Inherited defects in lymphocyte cytotoxic activity

Summary: The granule-dependent cytotoxic activity of lymphocytes plays a critical role in the defense against virally infected cells and tumor cells. The importance of this cytotoxic pathway in immune regulation is evidenced by the severe and often fatal condition, known as hemophagocytic lymphohistiocytic syndrome (HLH) that occurs in mice and humans with genetically determined impaired lymphocyte cytotoxic function. HLH manifests as the occurrence of uncontrolled activation of T lymphocytes and macrophages infiltrating multiple organs. In this review, we focus on recent advances in the characterization of effectors regulating the release of cytotoxic granules, and on the role of this cytotoxic pathway in lymphocyte homeostasis and immune surveillance. Analysis of the mechanisms leading to the occurrence of hemophagocytic syndrome designates γ-interferon as an attractive therapeutic target to downregulate uncontrolled macrophage activation, which sustains clinical and biological features of HLH.     

„Mal’s Dir nicht schön“ – Hautkrebsprävention am Arbeitsplatz

Background

In Germany about 234,000 people are diagnosed with skin cancer annually. Despite the introduction of a skin cancer screening and broad educational campaigns the increasing number of new cases is challenging the sustainability of public health education on skin cancer.

Methods

In 2009 the cancer society NRW organized on behalf of the Regional Tax Office Rhineland (Rheinland OFD) a number of information sessions on skin cancer and its potential prevention and early detection as part of workplace health promotion. The lectures were given by specialists in the departments of the Regional Tax Office Rhineland during working hours.

Objective

The objective was to motivate the staff to participate in skin cancer screening. The results were evaluated by means of a digital questionnaire. Another objective was to assess the feasibility of the chosen event design.

Results

Approximately 5,000 staff members attended 132 information sessions over a period of nine months. 43.0?% of the participants answering the questionnaire intended to protect their skin against UV radiation more than before. 92.9?% considered a regular skin check. A change in behavior was apparent in solarium visitors. Forty-two percentage of the respondents indicated to have attended a skin cancer screening following the event. For 35?% the result of the screening was positive with 4?% showing a malignant lesion.

Conclusion

Uniform events for skin cancer prevention as part of workplace health promotion are practicable. An off-site coordinator proves to be essential. Due to the short duration of the project sustainability statements can be made for half a year only. A change in behavior is reflected in handling the risk factor of artificial UV radiation. Also sensitivity towards the prevention in the form of an informed decision on the (non-)participation in skin cancer is increased.     

Patients with metastatic breast cancer leading to CD4+ T cell lymphopaenia have poor outcome

BackgroundLow lymphocyte count is a prognostic factor in cancer patients including metastatic breast cancer patients (MBC) but the relative role of each lymphocyte subtype is unclear in MBC.MethodsThe impact of lymphocyte subsets was analysed in two prospective MBC patients’ cohorts. Cohort A patients (n = 103) were included before the first line of chemotherapy and cohort B patients (n = 101) were included after at least one line of chemotherapy. Extensive phenotypic analyses were performed on fresh whole blood. Plasma cytokines levels were measured using commercially available Luminex-based multiplex kits. Prognostic value of lymphocyte subsets and circulating cytokines was analysed.ResultsIn both cohorts, severe lymphopaenia (<0.7 Giga/L) correlated with poor overall survival (OS) (median OS: 6.6 months versus 21.7 months in cohort A and 4.5 versus 9 months in cohort B). CD8⁺, CD19⁺ and CD56⁺ T cell counts had no significant prognostic value for OS. After stratification (?0.2, [0.20–0.45], >0.45 Giga/L), CD4 lymphopaenia appeared to be correlated with poor OS in both cohorts. Furthermore, severe CD4⁺ lymphopaenia (?0.2 Giga/L) was strongly correlated with poor OS in both cohorts (1.2 months versus 24.9 months in cohort A and 5.7 versus 13.1 months in cohort B). In multivariate analysis, after stratification CD4⁺ lymphopaenia appeared to be an independent prognostic factor for OS in both cohorts. CD4⁺ lymphopaenia correlated with low plasmatic levels of CCL22 that might directly contribute to CD4⁺ lymphopaenia.ConclusionsCD4⁺ lymphopaenia was associated with reduced OS in MBC patients regardless of the chemotherapy line. Decreased levels of plasmatic CCL22 may contribute to CD4⁺ lymphopaenia.     

