Cellular‐FLIP,Raji isoform (c‐FLIPR) modulates cell death induction upon T‐cell activation and infection

Dysregulation of apoptosis caused by an imbalance of pro‐ and anti‐apoptotic protein expression can lead to cancer, neurodegenerative, and autoimmune diseases. Cellular‐FLIP (c‐FLIP) proteins inhibit apoptosis directly at the death‐inducing signaling complex of death receptors, such as CD95, and have been linked to apoptosis regulation during immune responses. While the isoforms c‐FLIP_L and c‐FLIP_S are well characterized, the function of c‐FLIP_R remains poorly understood. Here, we demonstrate the induction of endogenous murine c‐FLIP_R in activated lymphocytes for the first time. To analyze c‐FLIP_R function in vivo, we generated transgenic mice expressing murine c‐FLIP_R specifically in hematopoietic cells. As expected, lymphocytes from c‐FLIP_R transgenic mice were protected against CD95‐induced apoptosis in vitro. In the steady state, transgenic mice had normal cell numbers and unaltered frequencies of B cells and T‐cell subsets in lymphoid organs. However, when challenged with Listeria monocytogenes, c‐FLIP_R transgenic mice showed less liver necrosis and better bacterial clearance compared with infected wild‐type mice. We conclude that c‐FLIP_R expression in hematopoietic cells supports an efficient immune response against bacterial infections.     

Microstructure and long-term stability of solder joints on nickel-plated aluminium formed during short soldering times

Within this work, we demonstrate that an easy soldering process in combination with wet chemical coating is suitable to realize a strong and reliable solder interconnection of Al substrates, even at short soldering times <5 s in ambient air. The microstructure of solder joints on wet chemically treated aluminum foils is investigated. A single and double zincate pre-treatment are compared to activate the Al surface, followed by electroless Ni plating. The quality of the solderable Ni surface is characterized by contact angle measurements, yielding good wettability (<60°), which is also achieved after isothermally heating (250 °C) the Ni-coated Al foils for 100 min. The microstructure of the Sn62Pb36Ag2 solder joints is investigated by SEM and EDX of cross sections, directly after soldering as well as after isothermal aging at 85 °C. Under the used soldering conditions, with a soldering temperature at about 280 °C, diffusion zones <500 nm were identified. Nonetheless, high peel forces after soldering >5 N mm⁻¹ show stable values under aging conditions of 85 °C for 1000 hours. This could be correlated to a mixed fracture pattern, promoting the high adhesion due to the absence of a dominant failure mechanism.

High mechanical reliability of tin-based solder joints processed by joining copper and nickel-coated aluminium with short soldering times in ambient air.     

Inhibition of interferon γ induced interleukin 12 production: A potential mechanism for the anti-inflammatory activities of tumor necrosis factor

Inflammation is associated with production of cytokines and chemokines that recruit and activate inflammatory cells. Interleukin (IL) 12 produced by macrophages in response to various stimuli is a potent inducer of interferon (IFN) γ production. IFN-γ, in turn, markedly enhances IL-12 production. Although the immune response is typically self-limiting, the mechanisms involved are unclear. We demonstrate that IFN-γ inhibits production of chemokines (macrophage inflammatory proteins MIP-1α and MIP-1β). Furthermore, pre-exposure to tumor necrosis factor (TNF) inhibited IFN-γ priming for production of high levels of IL-12 by macrophages in vitro. Inhibition of IL-12 by TNF can be mediated by both IL-10-dependent and IL-10-independent mechanisms. To determine whether TNF inhibition of IFN-γ-induced IL-12 production contributed to the resolution of an inflammatory response in vivo, the response of TNF^+/+ and TNF^−/− mice injected with Corynebacterium parvum were compared. TNF^−/− mice developed a delayed, but vigorous, inflammatory response leading to death, whereas TNF^+/+ mice exhibited a prompt response that resolved. Serum IL-12 levels were elevated 3-fold in C. parvum-treated TNF^−/− mice compared with TNF^+/+ mice. Treatment with a neutralizing anti-IL-12 antibody led to resolution of the response to C. parvum in TNF^−/− mice. We conclude that the role of TNF in limiting the extent and duration of inflammatory responses in vivo involves its capacity to regulate macrophage IL-12 production. IFN-γ inhibition of chemokine production and inhibition of IFN-γ-induced IL-12 production by TNF provide potential mechanisms by which these cytokines can exert anti-inflammatory/repair function(s).     

