Autoantibodies against bactericidal/permeability-increasing protein in patients with cystic fibrosis

Cystic fibrosis (CF), a genetic disorder, is characterized by chronic pulmonary infection/inflammation which leads to respiratory failure. The presence of anti-neutrophil cytoplasmic autoantibodies (ANCA) has previously been observed in the sera of patients with CF. In view of the known relationship of ANCA with primary vasculitis and of their putative pathogenetic role in these disorders, we studied the presence, specificity and isotype of ANCA and their clinical associations in 66 adult CF patients. None of the 66 CF samples had autoantibodies to the major ANCA antigens, proteinase 3 or myeloperoxidase. However, 60/66 (91%) CF samples contained IgG and 55/66 (83%) IgA, autoantibodies to bactericidal/permeability increasing protein (BPI), a recently characterized ANCA specificity. All the IgA anti-BPI-positive samples were also IgG anti-BPI-positive. The autoantibody specificity was confirmed by inhibition assay and immunoblotting of CF sera against a neutrophil granule preparation. Furthermore, in this cross-sectional study, anti-BPI levels were inversely correlated with the observed reductions in FEV1 and FVC (IgA anti-BPI and FEV1: r = 0.508, <it>p</it> &lt; 0.0001), and both IgG and IgA anti-BPI levels were higher in CF patients with secondary vasculitis (<it>n</it> = 6) than in those without (<it>p</it> &lt; 0.05). ANCA with specificity for BPI were present in the majority of CF sera in this study and autoimmune processes may be associated with the development of pulmonary injury in CF.      

大鼠眼外肌成肌细胞的增殖及分化特征

目的:完善眼外肌成肌细胞体外培养、鉴定的方法及观察其生物学特性。方法:实验于2005-02/08在青岛大学医学院附院中心实验室(省级实验室)完成。取出生后3～7d的大鼠,通过大鼠眼外肌细胞的取材、分离、消化、培养等技术,观察细胞的形态、生长曲线、细胞融合率,观察大鼠眼外肌卫星细胞的增殖与分化能力,利用成肌细胞标记物α-横纹肌肌动蛋白、中间丝结蛋白免疫细胞化学染色对所获得的细胞进行鉴定。结果:①成肌细胞的生长情况:在生长培养基作用下,细胞增殖旺盛;在分化培养基条件下,细胞分化良好,可融合成肌管。②成肌细胞融合率:在24h和48h融合率提高明显,72h达高峰,之后不再变化。③细胞免疫化学检测结果:α-横纹肌肌动蛋白和中间丝结蛋白免疫细胞化学染色阳性。结论:体外培养的大鼠眼外肌卫星细胞具有良好的增殖与分化能力,其生物学特征同骨骼肌卫星细胞。     

Impact of cardiac resynchronization therapy on inflammatory biomarkers and cardiac remodeling: The paradox of functional and echocardiographic response

Introduction

Response to cardiac resynchronization therapy (CRT) can currently be assessed by clinical or echocardiographic criteria, and there is no strong evidence supporting the use of one rather than the other. Reductions in B-type natriuretic peptide (BNP) and C-reactive protein (CRP) have been shown to be associated with CRT response. This study aims to assess variation in BNP and CRP six months after CRT and to correlate this variation with criteria of functional and echocardiographic response.

Serological Profile of Pretransplantation Liver Patients

Introduction

A liver transplantation is the first choice of treatment for patients with hepatic insufficiency due to chronic diseases. Infections in the postoperative period represent one of the main causes of mortality in these cases. However, few articles have evaluated the predominance of certain infectious diseases and their influence on postoperative mortality.

Methods

We retrospectively evaluated the medical records of 236 patients who underwent liver transplantation from January 1997 to January 2007. In these records we checked the serological profiles for these diseases: toxoplasmosis, syphilis, human T lymphotropic virus (HTLV) I and II infection, Chagas disease, hepatitis A, hepatitis B, hepatitis C, paracoccidioidomycosis, tuberculosis, acquired immunodeficiency syndrome, cytomegalovirus (CMV), and mononucleosis (Epstein-Barr virus [EBV]). The statistical analysis was performed by table frequencies.

Results

CMV showed positivity (CMV-IgG) in 94.7% of patients, 95.8% for EBV, 33.3% for toxoplasmosis, 47.9% for hepatitis C, and 5% for hepatitis B.

Conclusion

Our analysis showed the importance of serological investigations and diagnostic examinations before the transplantation procedure, seeking to minimize possible reactivation of the disease after the use of immunosuppression drugs, particularly in the first 6 months after transplantation, or even to avoid a primary infection.     

Placebo effect in child and adolescent psychiatric trials

Much literature has been written in the field of child psychiatry regarding the placebo as a tool to test drug efficacy in clinical trials, but quite little regarding the placebo effect itself or its clinical use in child psychiatry. In this article, we aim to critically review the literature regarding the placebo effect in children and adolescents with mental disorders, focusing especially on factors influencing the placebo effect and how they may influence the interpretation of clinical trials. The placebo effect seems to be more marked in children than adults, and particularly in children and adolescents with depression, although it is pervasive across ages and is present in non-psychiatric conditions as well. The use of a placebo in clinical trials as a comparator with drugs that have moderate efficacy at most makes it difficult to obtain positive results, and much effort is needed to design very high quality clinical trials that may overcome the limitations of using a placebo. In addition, the placebo effect across ages and clinical conditions must be tested directly (compared with no treatment whenever possible), in order to characterise which placebos work for what and to determine their use in clinical settings.     

