided into 3 groups, namely, 18 patients with complete injury, 5 patients with incomplete injury and 3 patients with dyspermatism. The number of sperms, the rate of movement and rate of deformation were measured for semen obtained by forced ejaculation. The number of sperms was kept at a relatively high level in the three groups, while the rate of movement fell off in all of the three groups. The rate of deformation was highest in the patients with complete injury and lowest in the patients with dyspermatism. As for blood hormone levels, LH, FSH and Testosterone (hereinafter referred to as TES) were determined by the RIA. The cases were classified into those in the acute stage and those in the chronic stage 3 months after sustaining injury for a comparative study. The subjects consisted of 27 cases in the acute stage and 47 cases in the chronic stage. For 8 patients in the acute stage, the blood hormone levels were determined even in the chronic stage and follow-up observations were made on the changes in the levels. The FSH level was low in both stages, while LH and TES tended to increase in the chronic stage. Particularly, the TES level was elevated in all the cases in the follow-up observations made in 8 patients. From the results mentioned above, transient disturbance of the interstitial function is suggested as the mechanism of male gonadal disturbance due to spinal cord injury.     

Lipopolysaccharide Induces CD25-Positive, IL-10-Producing Lymphocytes Without Secretion of Proinflammatory Cytokines in the Human Colon: Low MD-2 mRNA Expression in Colonic Macrophages

Despite the huge number of colonized Gram-negative bacteria in the colon, the normal colon maintains its homeostasis without any excessive immune response. To investigate the potential mechanisms involved, human colonic lamina propria mononuclear cells (LPMCs) obtained from uninflamed mucosa were cultured with lipopolysaccharide (LPS) prepared from Bacteroides vulgatus (BV-LPS) or Bacteroides fragilis (BF-LPS), as representatives of indigenous flora, or pathogenic Salmonella minnesota (SM-LPS). Colonic LPMCs failed to produce inflammatory cytokines in response to any type of LPS. Colonic macrophages barely expressed mRNA for MD-2, an essential association molecule for LPS signaling via Toll-like receptor 4. Further, BV-LPS induced CD25 and Foxp3 expression in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA. Thus, the low expression of functioning LPS receptor molecules and induction of IL-10-producing CD4(+)CD25(+) lymphocytes by indigenous LPS may play a central role in the maintenance of colonic immunological homeostasis.     

Pathological analyses of long-term intracoronary Palmaz-Schatz stenting; Is its efficacy permanent?

BACKGROUND: Angiographic regression of luminal narrowing occurs 6 months to 3 years poststenting. However, after 4 years lesions progressed gradually and late restenosis was observed in 28% of 179 Palmaz-Schatz-stented lesions during the past 10 years. Elucidating its pathogenesis is pivotal to developing preventive strategies. METHODS AND RESULTS: Histopathological and immunohistochemical studies were performed in 19 stented coronary arteries obtained from 19 patients autopsied after noncardiac death 2-7 years poststenting. The quality/severity of chronic inflammatory cells (T lymphocytes, macrophages and multinucleated giant cells) infiltration around the stent struts that is observed even in the absence of restenosis depended on the time elapsed from stenting: a) 2 years postprocedure, in spite of angiographic regression during the first year and pathologically expressed as maturation of the neointimal scar, there was chronic inflammatory response evidence: neovascularization and lymphocyte infiltration, b) > or = 3 years: the neointimal smooth muscle cells were sparse with abundant proliferation of collagen fibers. Presence of slight helper/inducer T lymphocytes and mild macrophage infiltration around the stent struts was evident immunohistochemically, c) > or = 4 years: prominent infiltration by lipid-laden macrophages with strong collagen-degrading matrix metalloproteinase immunoreactivity was observed around the struts. In two of these arteries, the surface contacting the stent was focally disrupted and covered by nonocclusive mural thrombi. CONCLUSIONS: Stainless steel stents evoke a remarkable foreign-body inflammatory reaction to the metal. These persistent peri-strut chronic inflammatory cells may accelerate new indolent atherosclerotic changes and consequent plaque vulnerability.     

