Functional analysis of α1β1 integrin in human natural killer cells

Upon activation with interleukin (IL)-2 human natural killer (NK) cells acquire on their surface the α1β1 and α2β1 integrins and down-regulate the expression of α6β1. By employing α1β1-specific monoclonal antibody (mAb) HP-2B6, characterized in our laboratory, we examined the functional role of the α1β1 integrin in NK cells. Treatment with HP-2B6 mAb partially interfered with attachment of cultured NK cells to type I collagen, and combined with an anti-α2β1 (TEA 1/41) mAb, it completely abrogated cell adhesion to this extracelular matrix protein. In contrast, NK cell attachment to laminin was completely blocked by the anti-β1 LIA 1/2 mAb, but was unaffected by α1 and α2-specific mAb; as α3β1 and α6β1 were undetectable, the data indicate that the α1β1 integrin binding sites for type I collagen and laminin are different. Incubation with anti-α1 HP-2B6 or its F(ab')₂ fragments specifically induced a rapid homotypic aggregation of NK cells that was dependent on active metabolism, an intact cytoskeleton and the presence of divalent cations (Ca²⁺ and Mg²⁺); homotypic cell adhesion was selectively blocked by anti-CD18, CD11a or CD54 mAb. In addition, stimulation of cultured NK cells with the anti-α1 HP-2B6 enhanced TNF-α production and induced tyrosine phosphorylation of a 110-kDa protein. Pretreatment with specific inhibitors of protein tyrosine kinase (PTK) activity (tyrphostin 25 and herbimycin A) completely abrogated the functional effects induced by the anti-α1 HP-2B6 mAb. Our data show that ligation of the α1β1 integrin positively modulates IL-2-activated NK cell function via a PTK-dependent pathway.     

Tyrosine kinase-dependent activation of human NK cell functions upon triggering through CD44 receptor

We recently showed evidence of CD44-mediated enhancement of natural killer (NK) cell cytotoxic activity and induction of intracellular Ca²⁺ flux. In this study, we evaluated whether CD44 plays a stimulatory role in NK cell functions, such as cytokine production and activation antigen expression. Our results indicate that ligation of the CD44 receptor results in the induction of expression of the CD69 surface activation antigen as well as in the enhancement of phorbol ester-induced TNF-α secretion. We report also evidence for the coupling of CD44 receptor to a protein tyrosine kinase(s) pathway. CD44 engagement rapidly stimulates the tyrosine phosphorylation of several cellular substrates. Pretreatment of NK cells with the tyrosine kinase inhibitor herbimycin A resulted in marked decrease of CD44-stimulated phosphorylation, indicating that it activates tyrosine kinase(s). Furthermore, the drug also prevents CD44-mediated TNF-α production and CD69 expression. These findings indicate that protein tyrosine phosphorylation is an early and critical event in CD44-mediated activation of NK cell functions.     

An evaluation of the effects of susceptibility changes on the water chemical shift method of temperature measurement in human peripheral muscle

Divergencies between chemical shift measurements of temperature and directly measured values using optical sensors have been studied in vivo in human peripheral muscle with the assistance of a variety of experimental and theoretical techniques. These include the modeling of both thermal and susceptibility changes using two- and three-dimensional finite element methods, as well as the use of multi-wavelength near infrared observations. The conclusion of these studies is that a simple temperature calibration is not accessible, with results affected by the complex response of the tissue itself.     

Pilot Study to Quantify Palladium Impurities in Lead-like Compounds Following Commonly Used Purification Techniques

Palladium-catalyzed reactions are among the most commonly used procedures in organic synthesis. The products have a range of uses, including as intermediates in total synthesis and as screening compounds for drug discovery or agrochemical projects. Despite the known and potentially deleterious effects of low-level metal impurities in biological assays, the quantification of metal remaining in reaction products to verify the effective removal of the transition element is rarely reported. Using palladium as an exemplar, we describe a pilot study that for the first time quantifies residual metal levels in reaction products following increasingly rigorous purification protocols. Our results demonstrate that significant levels of residual palladium can remain in isolated reaction products following chromatographic purification, and only by using a subsequent metal scavenging step are they reliably reduced to a low level. Finally, we provide a set of simple guidelines that should minimize the potential for issues associated with residual palladium in reaction products.     

