Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis

Background  

Previously we reported that mice deficient in toll-like receptor 4 (TLR-4) signalling were protected from diet-induced non-alcoholic steatohepatitis (NASH). Another member of the toll-like receptor family, TLR-2, has been shown to play a role in lipid trafficking via uptake of diacylated lipoproteins. However, a role for TLR-2 in NASH has not been elucidated. The objectives of the current study were to examine the influence of dietary fat quality and TLR-2 on NASH pathogenesis.     

HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD

Although systemic lupus erythematosus (SLE) is a multigenic autoimmune disorder, HLA-D is the most dominant genetic susceptibility locus. This study was undertaken to investigate the hypothesis that microbial peptides bind HLA-DR3 and activate T cells reactive with lupus autoantigens. Using HLA-DR3 transgenic mice and lupus-associated autoantigen SmD protein, SmD_79-93 was identified to contain a dominant HLA-DR3 restricted T cell epitope. This T cell epitope was characterized by using a T-T hybridoma, C1P2, generated from SmD immunized HLA-DR3 transgenic mouse. By pattern search analysis, 20 putative mimicry peptides (P2-P21) of SmD_79-93, from microbial and human origin were identified. C1P2 cells responded to SmD, SmD_79-93 and a peptide (P20) from Vibro cholerae. Immunization of HLA-DR3 mice with P20 induced T cell responses and IgG antibodies to SmD that were not cross-reactive with the immunogen. A T-T hybridoma, P20P1, generated from P20 immunized mice, not only responded to P20 and SmD_79-93, but also to peptides from Streptococcus agalactiae (P17) and human-La related protein (P11). These three T cell mimics (P20, P11 and P17) induced diverse and different autoantibody response profiles. Our data demonstrates for the first time molecular mimicry at T cell epitope level between lupus-associated autoantigen SmD and microbial peptides. Considering that distinct autoreactive T cell clones were activated by different microbial peptides, molecular mimicry at T cell epitope level can be an important pathway for the activation of autoreactive T cells resulting in the production of autoantibodies. In addition, the novel findings reported herein may have significant implications in the pathogenesis of SLE.     

Van der Woude syndrome: dentofacial features and implications for clinical practice

Background:  Van der Woude syndrome (VWS) is the most common clefting syndrome in humans. It is characterized by the association of congenital lower lip fistulae with cleft lip and/or cleft palate. VWS individuals have a high prevalence of hypodontia. Although caused by a single gene mutation, VWS has variable phenotypic expression. This study aimed to describe the range of clinical presentations in 22 individuals with VWS to facilitate its diagnosis.
Methods:  A retrospective study of 22 patients with a diagnosis of VWS was undertaken at the Australian Craniofacial Unit (ACFU) in Adelaide. Three extended families with affected members were included in the study cohort.
Results:  The overall prevalence of lip pits in this study cohort was 86%. Cleft phenotypes included bilateral cleft lip and palate (32%); unilateral cleft lip and palate (32%); submucous cleft palate (23%); and isolated cleft hard and soft palate (9%). Missing permanent teeth were reported in 86% of affected individuals.
Conclusions:  Submucous cleft palate in VWS may go undiagnosed if the lower lip pits are not detected. Associated hypodontia and resultant malocclusions will also require management by a dental team.     

The impact of cytokines on the expression of drug transporters,cytochrome P450 enzymes and chemokine receptors in human PBMC

Background and purpose:

The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.

Experimental approach:

Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes.

Key results:

We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 ± 11961) and protein (% control 200 ± 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-γ (IFNγ) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNγ respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r² = 0.545).

Conclusions and implications:

These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.     

Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: a Pediatric Oncology Group Study

