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Introduction: Smoothelin is a cytoskeletal protein of differentiated smooth muscle cells with contractile capacity, distinguishing it from other smooth muscle proteins, such as smooth muscle actin (SMA)., Objective: To evaluate the expression of smoothelin and SMA in the skin in order to establish specific localizations of smoothelin in smooth muscle cells with high contractile capacity and in the epithelial component of cutaneous adnexal structures., Methods: Immunohistochemical analysis (smoothelin and SMA) was performed in 18 patients with normal skin., Results: SMA was expressed by the vascular structures of superficial, deep, intermediate and adventitial plexuses, whereas smoothelin was specifically expressed in the cytoplasm of smooth muscle cells of the deepest vascular plexus and in no other plexus of the dermis. The hair erector muscle showed intense expression of smoothelin and SMA. Cells with nuclear expression of smoothelin and cytoplasmic expression of SMA were observed in the outer root sheath of the inferior portion of the hair follicles and intense cytoplasmic expression in cells of the dermal sheath to SMA., Conclusions: We report the first study of smoothelin expression in normal skin, which differentiates the superficial vascular plexus from the deep. The deep plexus comprises vessels with high contractile capacity, which is important for understanding dermal hemodynamics in normal skin and pathological processes. We suggest that the function of smoothelin in the outer root sheath may be to enhance the function of SMA, which has been related to mechanical stress. Smoothelin has not been studied in cutaneous pathology; however we believe it may be a marker specific for the diagnosis of leiomyomas and leiomyosarcomas of the skin. Also, smoothelin could differentiate arteriovenous malformations of cavernous hemangioma of the skin.

The prevalence of subclinical rejection is lower in patients receiving tacrolimus than in patients treated with cyclosporine. However, it is not known whether this difference is related to the modulation of a specific cell immunophenotype. We perform a two case-one control study in patients treated with tacrolimus (n=44) or cyclosporine (n=22) with a protocol biopsy performed at 4 to 6 months. Immunophenotype of infiltrating cells was evaluated with monoclonal antibodies directed against CD45 (all leukocytes), CD3 (T lymphocytes), CD68 (monocytes/macrophages), and CD20 (B lymphocytes) and expressed as interstitial positive cells/mm(2). The number of interstitial CD45 (290+/-209 vs. 696+/-560; P<0.01), CD3 (121+/-84 vs. 208+/-104; P<0.01), and CD68 (155+/-232 vs. 242+/-280; P<0.05) but not CD20 (137+/-119 vs. 197+/-154) positive cells was lower in tacrolimus-treated patients. T lymphocytes and macrophages interstitial infiltration was reduced in tacrolimus treated patients evaluated with protocol biopsies in comparison to cyclosporine-treated patients.

Poly (ADP-ribose) polymerase-1 (PARP-1)-deficient mice are protected against septic shock, type I diabetes, stroke and inflammation. It is now accepted that inflammation and related events, such as activation of NF-kappaB, are key components in the initiation and progression of epithelial cancer and in particular in the neoplastic transformation of keratinocytes and skin carcinogenesis. Here, we report that PARP-1-deficient mice display a strikingly reduced susceptibility to skin carcinogenesis. In parp-1(-/-) mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumor-bearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1(-/-) mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-kappaB is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-kappaB activation and induction kappaB-target genes did not take place during the promotion of tumor development. These results suggest that PARP-1 abolition impairs the promotion of skin carcinogenesis interfering with the activation of NF-kappaB and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.