Dimensionality of the Superconductivity in the Transition Metal Pnictide WP

We report theoretical and experimental results on the transition metal pnictide WP. The theoretical outcomes based on tight-binding calculations and density functional theory indicate that WP is a three-dimensional superconductor with an anisotropic electronic structure and nonsymmorphic symmetries. On the other hand, magnetoresistance experimental data and the analysis of superconducting fluctuations of the conductivity in external magnetic field indicate a weakly anisotropic three-dimensional superconducting phase.     

Optimizing infant HIV diagnosis with additional screening at immunization clinics in three sub‐Saharan African settings: a cost‐effectiveness analysis

IntroductionUptake of early infant HIV diagnosis (EID) varies widely across sub‐Saharan African settings. We evaluated the potential clinical impact and cost‐effectiveness of universal maternal HIV screening at infant immunization visits, with referral to EID and maternal antiretroviral therapy (ART) initiation.MethodsUsing the CEPAC‐Pediatric model, we compared two strategies for infants born in 2017 in Côte d’Ivoire (CI), South Africa (SA), and Zimbabwe: (1) existing EID programmes offering six‐week nucleic acid testing (NAT) for infants with known HIV exposure (EID), and (2) EID plus universal maternal HIV screening at six‐week infant immunization visits, leading to referral for infant NAT and maternal ART initiation (screen‐and‐test). Model inputs included published Ivoirian/South African/Zimbabwean data: maternal HIV prevalence (4.8/30.8/16.1%), current uptake of EID (40/95/65%) and six‐week immunization attendance (99/74/94%). Referral rates for infant NAT and maternal ART initiation after screen‐and‐test were 80%. Costs included NAT ($24/infant), maternal screening ($10/mother–infant pair), ART ($5 to 31/month) and HIV care ($15 to 190/month). Model outcomes included mother‐to‐child transmission of HIV (MTCT) among HIV‐exposed infants, and life expectancy (LE) and mean lifetime per‐person costs for children with HIV (CWH) and all children born in 2017. We calculated incremental cost‐effectiveness ratios (ICERs) using discounted (3%/year) lifetime costs and LE for all children. We considered two cost‐effectiveness thresholds in each country: (1) the per‐capita GDP ($1720/6380/2150) per year‐of‐life saved (YLS), and (2) the CEPAC‐generated ICER of offering 2 versus 1 lifetime ART regimens (e.g. offering second‐line ART; $520/500/580/YLS).ResultsWith EID, projected six‐week MTCT was 9.3% (CI), 4.2% (SA) and 5.2% (Zimbabwe). Screen‐and‐test decreased total MTCT by 0.2% to 0.5%, improved LE by 2.0 to 3.5 years for CWH and 0.03 to 0.07 years for all children, and increased discounted costs by $17 to 22/child (all children). The ICER of screen‐and‐test compared to EID was $1340/YLS (CI), $650/YLS (SA) and $670/YLS (Zimbabwe), below the per‐capita GDP but above the ICER of 2 versus 1 lifetime ART regimens in all countries.ConclusionsUniversal maternal HIV screening at immunization visits with referral to EID and maternal ART initiation may reduce MTCT, improve paediatric LE, and be of comparable value to current HIV‐related interventions in high maternal HIV prevalence settings like SA and Zimbabwe.     

Totally robotic soave pull-through procedure for Hirschsprung’s disease: lessons learned from 11 consecutive pediatric patients

Pediatric Surgery International - Since Hirschsprung’s disease (HSCR) already proved to benefit from robotic surgery, we aimed at describing a wider series of patients with this rare disease...     

Chronischer Husten bei Kindern

Monatsschrift Kinderheilkunde - Chronischer Husten ist in der Pädiatrie definiert als täglicher extensiver Husten über mindestens 4 Wochen. Prolongierter subakuter Husten...