The Evaluation of Tools Used to Predict the Impact of Missense Variants Is Hindered by Two Types of Circularity

Prioritizing missense variants for further experimental investigation is a key challenge in current sequencing studies for exploring complex and Mendelian diseases. A large number of in silico tools have been employed for the task of pathogenicity prediction, including PolyPhen‐2, SIFT, FatHMM, MutationTaster‐2, MutationAssessor, Combined Annotation Dependent Depletion, LRT, phyloP, and GERP++, as well as optimized methods of combining tool scores, such as Condel and Logit. Due to the wealth of these methods, an important practical question to answer is which of these tools generalize best, that is, correctly predict the pathogenic character of new variants. We here demonstrate in a study of 10 tools on five datasets that such a comparative evaluation of these tools is hindered by two types of circularity: they arise due to (1) the same variants or (2) different variants from the same protein occurring both in the datasets used for training and for evaluation of these tools, which may lead to overly optimistic results. We show that comparative evaluations of predictors that do not address these types of circularity may erroneously conclude that circularity confounded tools are most accurate among all tools, and may even outperform optimized combinations of tools.     

The Spectrum of Renal Involvement in Patients With Inflammatory Myopathies

Data regarding the incidence and outcome of renal involvement in patients with inflammatory myopathies (IM) remain scarce. We assessed the incidence and causes of acute kidney injury (AKI) and chronic kidney disease (CKD) in 150 patients with dermatomyositis, polymyositis, and antisynthetase syndrome followed in 3 French referral centers. Renal involvement occurred in 35 (23.3%) patients: AKI in 16 (10.7%), and CKD in 31 (20.7%) patients. The main cause of AKI was drug or myoglobinuria-induced acute tubular necrosis. Male sex, cardiovascular risk factors, cardiac involvement, and initial proteinuria >0.3 g/d were associated with the occurrence of AKI. The outcome of patients with AKI was poor: 13 (81%) progressed to CKD and 2 (12.5%) reached end-stage renal disease. In multivariate survival analysis, age at IM onset, male sex, a history of cardiovascular events, and a previous episode of AKI were associated with the risk of CKD. We also identified 14 IM patients who underwent a kidney biopsy in 10 nephrology centers. Renal pathology disclosed a wide range of renal disorders, mainly immune-complex glomerulonephritis. We identified in 5 patients a peculiar pattern of severe acute renal vascular damage consisting mainly of edematous thickening of the intima of arterioles.We found that AKI and CKD are frequent in patients with IM. Prevention of AKI is crucial in these patients, as AKI is a major contributor to their relatively high risk of CKD. A peculiar pattern of acute vascular damage is part of the spectrum of renal diseases associated with IM.     

Determination of capillary hemoglobin levels using the HemoCue system in intensive care patients

Purpose

The study aimed to compare hemoglobin (Hb) values determined using the portable HemoCue system (HemoCue Hb 201+; HemoCue AB, Ängelholm, Sweden) with laboratory Hb level determination.

Materials and Methods

Adult patients hospitalized in our surgical intensive care unit who required an Hb level determination were included. To determine Hb level, one drop of arterial (A) or venous (V) blood was analyzed using HemoCue (HemoCue_[A/V]), and also with an automated analyzer in the laboratory (Hb reference method, or Hb Lab_[A/V]). Capillary blood (Cap) sample obtained simultaneously by fingerstick was analyzed using HemoCue (HemoCue_[Cap]). Factors that could interfere with the accuracy of fingerstick measurements were also studied. Paired Hb level measurements were compared by Bland and Altman analysis (Hb Lab_[A/V] vs HemoCue_[A/V] and HemoCue_[Cap]).

Results

One hundred fifty blood samples were obtained from 79 patients. The mean absolute differences between Hb Lab [A] and HemoCue [A], Hb Lab [V] and HemoCue [V] and Hb Lab [A/V] and HemoCue [Cap] were 0.1 g/dl (95% confidence interval, −1.9 to + 2.2 g/dl), 0.1 g/dl (95%CI, −2.5 to +2.6 g/dl) and 1.1 g/dl (95%CI, −3.6 to + 5.8 g/dl, respectively. Edema was the sole independent risk factor for discordance between HemoCue_[Cap] and Hb Lab_[A/V] (odds ratio, 6.65; 95% CI, 1.99-22.21; P < .001].

Conclusions

Hemoglobin level determination using HemoCue should not be used in critically patients, especially when capillary blood samples are used and/or in presence of edema.