Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse

OBJECTIVE: To determine the gene-expression profile in dermal fibroblasts from type 1 tight-skin (Tsk1) mice, and to examine the expression and potential fibrotic activity of monocyte chemoattractant protein 3 (MCP-3) in Tsk1 mouse and human systemic sclerosis (SSc) skin. METHODS: Complementary DNA microarrays (Atlas 1.2) were used to compare Tsk1 fibroblasts with non-Tsk1 littermate cells at 10 days, 6 weeks, and 12 weeks of age. Expression of MCP-3 protein was assessed by Western blotting of fibroblast culture supernatants, and localized in the mouse and human skin biopsy samples by immunohistochemistry. Activation of collagen reporter genes by MCP-3 was explored in transgenic mouse fibroblasts and by transient transfection assays. RESULTS: MCP-3 was highly overexpressed by neonatal Tsk1 fibroblasts and by fibroblasts cultured from the lesional skin of patients with early-stage diffuse cutaneous SSc. Immunolocalization confirmed increased expression of MCP-3 in the dermis of 4 of 5 Tsk1 skin samples and 14 of 28 lesional SSc skin samples, compared with that in matched healthy mice (n = 5) and human controls (n = 11). Proalpha2(I) collagen promoter-reporter gene constructs were activated by MCP-3 in transgenic mice and by transient transfection assays. This response was maximal between 16 and 24 hours of culture and mediated via sequences within the proximal promoter. The effects of MCP-3 could be diminished by a neutralizing antibody to transforming growth factor beta. CONCLUSION: We demonstrate, for the first time, overexpression of MCP-3 in early-stage SSc and in Tsk1 skin, and suggest a novel role for this protein as a fibrotic mediator activating extracellular matrix gene expression in addition to promoting leukocyte trafficking. This chemokine may be an important early member of the cytokine cascade driving the pathogenesis of SSc.     

Effects of Coffee Intake on Incident Chronic Kidney Disease: A Community-Based Prospective Cohort Study

Background

Drinking coffee can raise public health problems, but the association between coffee and kidney disease is unknown. We studied whether coffee intake can affect the development of chronic kidney disease in the general population.

Metabolic changes in the rat anterior pituitary and prolactin production following estradiol treatment

The effects of estradiol treatment on the synthesis and release of prolactin and GH in castrated male rats were studied in connection with the anterior pituitary enzymes that represent the hexosemonophosphate shunt, glycolytic, oxidative, and lysosomal activity. LDH and G6P-DH activities increased by 15%–30% at 12 hr and by 70% at 72 hr after estrogen administration. PK activity showed a statistically significant elevation of 20%–40% only after 48–72 hr. ICDH, MDH, acid phosphatase activities, and water-soluble protein concentrations were unchanged. Serum prolactin concentration increased about 400% 24 hr after estradiol injection, and the pituitary synthesized 1000%–1500% more radioactive prolactin in vitro than did control glands. However, no significant increase in prolactin synthesis was observed 12 hr after estradiol treatment.It is suggested that the primary effect of estradiol is on the synthesis of prolactin and that the increased rate of secretion is secondary. Radioimmunoassayable prolactin in the incubated gland tissue and its medium was greatly increased after estradiol treatment. A slight but statistically significant accumulation and decreased release of radioactive GH were also observed. The results suggest a correlation of pituitary prolactin production with the tissue's metabolic activity.     

Scleroderma in children

Juvenile systemic scleroderma (jSSc) is a rare childhood disease. In the review period covered within this article, there were few reports devoted exclusively to it. In the past year, there was no breakthrough regarding pathogenesis, classification, or treatment. In the pediatric field, the proposed classification system for jSSc shows significant progress toward a definition of the pediatric population. It should allow better evaluation of this patient group. In adult systemic scleroderma, European efforts to establish indices for disease activity have been published. They should help to assess the disease activity in a standardized way and therefore enable earlier adequate treatment for patients. Biologic markers and new assessment methods for particular organ involvement help to determine disease activity/severity as well. There is still no effective disease-modifying treatment for systemic scleroderma and jSSc. The summarized data of the phase I/II autologous stem cell transplantation trial have been published. The first guidelines for autologous stem cell transplantation for jSSc are proposed. In organ-specific treatment, the introduction of bosentan, a dual endothelin receptor antagonist, to control pulmonary hypertension is a real gain in the therapeutic options. New methods to assess prognosis are evolving and need to be validated in a larger patient population.     

Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions

A murine model of minor histocompatibility antigen (miHCag)-mismatched bone marrow transplantation (BMT) was used to study the development of immunoregulatory cells in the posttransplantation period and their possible involvement in the dissociated graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity of posttransplantation donor lymphocyte infusions (DLIs). DLI, applied immediately after BMT, induced GVH disease (GVHD), but when DLI was delayed for 3 weeks, GVHD was avoided while a distinct GVL response was allowed to develop. A population of Mac1+Ly6-G+Ly6-C+ immature myeloid cells, found in small numbers in normal mice, strongly expanded in spleens of chimeras, reaching a maximum level at week 3 and returning to base level by week 12. Upon isolation, these cells exhibited interferon-gamma (IFN-gamma)-dependent, nitric oxide (NO)-mediated suppressor activity toward in vitro alloresponses, suggesting that, after in vivo DLI, they are activated by IFN-gamma to produce NO and suppress GVH reactivity. Because not only alloactivated T-cell proliferation but also leukemia cell growth was found susceptible to inhibition by exogenous NO, in vivo activation of these cells after DLI may explain the occurrence of a GVL effect despite suppression of GVHD. This suggested sequence of events was supported by the finding that the ex vivo antihost proliferative response of spleen cells, recovered shortly after in vivo DLI, was characterized by strong mRNA production of the monokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) and of inducible nitric oxide synthase (iNOS). Our data suggest that transiently expanding Mac1+Ly6-G+Ly6-C+ immature myeloid cells (probably as a result of extramedullary myelopoiesis) may play a role in controlling GVH while promoting GVL reactivity of DLI after allogeneic BMT.     

Homocysteine levels in men and women of different ethnic and cultural background living in England

This population-based cross-sectional study in South London looks at the total homocysteine (tHcy) levels in groups of different ethnic background and the possible role of environmental factors and the 677C-->T genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR). Fasting plasma tHcy was measured in 1392 men and women, age 40-59 years; 475 were white, 465 of African origin (of whom 180 were West Africans and 280 Caribbeans) and 452 South Asian (of whom 222 were Hindus and 167 Muslims). The homozygous MTHFR TT variant had observed frequencies of 0.10 in whites, 0.01 in people of African origin and 0.02 in South Asians (P<0.001). tHcy levels were 16% (95% CI 8-26) higher amongst TT than CC. tHcy levels were 25% (21-29) higher in men than women. Levels were significantly higher in South Asians than whites (8% [3-13]). Vegetarians had higher levels than non-vegetarians (25% [18-33]). These differences were present after adjustments for age, sex, smoking, body mass index (BMI), MTHFR 677C-->T polymorphism and socio-economic status. Compared with whites (10.0 [9.7-10.3] micromol/l), and allowing for confounders, Hindus had significantly higher levels of tHcy (12.1 [11.6-12.6] micromol/l). This difference was attenuated by the inclusion of vegetarianism in the model (11.3 [10.8-11.9] micromol/l). In contrast Muslims had similar tHcy levels to whites while both West Africans and Caribbeans had slightly lower levels, though differences were not significant. The reported higher levels of tHcy in South Asians are due to high levels amongst Hindus only. They are in part accounted for by their vegetarianism. These differences in tHcy are large enough to be important contributors to the risk of vascular disease and may be preventable by simple targeted population strategies.     

Management of patients with community-acquired pneumonia treated in hospital in Sweden

To investigate the management of patients with community-acquired pneumonia (CAP) treated in hospital in Sweden, a multicentre retrospective cohort study was performed with medical record review of 982 patients (mean age 63 y) at 17 departments of infectious diseases at hospitals in Sweden. Information on antimicrobial therapy, demographic characteristics, comorbid conditions, physical examination findings, and laboratory and microbiological test results were recorded. Outcome measures were in-hospital mortality and length of hospital stay (LOS). Cultures were obtained from blood in 80% and from sputum in 22% of the patients. A microbiological aetiology was determined for 23% of the patients, with Streptococcus pneumoniae as the dominating agent (9%). The initial antibiotic treatment was mostly given intravenously (78%). Penicillin (50%) or a cephalosporin (30%) was the most common choice. Both of these drugs were usually given as a single agent. The overall mortality was 3.5% and the mean LOS was 6.4 d. Thus, the outcome was favourable despite the empirical antibiotic treatment having a narrow spectrum compared with the broader approach recommended in most recent guidelines on the management of CAP. These findings suggest that a majority of patients who are hospitalized with moderately severe pneumonia can be treated initially with penicillin alone.     

中药慢肝消治疗酒精性肝病的临床研究

目的观察中药复方慢肝消对酒精性肝病的治疗效果．方法酒精性肝病９２例，分治疗组６４例，对照组２８例．治疗组用慢肝消，对照组用加味逍遥散．治疗组和对照组中脂肪肝分别为１３例（１２０％）和９例（３２１％），肝炎分别为１９例（２７７％）和６例（３２１％），肝硬变分别为２２例（３４４％）和９例（３２１％），混合型各为１０例（１５６％）和４例（１４３％）．临床主要表现为纳呆、腹胀、胁胀或痛，呕恶便溏，乏力．３ｍｏ１疗程，观察结束后，对症状、体征、肝功能、胶原代谢，及免疫功能等方面的变化进行分析研究．结果治疗组临床治愈５例，显效３６例，好转１９例，无效４例，总有效率为９３８％，对照组临床治愈０例，显效１２例，好转８例，无效８例，总有效率为７１４％．结论慢肝消具有改善肝功能，抗肝纤维化，调解免疫功能的作用，明显优于对照组