Abnormal IgG galactosylation in MRL-lpr/lpr mice: pathogenic role in the development of arthritis

MRL-lpr/lpr (MRL/lpr) mice spontaneously develop arthritis by an increase in the incidence of agalactosylated oligosaccharides in serum IgG, similar to rheumatoid arthritis patients. However, whether this association has a pathogenic significance is still unknown. In this study, we analyzed the oligosaccharide structure of serum IgG in various MRL mice with or without arthritis, to clarify the relationship between the oligosaccharide abnormality and the development of arthritis. The level of agalactosylation in serum IgG was comparable in both arthritis-free MRL/lpr and MRL-+/+ (MRL/+) mice at 6 weeks of age. In contrast, the incidence of IgG lacking galactose markedly increased in MRL/lpr mice at 6 months of age (the age at which arthritis occurred), compared with that from age-matched MRL/+ mice without arthritis. However, the proportion of agalactosylated IgG increased similarly in anti-CD4 monoclonal antibody-treated MRL/lpr mice at 6 months of age, despite the absence of the development of arthritis, because of depletion of CD4+ T cells. These results suggest that the abnormality in IgG galactosylation of MRL/lpr mice developed in an age-dependent manner, but it did so independently of CD4+ T cell-dependent B-cell activation and is not a consequence of the development of arthritis.     

An immunodominant haptenic epitope of carbamazepine detected in serum from patients given long-term treatment with carbamazepine without allergic reaction

An anticarbamazepine antibody was detected in the serum of a patient with severe carbamazepine-induced serum sickness. We found that the patient's T cells and IgG antibody recognized an epitope which appeared in subjects showing an allergic reaction, as well as that in subjects who showed no allergic reaction, after long-term carbamazepine therapy. These results show that an anti-carbamazepine immune response does not occur in the majority of subjects who undergo long-term carbamazepine therapy without developing allergic symptoms, although the immunodominant haptenic epitope of carbamazepine is present in their sera.     

Does the deletion within T cell receptor β-chain gene of NZW mice contribute to autoimmunity in (NZB × NZW)F1mice?

To determine the transacting genetic factors of NZW contributing to the development of autoimmune disease in (NZB X NZW)F1 (B/W F1) mice, we examined the relationship between the T cell receptor beta chain gene deletion and the severity of autoimmune manifestations in 76 B/W F1 X NZB backcross mice. Very high association between the T cell receptor beta chain gene deletion and the development of autoimmune manifestations including the production of IgG anti-DNA antibodies and circulating retroviral gp70 immune complexes was observed, indicating that a defect in the NZW T cell receptor beta chain gene or a locus closely linked to it contributes to the autoantibody formation in B/W F1.     

Apoptosis with FasL+ cell infiltration in the periphery and thymus of corrected autoimmune mice.

Fas (CD95) ligand (L) is a death factor that binds to its receptor, Fas, and induces apoptotic cell death, a crucial process in immunological tolerance. gld (generalized lymphoproliferative disorder) mice, which have a point mutation in the FasL gene, develop spontaneous systemic autoimmune syndromes characterized by hypergammaglobulinaemia and lymphoid hyperplasia owing to accumulation of abnormal B220+ CD3+ cells. Transplantation of wild-type (wt) bone marrow cells into old gld mice on the same strain background results in normalization of autoimmune syndromes. We characterized the cellular mechanisms (functionally and histologically) of the above phenomena in gld mice after bone marrow transplantation (BMT) to determine the role of apoptosis via Fas/FasL interactions in inducing and maintaining self-tolerance in vivo. Activated splenocytes from wt and BMT (wt to gld) mice showed significant cytotoxic activity against Fas transfectant cells while those from BMT (gld to gld) mice did not. Cells in the thymus, spleen and lymph nodes of gld mice uniformly upregulated Fas expression and were sensitive to Fas-mediated apoptosis compared with those in wt mice. Cells sensitive to Fas-mediated apoptosis in gld mice resided not only among abnormal B220+ CD3+ cells but also among conventional lymphocytes. More importantly, histological analysis revealed that cells in the spleen, lymph nodes and thymus frequently underwent apoptosis with infiltration of FasL+ cells in BMT (wt to gld) mice compared with BMT (gld to gld) mice. Our results indicated that apoptosis via Fas/FasL interactions can directly eliminate pathogenic cells responsible for autoimmunity in the periphery and possibly in the thymus in vivo.     