In Vitro Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates.     

Biometrical analysis of the shoulder joint regarding glenoid implant dimensions for arthroplasty

Purpose

Reduced bone stock and difficult intraoperative orientation are challenges in glenoid replacement surgery. New implant designs and methods for fixation, such as locking screws, extra-long central pegs and/or central compression screws are targeting these issues. The objective of this study is the analysis of the glenoid dimension regarding maximum central peg diameter and peg length (PL), and maximum screw length (SL) for glenoid fixation.

Methods

Retrospective analysis of magnetic resonance imaging (n = 50) scans. Measurement of the maximum inferior glenoid diameter (GD), SL, maximum length of a 9.9, 10 and 11.4 mm central peg (PL) in the transverse plane; glenoid version (GV), humeral head diameter (HHD). Two independent measurements.

Results

Mean age: 49.0 ± 15.7 years (17–80) (n = 20 female, 49.6 ± 16.0; n = 30 male, 48.6 ± 15.7). Mean values of measurement were GD: 28.9 ± 3.7 mm (21–39); SL: 34.1 ± 4.9 mm (26–44); PL 9.9 mm: 19.4 ± 4.3 mm (9–30); PL 10 mm: 19.0 ± 4.4 mm (8–30); PL 11.4 mm: 16.5 ± 4.1 mm (7–26) with significant gender differences (p = 0.001; p = 0.022; p = 0.001); GV: ?0.6° ± 4.9° (?10 to 11); HHD: 50.0 mm ± 4.9 (41–61). There was good correlation between PL and SL (r = 0.32, p = 0.024) and for GD and PL (r = 0.61, p = 0.001; r = 0.57, p = 0.001; r = 0.96, p = 0.001). The ratio of HHD and GD was very constant with 0.6 ± 0.07.

Conclusions

These data indicate the high interindividual variability of glenoid morphology including significant gender-related differences. The good correlation between humeral head size and GD and maximum central PL can be helpful for cases with reduced bone stock in decision-making about implant size and bone grafting.     

Efficacy of SpyGlass~(TM)-directed biopsy compared to brush cytology in obtaining adequate tissue for diagnosis in patients with biliary strictures

AIM: To evaluate the diagnostic yield(inflammatory activity) and efficiency(size of the biopsy specimen) of SpyGlassTM-guided biopsy vs standard brush cytology in patients with and without primary sclerosing cholangitis(PSC).METHODS: At the University Medical Center Mainz, Germany, 35 consecutive patients with unclear biliarylesions(16 patients) or long-standing PSC(19 patients) were screened for the study. All patients underwent a physical examination, lab analyses, and abdominal ultrasound. Thirty-one patients with non-PSC strictures or with PSC were scheduled to undergo endoscopic retrograde cholangiography(ERC) and subsequent per-oral cholangioscopy(POC). Standard ERC was initially performed, and any lesions or strictures were localized. POC was performed later during the same session. The Boston Scientific SpyGlass SystemTM(Natick, MA, United States) was used for choledochoscopy. The biliary tree was visualized, and suspected lesions or strictures were biopsied, followed by brush cytology of the same area. The study endpoints(for both techniques) were the degree of inflammation, tissue specimen size, and the patient populations(PSC vs non-PSC). Inflammatory changes were divided into three categories: none, low activity, and high activity. The specimen quantity was rated as low, moderate, or sufficient.RESULTS: SpyGlassTM imaging and brush cytology with material retrieval were performed in 29 of 31(93.5%) patients(23 of the 29 patients were male). The median patient age was 45 years(min, 20 years; max, 76 years). Nineteen patients had known PSC, and 10 showed non-PSC strictures. No procedure-related complications were encountered. However, for both methods, tissues could only be retrieved from 29 pa-tients. In cases of inflammation of the biliary tract, the diagnostic yield of the SpyGlassTM-directed biopsies was greater than that using brush cytology. More tissue material was obtained for the biopsy method than for the brush cytology method(P = 0.021). The biopsies showed significantly more inflammatory characteristics and greater inflammatory activity compared to the cy-tological investigation(P = 0.014). The greater quantity of tissue samples proved useful for both PSC and non-PSC patients.CONCLUSION: SpyGlassTM imaging can be recom-mended for proper inflammatory diagnosis in PSC pa-tients. However, its value in diagnosing dysplasia wasnot addressed in this study and requires further investi-gation.