The immunophenotypes of lymphoblasts from children with newly diagnosed T-cell acute lymphoid leukemia (T-ALL, n = 101) or T-cell non-Hodgkin lymphoma (T-NHL, n = 31) were analyzed to correlate stage of thymocyte differentiation with clinical features and outcome. The 67 boys and 34 girls with T-ALL were 1 month to 18 years old (median, 8 years) with leukocyte counts ranging from 2 to 810 x 10(9)/L (median, 55 x 10(9)/L). Eighteen of these patients were black, and 70 had a mediastinal mass. Twenty-six boys and five girls with a median age of 9 years (range, 1 to 20 years) had T-NHL. Seven of these patients were black, and 24 had a mediastinal mass. The distributions of thymocyte developmental stages (early [CD7+], intermediate [CD1+ and/or CD4+ and/or CD8+], and mature [CD3+]) in cases of T-ALL and T-NHL were significantly different: 34%, 43%, and 23% v 6%, 62%, and 32% (P = .02). A comparison of the patients' clinical features according to the maturational stage of thymocytes failed to disclose significant differences in the majority of characteristics studied. However, patients with mature-stage T-NHL, with or without the addition of subjects with mature-stage T-ALL, were less likely to have a mediastinal mass (P = .02 for both comparisons). Those with intermediate-stage T-cell malignancy (T-ALL and T-NHL combined) were the subgroup most likely to have a mediastinal mass (P = .01). Response to remission induction therapy was significantly worse in the T-ALL subgroup with an early-stage phenotype: a failure rate of 21% v 0% and 6% for the two more differentiated phenotypic subgroups (P = .007). Event-free survival was not affected by thymocyte maturational stage in cases of either T-ALL or T-NHL. Despite evidence of clinical heterogeneity among the maturational stages of T-cell malignancies in children, these developmental subdivisions do not appear to be critical determinants of outcome once remission is achieved. We conclude that such phenotypes need not be included in the stratification plans for clinical trials using common induction treatment.     

氟尼辛葡甲铵的解热镇痛效应

目的:通过小白鼠醋酸扭体法、家兔蛋白胨致热法观察氟尼辛葡甲铵的解热、镇痛作用。方法:实验于2004-03/06在南京农业大学药理及毒理教研室实验室完成。①小鼠扭体实验:取清洁级KM小鼠80只按随机数字表法分为8组,每组10只:双氯芬酸钠16.25mg/kg组、安乃近32.5mg/kg组、氟尼辛葡甲铵10,5,2.5,1.25,0.625mg/kg组、生理盐水对照组。除双氯芬酸钠采取口服外,其余各组分别肌肉注射相应剂量的药品,生理盐水对照组给予等体积量的生理盐水。给药30min后立即给各组小鼠腹腔注射1.2%的冰醋酸溶液0.2mL/只,观察记录15min内出现扭体反应的次数。②蛋白胨致热实验:健康家兔36只,按随机数字表法分成6组,每组6只:空白对照组(生理盐水1mL/kg)、氟尼辛葡甲铵1,2,4mg/kg组、安乃近0.2g/kg组和氨基比林0.2g/kg组。实验前测定各组兔子的直肠体温。在家兔大腿肌肉注射40%蛋白胨,剂量为2mL/kg,然后按上述分组分别给予相应的药物。给药后8h内每小时各测体温1次。结果:80只小鼠和36只家兔均进入结果分析,中途无脱落。①与生理盐水对照组相比,安乃近32.5mg/kg组、氟尼辛葡甲铵10,5,2.5,1.25mg/kg组和双氯芬酸钠16.25mg/kg组对醋酸所致小鼠的扭体反应有显著的镇痛作用[(4.3±4.1),(10.4±5.7),(0.0±0.0),(0.9±1.9),(1.8±2.4),(3.2±4.2),(3.6±3.9)次/15min;P<0.05,P<0.01]。②与空白对照组比较,氟尼辛葡甲铵高、中剂量组及安乃近0.2g/kg组、氨基比林0.2g/kg组对由蛋白胨引起的家兔发热,在给药后4～8h均有显著的抑制作用(P<0.05),氟尼辛葡甲铵高、中剂量和安乃近0.2g/kg组在给药后6～8h作用极显著(P<0.01)。氟尼辛葡甲铵高剂量组在给药后5～7h显著强于安乃近0.2g/kg组(P<0.05),与氨基比林0.2g/kg组相比,差异极显著(P<0.01)。氟尼辛葡甲铵中剂量组作用稍逊于安乃近0.2g/kg组,差异不显著。氟尼辛葡甲铵低剂量组与氨基比林0.2g/kg组相当。结论:氟尼辛葡甲铵具有明显的解热、镇痛作用。     

Patellofemoral joint arthroplasty: patient selection,surgical technique and outcomes

Isolated patellofemoral arthritis is an increasingly recognized entity, and is usually associated with previous patellofemoral dysplasia or instability. Patellofemoral arthroplasty (PFA) has evolved significantly in recent years, both in terms of implant design and importantly in the understanding of appropriate patient selection. This review outlines the indications and investigations for PFA, provides a brief history of the development of contemporary implants, and presents the clinical outcomes for the prostheses most commonly used in the UK. In addition, it provides a detailed surgical technique for implantation of an onlay implant, with tips on how to optimize patellofemoral biomechanics and thus achieve a consistently good outcome.