Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus‐prone mice

Objective

Spleen tyrosine kinase (Syk) is involved in membrane‐mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB × NZW)F₁ lupus‐prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus‐prone mice and whether they result in improvement in skin disease and modification of established disease.

Methods

Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow.

Results

We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks.

Conclusion

Syk inhibition suppresses the development of lupus skin and kidney disease in lupus‐prone mice, suppresses established disease in lupus‐prone mice, and may represent a valuable treatment for patients with SLE.

     

Nurse staffing levels and hospital mortality in critical care settings: literature review and meta-analysis

AIM: This paper reports a review of the literature on the association between critical care nurse staffing levels and patient mortality. BACKGROUND: Statistically significant inverse associations between levels of nurse staffing and hospital mortality have not been consistently found in the literature. Critical care settings are ideal to address this relationship due to high patient acuity and mortality, high intensity of the nursing care required, and availability of individual risk adjustment methods. METHODS: Major electronic databases were searched, including MEDLINE, EMBASE, and the Cumulative Index of Nursing and Allied Health Literature. The search terms included critical/intensive care, quality of health care, mortality/hospital mortality, personnel staffing and scheduling, and nursing staff (hospital). Only papers published in English were included. The original search was conducted in 2002 and updated in 2005. RESULTS: Nine studies were selected from 251 references screened. All nine were observational. Six were conducted in the United States of America, one in Austria, one in Brazil, and one in Scotland. The unadjusted risk ratio of nurse staffing (high vs. low) on hospital mortality were combined meta-analytically (five studies). The pooled estimate was 0.65 (95% confidence interval 0.47-0.91). However, after adjusting for various covariates within each study, the individually reported associations between high nurse staffing and low hospital mortality became non-significant in all but one study. CONCLUSION: The impact of nurse staffing levels on patients' hospital mortality in critical care settings was not evident in the reviewed studies. Methodological challenges that might have impeded correct assessment of the association include measurement problems in exposure status and confounding factors, often uncontrolled. The lack of association also indicates that hospital mortality may not be sensitive enough to detect the consequences of low nurse staffing levels in critical care settings.     

氟康唑与玉屏风散对小鼠深部白色念珠菌感染的干预作用

目的 探讨氟康唑与玉屏风散对深部白色念珠菌感染的疗效.方法 建立小鼠深部白色念珠菌病模型,观察氟康唑与玉屏风散对小鼠生存时间、小鼠腹腔巨噬细胞吞噬白色念珠菌的吞噬率(pp)及血清内一氧化氮(NO)、肿瘤坏死因子(TNF-α)含量的变化.结果 在非免疫抑制状态下,氟康唑组联合治疗组小鼠生存时间分别为(9.10±1.43)d、(9.20±1.62)d,与模型组[(8.00±1.63)d]比较,差异均有统计学意义(P均＜0.05).玉屏风散组血清中NO、TNF-α、pp含量分别为(90.00±4.50) μmol/L(0.52±0.05) nmol/L、(40.20±2.60)％,联合治疗组分别为(89.90±4.20) μmol/L、(0.45±0.05)nmo1/L、(40.50±2.50)％,与模型组[分别为(93.10±3.50) μmol/L、(3.98±0.31) nmol/L、(38.50±2.30)％]比较差异均有统计学意义(P均＜0.05).在免疫抑制状态下,玉屏风散组小鼠生存时间以及血清中NO、TNF-α pp含量分别为(7.90±1.86)d、(83.90±4.10) μmol/L、(0.72±0.05) nmol/L、(39.90±2.80)％,联合治疗组分别为(8.4±1.91)d、(83.50±4.20)μmol/L、(0.52±0.04) nmol/L、(39.20±1.90)％,与模型组(分别为(6.40±1.90)d、(86.60±3.80) μmol/L、(4.22±0.23) nmol/L、(25.30±2.30)％)比较,差异均有统计学意义(P均＜0.05).结论 玉屏风散与氟康唑合用对深部白色念珠菌感染的治疗有协同作用,可能与玉屏风散调节机体免疫、平衡体内炎症介质有关.     