Natural cytotoxic autoantibody against thymocytes in NZB mice

NZB mice were found to produce natural thymocytotoxic autoantibody in high prevalence and antibody titre. This autoantibody in NZB mice was detectable by the cytotoxicity test at both 4°C and 37°C; the prevalence and antibody titre were generally higher at 4°C. Mice of other strains also produced natural thymocytotoxic autoantibody although in lower prevalence and antibody titre and in some instances the activity was greater at 37°C than at 4°C. Natural thymocytotoxic autoantibody in NZB mice reacted equally with the thymocytes of virtually all strains of mice tested but to a lesser degree with the thymocytes of SJL/J mice. A serum pool obtained from old NZB mice had an extremely high titre of natural thymocytotoxic autoantibody (1:1024 at 4°C). Nevertheless, the cells in lymph nodes, spleen and blood leucocytes were only partially sensitive to this serum pool, and bone marrow cells were for the most part negative. By absorption, the antigen reacting with natural thymocytotoxic autoantibody was found in thymus, lymph node, spleen and brain of adult mice, thymus of newborn mice and some leukaemias. Natural thymocytotoxic autoantibody in NZB mice was an IgM-globulin as determined by sensitivity to 2-mercaptoethanol treatment and by Sephadex G-200 column chromatography in contrast to other natural antibodies (antinuclear, antierythrocyte and G antibodies) of IgG-globulin class. NZB mice also produced natural antibodies against thymocytes of the rat and the hamster; these antibodies were species-specific and did not react with the thymocytes of any but the homologous species.     

Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells

Our recent studies on an autoantibody-transgenic mouse linedemonstrated that peritoneal B-1 cells are responsible for autoimmunesymptoms. However, whether B-1 cells in the peritoneum are generallyinvolved in the pathogenesis of autoimmune disease remains controversial.To test the possible involvement of peritoneal B-1 cells inautoimmune symptoms of autoimmune-prone NZB mice, we eliminatedthe peritoneal cells by hypotonic shock with repeated I.p. injectionof distilled water every 7 days into neonatal or 8-week-oldNZB mice. By this treatment, B-1 cells, which self- renew withinthe peritoneal cavity, are expected to be preferentially eliminated,while other peritoneal cells can be easily supplied from bonemarrows after this treatment indeed, in distilled water-treatedold NZB mice, the number of B-1 cells decreased in spleen aswell as in lamina propria of the gut but the numbers of conventionalB cells and T cells did not change. Moreover, the productionof autoantibodies against erythrocytes significantly decreasedand the occurrence of autoimmune hemolytic anemia was reducedin 12-month-old treated NZB mice. Similarly, the eliminationof peritoneal cells of NZB/NZW (NZB/W) F₁; mice by water injectiondecreased anti-DNA IgG antibodies in the sera and reduced thepathological changes of the kidney. These results suggest thatperitoneal B-1 cells may be a source of autoantibody-producingcells in autoimmune diseases of NZB and NZB/W F₁; mice.     

Renal cell adenomas and carcinomas in hemodialysis patients: Relationship between hemodialysis period and development of lesions

Step-sections of 96 whole kidneys from 50 chronic hemodialysis patients were subjected to a histopathological and quantitative investigation with regard to the development of renal neoplastic lesions. The range of hemodialysis duration was from 1 to 222 months. A total of 349 renal cell adenomas were found in 41 cases (82%). They were commonly multiple and present bilaterally. Renal cell carcinomas were evident in four cases (8%), with hemodialysis durations of 54, 57, 112 and 222 months. The incidence of adenomas increased in a hemodialysis duration-dependent manner, indicating a high risk of renal cell tumor development in chronic hemodialysis patients. Furthermore, acquired cystic disease of the kidney (ACDK) was also observed in 12 cases (24.0%), where the mean hemodialysis period was 143.4 ± 48.0 months. This value was significantly longer than that of non-ACDK cases (P < 0.001). There was, however, no clear relationship between the appearance of ACDK and renal cell tumors. The present results underline the necessity for attention to possible neoplasia of the kidney in patients on long-term hemodialysis.