A diagnostic delay of several years in primary Sj02gren's syndrome is common, even in patients who present with sicca symptoms. It is much more likely in cases with prominent symptomatic extraglandular involvement. We report on three such patients who presented as Coomb's positive haemolytic anaemia, systemic symptoms with agranulocytosis and gingival bleeding due to immune thrombocytopenia, to alert clinicians to the fact that primary Sj02gren's syndrome may present as clinically significant immune-mediated cytopenia in the absence of sicca symptoms. Sj02gren's syndrome, a common autoimmune disorder, should be considered in the differential diagnosis of apparently 'idiopathic' cytopenias and actively sought by directed history, Schirmer test and autoantibody screening.

There is evidence showing the importance of reaching immunosuppressant target concentrations as soon as possible. The aim of this study was to evaluate the relationship between tacrolimus trough concentrations within the first week after transplantation and the rate of acute rejection. In this descriptive-analytic study, we included 57 renal transplant patients receiving tacrolimus as the primary immunosuppressive drug. After univariate analysis, donor age, duration of hospital stay, and creatinine clearance (third month) showed significant differences between rejecters and nonrejecters. In addition, mean tacrolimus trough concentrations on day 5, day 7, mean of days 1-7, and mean of days 5-7 were found to be significantly lower in rejecters (P = 0.009, P = 0.012, P = 0.006, and P = 0.035, respectively). Receiver operating characteristic curve analysis with tacrolimus trough concentrations measured on days 5 and 7 was able to discriminate between patients with and without acute rejection (P = 0.028 and P = 0.048 after Bonferroni correction). The tacrolimus trough concentration with the best sensitivity-specificity balance was 9.3 ng/mL on day 5 and 8.7 ng/mL on day 7. In the Kaplan-Meier analysis, patients with tacrolimus trough concentrations below 9.3 mg/mL on day 5 showed a lower survival time without acute rejection (P = 0.048 after correction) in comparison with patients with tacrolimus trough concentrations above this concentration. After logistic regression, we obtained a model relating rejection with sex, donor age, and tacrolimus trough concentrations on day 5 (P = 0.004). No significant relationship between tacrolimus trough concentrations and delta creatinine clearance from week 1 to month 3 was obtained. These results confirm that tacrolimus trough concentrations during the first week are an important predictor of acute rejection. Therefore, it is critical to reach target blood concentrations of tacrolimus as soon as possible to improve allograft survival.

Immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) inhibit cytokine production by activated lymphocytes through interfering with calcineurin. However, little is known about their effects on the function of nonlymphoid cells. We found that, in renal tubular cells, induction of MCP-1 by inflammatory cytokines was blunted by CsA and FK506. This suppression was correlated with induction of unfolded protein response (UPR) evidenced by endogenous and exogenous indicators. The induction of UPR by these agents was reversible and observed generally in other nonimmune cells. Furthermore, administration with CsA in reporter mice caused rapid, systemic induction of UPR in vivo. In TNF-alpha-treated cells, suppression of MCP-1 by CsA or FK506 was associated with blunted responses of NF-kappaB, the crucial regulator of MCP-1. The suppression of NF-kappaB was reproduced by other inducers of UPR including AB(5) subtilase cytotoxin, tunicamycin, thapsigargin, and A23187. CsA and FK506, as well as other UPR inducers, caused up-regulation of C/EBP family members, especially C/EBPbeta and CHOP (C/EBP homologous protein), and overexpression of either C/EBPbeta or CHOP significantly attenuated TNF-alpha-triggered NF-kappaB activation. Furthermore, down-regulation of C/EBPbeta by small interfering RNA substantially reversed the suppressive effect of CsA on TNF-alpha-induced MCP-1 expression. These results suggested that CsA and FK506 confer insensitiveness to TNF-alpha on resident cells through UPR-dependent induction of the C/EBP family members.