Social workers’ perceptions of barriers to interpersonal therapy implementation for treating postpartum depression in a primary care setting in Israel

Research on evidence‐based practice (EBP) implementation in social work often neglects to include evaluation of application barriers. This qualitative study examined social workers’ perspectives of provider‐ and organisational‐related barriers to implementing a brief eight‐session interpersonal therapy (IPT) intervention, a time‐limited EBP that addresses reducing depressive symptoms and improving interpersonal functioning. Implementation took place in a primary care setting in Israel and was aimed at treating women who have postpartum depression (PPD) symptoms. Using purposeful sampling, 25 primary care licensed social workers were interviewed between IPT training and implementation regarding their perceived barriers to implementing IPT in practice. Data analysis was facilitated using a phenomenological approach, which entails identifying the shared themes and shared experiences of research participants regarding barriers to implementing IPT. Three themes emerged from the analysis of interviews: Perceived lack of flexibility of IPT intervention in comparison with more familiar methods social workers previously applied, specifically regarding the number of sessions and therapeutic topics included in the IPT protocol; insecurity and hesitance to gain experience with a new method of intervention; and organisational barriers, including difficulties with referrals, the perception of HMOs as health facilities not suitable for therapy, and time constraints. Addressing perceived barriers of social workers toward implementing EBPs, such as IPT for postpartum depression, during the training phase is crucial for enabling appropriate implementation. Future training should include examining practitioners’ attitudes toward implementation of EBPs, as part of standardised training protocols.     

Primary effusion lymphoma presenting as a cutaneous intravascular lymphoma

Primary effusion lymphoma (PEL) is a rare and aggressive lymphoma that arises in the context of immunosuppression and is characterized by co‐infection with Epstein–Barr virus (EBV) and human herpesvirus‐8/Kaposi sarcoma‐associated herpesvirus (HHV‐8/KSHV). It was originally described as arising in body cavity effusions, but presentation as a mass lesion (extracavitary PEL) is now recognized. Here, we describe a case of PEL with an initial presentation as an intravascular lymphoma with associated skin lesions. The patient was a 53‐year‐old man with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) who presented with fevers, weight loss and skin lesions concerning for Kaposi sarcoma (KS). A skin biopsy revealed no evidence of KS; however, dermal vessels contained large atypical cells that expressed CD31 and plasma cell markers but lacked most B‐ and T‐cell antigens. The atypical cells expressed EBV and HHV‐8. The patient subsequently developed a malignant pleural effusion containing the same neoplastic cell population. The findings in this case highlight the potential for unusual intravascular presentations of PEL in the skin as well as the importance of pursuing microscopic diagnosis of skin lesions in immunosuppressed patients.     

Effects of the organophosphate insecticides phosmet and chlorpyrifos on trophoblast JEG-3 cell death,proliferation and inflammatory molecule production

Epidemiological data have associated environmental organophosphate insecticide (OP) exposure during pregnancy with fetal growth deficits. To better understand OP injury that may adversely affect pregnancy, we used the JEG-3 choriocarcinoma cell line, which provide a recognized in vitro model to study placental function. The effects of the OP phosmet (Pm) and chlorpyrifos (Cp) on JEG-3 cells viability, proliferation, cell cycle and inflammatory molecule production were evaluated. Both insecticides affected cellular viability in a concentration- and time-dependent manner, inducing apoptosis and decreasing [³H]-thymidine incorporation. However, only Pm reduced DNA synthesis independently of cellular death and decreased the cell percentage at the S-phase. Unlike apoptosis, TNFα production varied with the concentration tested, suggesting that other TNFα independent mechanisms might trigger cell death. No induction of the inflammatory molecule nitric oxide was detected. The mRNA levels of pro-inflammatory IL-6, IL-17 and the anti-inflammatory IL-13 cytokines were differentially modulated. These findings show that Pm and Cp generate a specific toxicity signature, altering cell viability and inducing an inflammatory cytokine profile, suggesting that trophoblasts may represent a possible target for OP adverse effects.