Background: Although studies have shown that mycophenolate mofetil (MMF) with cyclosporine (CsA) and prednisone can reduce the incidence of acute rejection and increase the half-life of the graft, the effects of MMF on established chronic allograft nephropathy (CAN) are controversial., Methods: We studied 121 patients with biopsy-proven CAN, 59 treated with CsA and prednisone and 62 treated with triple-drug therapy with azathioprine. At inclusion, each group received 2 g per day of MMF and azathioprine was stopped. Renal function was measured by the glomerular filtration rate (GFR) obtained by creatinine clearance (Cockcroft-Gault) and monitored by the slope of the GFR, adjusted using linear regression., Results: The median follow-up, after incorporation of MMF, was 36 (13-36) months, with 103 (85.1%) having a full 3-year follow-up. Before the introduction of MMF, there was progressive deterioration in renal function (GFR: 54.8+/-20.9 vs. 39.7+/-14.0 mL/min, P<0.001). After introduction of MMF, renal function remained stable (GFR: 39.7+/-14.0 vs. 41.3+/-10.8 mL/min, P=NS), with a significant change in the slope of the GFR (-0.0144 vs. +0.00045, P<0.001). In 65 patients in whom CsA blood levels remained unchanged during follow-up (148.0+/-65.6 vs. 154.1+/-58.2, P=NS), the slope of the GFR showed a reduction in loss of renal function (-0.0147 vs. -0.0001, P<0.001)., Conclusions: Treatment with MMF reduced the progressive deterioration of renal function in patients with CAN, independently of the blood levels of CsA.

Previous studies have shown that in non-Hodgkin's lymphomas and others neoplasms, tumoral progression, treatment response, and outcome are related to the expression of different oncogenic and tumor suppressor proteins. This study aimed to determine the prognostic significance of the expression of p53, bcl2, retinoblastoma protein (Rb), Ki67, CD15, and latent membrane protein 1-Epstein-Barr Virus (LMP1-EBV) proteins in Hodgkin's disease. A retrospective study was performed on 140 patients collected at the 11 participating centers belonging to the Spanish Collaborative Group for the Study of Hodgkin's Disease. A highly sensitive immunohistochemical method with previous microwave-induced antigen retrieval technique was used for the demonstration of the above-mentioned proteins. A Cox's multivariate analysis was performed to evaluate the impact of the variables in the overall survival, together with a logistic regression model for the achievement of complete remission. Univariate statistical analysis confirmed the prognostic significance of the alredy known clinical parameters: stage, age over 60 years, and B symptoms. High proliferation index (Ki67) and loss of Rb expression were also found to be adverse prognostic factors influencing respectively lower overall survival and failure to achieve complete remission. Multivariate analysis confirmed the independent significance of these two parameters and additionally identifies LMP1-EBV expression as a favorable prognostic marker, in relation with overall survival. Histopathological type, p53, bcl2, and CD15 expression lack significant influence on the outcome of this series. The progression of the disease or the response to treatment in HD patients is the consequence of the interrelationship of different factors, among which LMP1 expression, loss of Rb, and high growth fraction seems to play a more relevant role.

Glomerular and interstitial leukocyte subpopulations were analyzed in renal biopsies from 18 patients with IgM mesangial proliferative glomerulonephritis (IgM MPGN), 19 patients with minimal change nephrotic syndrome (MC) and 10 patients with immune-negative mesangial proliferative glomerulonephritis (IN MPGN), by immunoperoxidase techniques with monoclonal antibodies. Mesangial cell proliferation was strongly correlated with absolute numbers of intraglomerular T lymphocytes (r = 0.71; p < 0.01) in IgM MPGN, but not in MC or IN MPGN. Significant differences were found in the numbers of macrophages, CD4- and CD8-positive glomerular cells (Student's t test p < 0.01, 0.05 and 0.01, respectively) in IgM MPGN, but not in MC or IN MPGN. The numbers of CD45-, CD3- and CD8-positive cells also differed in each patient group (ANOVA p < 0.01, 0.05 and 0.05, respectively), the greatest and smallest values appearing in IgM MPGN and MC, respectively. Multiple regression test showed initial proteinuria values in IgM MPGN to be closely dependent on the density of neutrophils, macrophages, T and B lymphocytes and CD4 cell inflammatory infiltrates (r2 = 0.92; p < 0.01). At the end of the follow-up, proteinuria in IgM MPGN, but not in MC or IN MPGN, was dependent on T cell infiltrate (r2 = 0.97; p < 0.01). Our findings suggest that proteinuria in IgM MPGN results from local mesangial damage rather than from the effects of a soluble circulating factor, as has been proposed for MC. The clinical and immunohistochemical differences observed between these two processes support the notion that they should be considered as separate entities.

