Protein kinase mediators of integrin signal transduction

 Protein kinases are important mediators of signal transduction initiated by soluble growth factors and cytokines. Cellular interactions with the extracellular matrix are mediated largely by members of the integrin class of cell adhesion molecules, which also subsume signal transduction functions required for cell growth, differentiation, and survival. Here we review the involvement of protein kinases in mediating integrin intracellular signal transduction and the possible role for these molecules in regulating integrin adhesion. Although in most cases mechanistic details are incomplete, the emerging theme of protein kinases mediating cross-talk between growth factor receptor and integrin signalling systems provides a timely backdrop against which to present new developments in this area. The contribution of the actin cytoskeleton to integrin signal transduction is discussed, with respect to the concept of ’solid-state’ signalling providing a mechanism for imposing order on the protein-protein interactions which underlie signal discrimination. Moreover, we review evidence that dysregulated integrin signalling contributes to pathological processes including arthritis, thrombasthenia, leucocyte adhesion deficiencies, and tumour angiogenesis and invasion. Received: 14 May 1996 / Accepted: 2 July 1996     

The Role of Community Health Workers Within the Continuum of Services for HIV,Viral Hepatitis,and Other STIs Amongst Men Who Have Sex with Men in Europe

Journal of Community Health - Little is known about Community Health Workers (CHWs) who work in non-clinical settings to provide sexual health support around HIV, viral hepatitis, and other...     

Pain,Perceived Injustice,and Pain Catastrophizing in Chronic Pain Patients in Ireland

Chronic pain is a public health concern affecting 20% to 30% of the population of Western countries. Psychological risk factors can worsen chronic pain patients. Themes of perceived injustice (PI) and pain catastrophizing are related to poor clinical outcomes. Particularly, perceived injustice has not been assessed systematically in patients at their first presentation in chronic pain clinics in Ireland. This study aims to assess the Injustice Experience Questionnaire (IEQ)'s internal consistency in the Irish population, assess PI in patients attending a chronic pain clinic in Ireland using the IEQ, investigate pain catastrophizing through the Pain Catastrophizing Scale (PCS) and its relationship with IEQ scores, and explore their relationships with self‐reported Numeric Pain Rating Scale. One hundred adult patients were randomly selected from those attending the clinic for the first time. Eighty completed the IEQ (mean age 49 years, ranged 22 to 90 years; 59% female). The internal consistency of the IEQ was excellent (Cronbach's alpha = 0.93). Twenty‐six patients (33%) had IEQ scores classified as severe. Patients whose cause of pain was trauma or road traffic accidents were more likely to have clinically severe scores than all other causes of pain (47% vs. 23%, P = 0.03). This has clinical consequences and may have legal implications. Pain catastrophizing scores were strongly correlated with IEQ (r = 0.60, P < 0.001). The correlation between IEQ and the Numeric Pain Rating Scale was weak (r = 0.25, P = 0.048). The results suggest that the IEQ may provide an additional tool to assess psychological contributors in problematic chronic pain patients and to institute targeted therapies to improve clinical outcomes.     

Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb

Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.     

Effects of Prenatal Exposure to Alcohol Plus Caffeine in Rats: Pregnancy Outcome and Early Offspring Development

The factors determining susceptibility to fetal alcohol syndrome (FAS) are not fully understood. We used an animal model of alcohol-related birth defects to assess the coteratogenic potential of caffeine as a risk factor in FAS. Rats were exposed prenatally to alcohol (˜15 g/kg/day) with or without caffeine (˜84 mg/kg/day) from gestation days 6 through 20 via liquid diet. All control groups were pair-fed to the alcohol-exposed groups. In addition, some controls had free access to lab chow and water. Prenatal exposure to alcohol or caffeine reduced both maternal weight gain during pregnancy and birth-weight of offspring. The combination of alcohol plus caffeine produced an additive effect in reducing birthweight and synergistic effects in increasing postnatal offspring mortality. Prenatal alcohol exposure had a significant negative impact on several developmental indices, including grip strength and negative geotaxis. Prenatal caffeine exposure did not affect maturational measures and did reduce offspring serum levels of the zinc-dependent enzyme alkaline phosphatase. This study in rats demonstrated that caffeine can exacerbate some of the effects of alcohol on prenatal development, specifically reduced birthweight, litter size, and postnatal survival, but that caffeine does not appear to alter prenatal alcohol-induced delays in early postnatal maturation of survivors. The relative impact of intralitter birthweight rank on developmental outcome was also assessed. Birthweight influenced development, but did not interact significantly with either prenatal alcohol or caffeine. The results imply that high levels of maternal caffeine intake in humans could increase the likelihood that a child exposed prenatally to alcohol would be born with significantly lowered birthweight, one of the cardinal diagnostic criteria for FAS.     

Quality of written communication and master impressions for fabrication of removable partial prostheses in the Kingdom of Bahrain

The aim of this study was to examine the quality of written instructions and choice of impression trays and materials for removable partial dentures (RPDs) in the Kingdom of Bahrain. All six private dental laboratories in Bahrain were contacted and invited to participate in the study. Five laboratories participated, and submitted written instructions received by them for fabrication of both acrylic (A-RPDs) and cobalt-chromium (CC-RPDs) RPDs. These were examined for evidence of selected design variables. Types of impression trays and materials used were also recorded. One hundred and thirty-one written instructions were examined. Eleven percent (n = 14) were for CC-RPDs, 89% (n = 117) for A-RPDs. All treatments were provided on a private basis. Fifty-seven percent (n =1 8) of CC-RPD instructions requested the technician to design the prosthesis, 43% (n = 6) contained a diagram and 43% (n = 6) mentioned all design variables. Seventy-nine percent (n = 92) of A-RPDs requested the technician to design the denture, and only 1% (n = 1) mentioned all design variables. Alginate impression material was most commonly used for master impressions (83% of impressions (n = 109); 85% (n = 99) of A-RPDs, and 71% (n = 10) of CC-RPDs). Master casts were poured after a minimum of 24 h. Acrylic custom trays were used in 14% (n = 19) of cases (43% (n = 6) of CC-RPDs; 13% (n = 15) of A-RPDs). The quality of written instructions to dental laboratories for the fabrication of RPDs was found to be inadequate in Kingdom of Bahrain. There was widespread use of inappropriate impression trays and materials.