目的 明确抗血小板抗体在系统性红斑狼疮(SLE)血小板减少患者中的临床意义.方法 采用改良抗原捕获酶联免疫吸附试验(ELISA)法检测抗血小板抗体(抗GPⅡb/Ⅲa、GPⅠb/Ⅸ、GPⅠa/Ⅱa、GPⅣ抗体),分别比较治疗前 SLE血小板减少与SLE非血小板减少患者抗血小板抗体的阳性率、SLE血小板减少患者治疗前后抗血小板抗体的阳性率、SLE血小板减少治疗前患者病情与 抗血小板抗体的关联性.统计方法采用秩和检验和x2检验.结果 治疗前SLE血小板减少组抗GPⅡb/Ⅲa抗体、抗GP Ⅰb,Ⅸ抗体阳性率分别为50%、67%.非血小板减少组阳性率分别为11%、28%,2组间阳性率差异有统计学意义(P＜0.05);治疗后SLE血小 板减少组抗GPⅡb/Ⅲa抗体、抗GP Ⅰb/Ⅸ抗体阳性率分别为6%、28%,较治疗前显著降低(P＜0.05);SLE血小板减少组治疗前抗GPⅡb/Ⅲa抗体、抗GP Ⅰb/Ⅸ抗体之间显著关联,该2种抗体均与SLEDAI评分有显著关联性,与抗核抗体、抗双链DNA(dsDNA)抗体、抗中性粒细胞胞质抗体 (ANCA)则无显著关联;各组间未检测出抗GPⅣ和GPⅠa/Ⅱa抗体.结论 抗GPⅡb/Ⅲa、GPⅠb/Ⅸ抗体在病情活动SLE血小板减少患者中表达显著升高,与SLE血小板减少病情发生发展和转归相关.

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients.Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates.Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 鈥榓cceptable鈥 ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

Background In workplace health promotion, all potential resources needs to be taken into consideration, not only factors relating to the absence of injury and the physical health of the workers, but also psychological aspects. A dynamic balance between the resources of the individual employees and the demands of work is an important prerequisite. In the home care services, there is a noticeable trend towards increased psychosocial strain on employees at work. There are a high frequency of work-related musculoskeletal disorders and injuries, and a low prevalence of sustainable work ability. The aim of this research was to identify factors promoting work ability and self-efficacy in care aides and assistant nurses within home care services. Methods This study is based on cross-sectional data collected in a municipality in northern Sweden. Care aides (n = 58) and assistant nurses (n = 79) replied to a self-administered questionnaire (response rate 46%). Hierarchical multiple regression analyses were performed to assess the influence of several independent variables on self-efficacy (model 1) and work ability (model 2) for care aides and assistant nurses separately. Results Perceptions of personal safety, self-efficacy and musculoskeletal wellbeing contributed to work ability for assistant nurses (R 2 adj of 0.36, p < 0.001), while for care aides, the safety climate, seniority and age contributed to work ability (R 2 adj of 0.29, p = 0.001). Self-efficacy was associated with the safety climate and the physical demands of the job in both professions (R 2 adj of 0.24, p = 0.003 for care aides), and also by sex and age for the assistant nurses (R 2 adj of 0.31, p < 0.001). Conclusions The intermediate factors contributed differently to work ability in the two professions. Self-efficacy, personal safety and musculoskeletal wellbeing were important for the assistant nurses, while the work ability of the care aides was associated with the safety climate, but also with the non-changeable factors age and seniority. All these factors are important to acknowledge in practice and in further research. Proactive workplace interventions need to focus on potentially modifiable factors such as self-efficacy, safety climate, physical job demands and musculoskeletal wellbeing.

AbstractBackground/Aims: The purpose of this study was to examine whether tacrolimus is effective and safe, and to determine the optimal dose of tacrolimus for maintenance treatment in patients with lupus nephritis (LN). Methods: A total of 17 adult patients (1 man and 16 women) with LN were enrolled. Tacrolimus was initiated at a dose of 3 mg/day which was administered once per day after the evening meal. Prospective data on renal response and serologic lupus activity were collected and followed for a year. Results: Mean age at baseline was 48.8 &plusmn; 12.6 years (range 31&ndash;72 years). The mean urinary protein/creatinine ratio significantly decreased from 1.14 &plusmn; 1.74 at baseline to 0.23 &plusmn; 0.47 at 1 year (p &lt; 0.05). Mean serum C3 significantly increased from 73.0 &plusmn; 12.3 mg/dl at baseline to 84.7 &plusmn; 12.2 mg/dl at 1 year (p &lt; 0.01). Mean serum creatinine levels were unchanged after tacrolimus treatment. The mean blood concentration of tacrolimus was 3.9 &plusmn; 2.1 ng/ml. There was no relationship between the incidence of adverse effects and blood tacrolimus level. Conclusion: Our results suggest tacrolimus to be potentially effective and safe for maintenance treatment in patients with LN.Copyright &copy; 2009 S. Karger AG, Basel