Surgical specimens from four patients with diffuse sclerosing papillary carcinoma of thyroid were examined by electronmicroscopy. In addition, immunohistochemical examination using a panel of monoclonal and polyclonal antibodies was carried out in order to investigate the expression of HLA-DR antigen, the presence of Langerhans' cells and the phenotypic characteristics of the inflammatory infiltrate. The ultrastructural study showed that the intraglandular dissemination, typical of this tumour, was due to massive lymphatic invasion. Many Langerhans' cells were observed among tumour cells and in the lymphoid infiltrates in proximity to tumour foci. HLA-DR expression was seen on macrophages, Langerhans' cells, endothelial cells, lymphoid cells, many tumour cells and in some non-neoplastic follicles close to tumour clusters and lymphoid infiltrates. The immunohistochemical analysis of the inflammatory infiltrates showed a high proportion of B- and T-cells, and moderate numbers of plasma cells. Our results suggest that the tumour-specific immune response can give rise to an autoimmune reaction involving non-neoplastic follicles. It is suggested that this could be one of the mechanisms responsible for immunofacilitation of tumour growth.

An ultrastructural and light-microscopic study of the second published case of epithelioid leiomyoma of the vulva is reported. The tumor occurred in the right labium minus of a 26-year-old nonpregnant female. Optic microscopy revealed a clear cell neoplasm with a marked relationship to arterial vessels from which it may originate. The ultrastructure was analogous to that of similar cases reported in the uterus and stomach.

A case of solitary hamartomatous jejunal polyp with adenomatous and carcinomatous changes in a 16-year-old girl is reported. In the hamartomatous polyp, neutral and acid non-sulfate mucosubstance was detected, principally in goblet cells; carcinoembryonic antigen was demonstrated on the surfaces of the microvilli and luminal border of the crypts and glands; absorptive columnar, goblet, argentaffin, argyrophil and Paneth cells were evident. The adenomatous and, mainly, the carcinomatous areas revealed a decreased amount of mucosubstance and a variable degree of positive intracytoplasmic staining for carcinoembryonic antigen. With electron microscopy, the adenomatous areas showed columnar absorptive cells and mucus-secreting goblet cells; also immature columnar cells were observed in the dysplastic zones. To our knowledge, this is the first study to document the histochemical, immunohistochemical and ultrastructural features of a hamartomatous polyp with neoplastic transformation.

Four cases of primary small cell carcinoma of the skin (PSCCS) are presented (ages ranging from 60 to 68 years). Ultrastructurally, two cell types were identified, with both presenting electron-dense secretory granules and paranuclear intermediate filaments. Argyrophylia was positive in one case. Intense solar elastosis in two cases and actinic keratosis in one case suggest a possible role from solar damage in the pathogenesis of this tumor. According to comparative ultrastructural features, different histogenetic possibilities in Merkel cells (MC), peripheral neuroblastic tissue, and totipotential cells are discussed. Some neurosecretory-like granules were observed in basal cell carcinoma (BCC). We consider that PSCCS reproduces cells similar to MC and probably originates in stem cells with totipotential capacity.

We studied a case of blue nevus of the maxillary sinus by immunocytochemical and electron microscopic techniques. Blue nevus has not been reported previously to occur in the maxillary sinus. The melanocytic nature of this lesion was established based upon the ultrastructural demonstration of pre- and melanosomes, and the presence of S100 protein immunoreactivity in the pigmented cells. Histogenetic aspects of the blue nevus of the maxillary sinus are discussed and an origin in multipotential undifferentiated cells is postulated.