Nicotine withdrawal disrupts new contextual learning

Interactions between nicotine and learning could contribute to nicotine addiction. Although previous research indicates that nicotine withdrawal disrupts contextual learning, the effects of nicotine withdrawal on contextual memories acquired before withdrawal are unknown. The present study investigated whether nicotine withdrawal disrupted recall of prior contextual memories by examining the effects of nicotine withdrawal on recall of nicotine conditioned place preference (CPP) and contextual fear conditioning. C57BL/6J mice trained in CPP exhibited a significant preference for an initially non-preferred chamber that was paired with 0.35 mg/kg nicotine. Following CPP, mice were implanted with mini-osmotic pumps containing 6.3 mg/kg/d nicotine or saline. Pumps were removed twelve days later and nicotine CPP was retested 24 h later. Mice withdrawn from chronic nicotine exhibited CPP, suggesting that older drug-context associations are not disrupted by nicotine withdrawal. One hour later, the same mice were trained in contextual and cued fear conditioning; nicotine withdrawal disrupted contextual but not cued fear conditioning. A subsequent experiment demonstrated that nicotine withdrawal did not disrupt recall of contextual or cued fear conditioning when acquisition occurred before nicotine withdrawal. These data suggest that nicotine withdrawal disrupts new contextual learning, but does not alter contextual learning that occurred before withdrawal.     

Tobacco smoke affects expression of peroxisome proliferator-activated receptor-γ in monocyte/macrophages of patients with coronary heart disease

Background and purpose:

Tobacco smoke represents a relevant risk factor for coronary heart disease (CHD). Although peroxisome proliferator-activated receptor (PPAR)γ activation reduces inflammation and atherosclerosis, expression of PPARγ in cells and its modulation by smoking are poorly investigated. We previously reported that monocyte/macrophages from healthy smokers exhibited an enhanced constitutive expression of PPARγ. Here, we evaluated PPARγ expression and basal cytokine release in monocytes and monocyte-derived macrophages (MDMs) from 85 CHD patients, classified by their smoking habit (smokers, non-smokers and ex-smokers), and assessed the role of PPARγ ligands in this context.

Experimental approach:

PPARγ protein was detected by Western blot and semi-quantified by PPARγ/β-actin ratio; cytokine release was measured by elisa and nuclear factor-kappaB (NF-κB) translocation by electrophoretic mobility shift assays.

Key results:

As compared to the other groups, MDMs from smoker CHD patients exhibited a reduced PPARγ/β-actin ratio and an increased spontaneous release of tumour necrosis factor-α (TNF-α) and interleukin-6, but with no major variations in monocytes. In cells from selected CHD patients, rosiglitazone inhibited TNF-α release and NF-κB translocation induced by phorbol-12-myristate 13-acetate. The selective PPARγ antagonist GW9662 reversed these effects, with some variations related to smoking habit.

Conclusions and implications:

In CHD patients, exposure to tobacco smoke profoundly affected PPARγ expression, and this was related to levels of secretion of pro-inflammatory cytokines. MDMs from CHD smokers showed the lowest PPARγ expression and released more inflammatory cytokines. Moreover, rosiglitazone''s ability to inhibit cytokine release and its reversal by GW9662 clearly indicated PPARγ involvement in these changes in CHD patients.     

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research

Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.     

Circumvention of the multidrug-resistance protein (MRP-1) by an antitumor drug through specific inhibition of gene transcription in breast tumor cells

Multidrug-resistance protein 1 (MRP-1) confers resistance to a number of clinically important chemotherapeutic agents. The promoter of the mrp-1 gene contains an Sp1-binding site, which we targeted using the antitumor bis-anthracycline WP631. When MCF-7/VP breast cancer cells, which overexpress MRP-1 protein, were incubated with WP631 the expression of the multidrug-resistance protein gene decreased. Conversely, doxorubicin did not alter mrp-1 gene expression. The inhibition of gene expression was followed by a decrease in the activity of the MRP-1 protein. The IC(75) for WP631 (drug concentration required to inhibit cell growth by 75%) circumvented the drug-efflux pump, without addition of resistant modifiers. After treatment with WP631, MCF-7/VP cells were committed to die after entering mitosis (mitotic catastrophe), while treatment with doxorubicin did not affect cell growth. This is the first report on an antitumor drug molecule inhibiting the mrp-1 gene directly, rather than being simply a poor substrate for the transporter-mediated efflux. However, both situations appeared to coexist, thereby a superior cytotoxic effect was attained. Ours results suggest that WP631 offers great potential for the clinical treatment of tumors displaying a multidrug-resistance phenotype.     

Panniculitis–an unusual cutaneous manifestation of systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune systemic disease characterized by small vessel involvement that leads to tissue ischemia and fibroblast stimulation resulting in accumulation of collagen (fibrosis) in the skin and internal organs. Lipomembranous panniculitis is a peculiar type of fat necrosis and has been reported with clinical conditions, commonly with peripheral vascular diseases. We describe a case of a 43‐year‐old woman with SSc manifestations, who presented with black scaly skin plaques, associated with thickening of the subcutaneous fat tissue, on the lateral surface of her thighs, her calves, gluteal area and lower abdomen. Biopsy revealed lipomembranous panniculitis. Lipomembranous changes have been seen in connective tissue disorders such as lupus profundus, morphea, systemic sclerosis and panniculitis associated with dermatomyositis, but rarely in thighs, calves, gluteal area and lower abdomen. Almeida MSTM, Lima SCB, Carvalho LL, Almeida JVM, Santos LG, Rolim JRA, Rocha TE. Panniculitis–An unusual cutaneous manifestation of systemic sclerosis.