To prospectively evaluate the safety of tacrolimus in active rheumatoid arthritis (RA) in elderly patients with insufficient response to disease-modifying antirheumatic drugs (DMARDs). Fifty-seven patients aged > or =65 yr with RA for > or =6 months were enrolled in an open-label, non-controlled study. All DMARDs were discontinued and tacrolimus was administered orally once daily after the evening meal for 28 weeks. Tacrolimus, initiated at 1.5 mg/day, was increased to 3 mg/day after 6 weeks if no abnormal changes developed. Existing NSAID and oral corticosteroid (< or =7.5 mg/day prednisolone equivalent) therapy could be continued during the study. Safety was evaluated as clinical symptoms, abnormal changes in laboratory values and the development of infection. Treatment response was determined using the American College of Rheumatology (ACR) criteria for improvement. Whole blood concentrations of tacrolimus 12 h after administration were measured by high-performance liquid chromatography and tandem mass spectrometry. Clinical adverse events developed in 25 patients (46.3%). Abnormal changes in laboratory values occurred in 25 patients (46.3%). Ten patients (18.5%) developed infection. An ACR20 response was achieved by 50.0% of efficacy-evaluable patients and ACR20 success rates (the proportion of patients achieving ACR20 response and completing the study) was 46.3%. The ACR50 response rate was 18.5% of evaluable patients. Mean blood concentration of tacrolimus was 3.3 and 5.3 ng/ml in patients receiving 1.5 and 3.0 mg daily, respectively. No relationship between its concentration and adverse reactions was observed. In elderly patients with insufficient response to DMARD therapy, tacrolimus at 1.5-3.0 mg/day is safe and well-tolerated and provides clinical benefit.

The arrival of tacrolimus has drastically improved AALDLT recipients' survival. However, little data of tacrolimus have been reported concerning its effects on lipid metabolism for AALDLT recipients.Out aim was to investigate the relationship between tacrolimus blood concentration and lipid metabolism in AALDLT recipients.The pre and postoperative data of 77 adult patients receiving AALDLT between 2002 and December 2007 were retrospectively reviewed. The postoperative immune suppressive regimen was prednisone with tacrolimus ± mycophenolate mofetil. Prednisone was withdrawn within the first postoperative month. Blood lipids and tacrolimus concentration were detected at the first, third, and sixth month during follow-up. Episodes of acute rejection were diagnosed based on biopsy.Overall prevalence of post-transplantation hyperlipidemia was 29.9% (23/77) at the sixth postoperative month. The patients were divided into two groups, the hyperlipidemia group and the ortholipidemia group. In the 23 patients with hyperlipidemia, 15 (65%) were hypercholesterolemia, five (22%) were hypertriglyceridemia, and three (13%) patients had both hypercholesterolemia and hypertriglyceridemia. In univariate analysis, only tacrolimus blood concentration at the third and sixth post-transplantation months showed significant difference (8.7 ± 2.1 vs. 6.9 ± 3.2, p = 0.013; 9.2 ± 2.7 vs. 7.3 ± 3.8, p = 0.038, respectively). In multivariate logistic analysis, only two factors appear to be risk factors, namely, tacrolimus blood concentration at the third and sixth post-transplantation months (8.7 ± 2.1 vs. 6.9 ± 3.2, p = 0.043; 9.2 ± 2.7 vs. 7.3 ± 3.8 p = 0.035, respectively).Higher tacrolimus blood concentration was related to hyperlipidemia at an early postoperative period. This indicates that tacrolimus blood concentration should be controlled as low as possible in the premise that there is no risk of rejection to minimize post-transplant hyperlipidemia after AALDLT.

<strong>目的:</strong>观察服用他克莫司(Tacrolimus)的肾移植受者<em>ABCB1</em>基因多态性对于术后感染发生的影响。<strong>方法:</strong>选取行肾移植手术并服用他克莫司的患者90例,根据术后是否存在感染分为感染组和对照组,检测所有患者的<em>ABCB1</em>基因型3435C&gt;T,1236C&gt;T和2677G&gt;A/T。采用<em>&chi;</em>²检验,方差分析和独立样本<em>T</em>检验的方法对患者的基本临床资料进行检验。采用卡方检验比较感染组和未感染组的基因多态性频率分布差异。<strong>结果:</strong>患者C1236T,C3435T,G2677A/T等位基因频率,均符合Hardy-Weinberg平衡。感染组和非感染组患者的年龄,性别,体质量,临床诊断,吗替麦考酚酯(Mycophenolate Mofetil)的用量均没有显著性差异。2组患者的平均血药谷浓度在一年内均无统计学差异。C1236T单核苷酸多态性对肾移植术后感染发生的影响具有统计学意义(<em>P</em>=0.034)。G2677A/T突变的发生对肾移植术后感染发生的影响具有统计学意义(<em>P</em>=0.010)。<strong>结论:</strong><em>ABCB1</em>基因多态性中,仅C1236T的SNP多态性与G2677A/T的突变对肾移植术后感染发生的影响具有统计学意义。