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     

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.     

Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women

OBJECTIVE: Oral but not transdermal oestrogen administration reduces IGF-I, and increases GH binding protein (GHBP) reflecting effects on hepatic endocrine function in postmenopausal women. As progestogens attenuate the effects of oestrogen on circulating lipid levels according to their androgenic properties, we have investigated the impact of progestogen types on the hepatic endocrine effects of oestrogen. DESIGN: Four progestogens differing in androgenicity were co-administered in a monthly cyclical regimen in random order to postmenopausal women receiving either oral (n = 9, premarin 1.25 mg) or transdermal (n = 10, Estraderm 100 microg patches twice weekly). The four progestogens were cyproterone acetate (CA 5 mg, antiandrogenic), dydrogesterone (20 mg, neutral), medroxyprogesterone acetate (MPA 10 mg, mildly androgenic), norethisterone (2.5 mg, androgenic). PATIENTS: Nineteen postmenopausal women (age 57 +/- 3 years, mean +/- SE) were studied. MEASUREMENTS: The effects of oestrogen alone and the combined effects with each progestogen type on IGF-I, GHBP, SHBG, cholesterol, triglycerides and lipoprotein(a) were investigated. RESULTS: Mean IGF-I fell while GHBP and SHBG levels increased with oral (P < 0.01) but not transdermal oestrogen administration. When the combined effects were examined, progestogens did not affect IGF-I, GHBP and SHBG during oral oestrogen treatment, while they significantly increased (P < 0.01) mean IGF-I levels during transdermal therapy. Among the progestogen types, only norethisterone prevented the fall in IGF-I induced by oral oestrogen. During transdermal therapy, MPA and norethisterone but not CA or dydrogesterone significantly increased (P < 0.005) IGF-I. The rise in GHBP induced by oral oestrogens tended to be lower during co-administration of MPA and norethisterone. The increase in SHBG induced by oral oestrogen was attenuated (P < 0.05) by norethisterone which was the only progestogen that lowered SHBG (P < 0.05) during transdermal oestrogen treatment. Mean IGF-I was higher (P < 0.001), GHBP and SHBG lower during co-administration of androgenic progestogens (MPA and norethisterone). CONCLUSIONS: Oestrogen effects on IGF-I, GHBP and SHBG are dependent on the route of administration with progestogens having variable effects. Among the progestogen types, norethisterone, the most androgenic, had the greatest effect, particularly on IGF-I. Progestogens modulate the effects of oestrogen on hepatic endocrine function in relation to their intrinsic androgenic properties. The modulatory effects of progestogens on IGF-I during oestrogen therapy may have long-term implications for lean body mass.     

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.     

EXOGEN Ultrasound Bone Healing System for Long Bone Fractures with Non-Union or Delayed Healing: A NICE Medical Technology Guidance

A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC’s findings, and the final NICE guidance issued.     

Emergency Medical Care of Multiple Sclerosis Patients: Primary Data from the Mount Sinai Resource Utilization in Multiple Sclerosis Project

Background and Purpose

There has been no systematic analysis of emergency department (ED) utilization in the multiple sclerosis (MS) population. We investigated the acute-care needs of MS patients using ED as a route for entry into healthcare services.

Methods

ED visits made by MS patients were identified. Data extracted included demographics, medical/neurological history, and workup/management in the ED.

Results

The Mount Sinai ED received 569 visits from 224 MS patients during a 3-year period, of whom 33.5% were covered by Medicaid and 12.9% were uninsured. Patients with an Expanded Disability Status Scale score of ≥6 accounted for 54%, 50.5% of relapsing remitting MS patients were being treated with disease-modifying therapies, and 74.5% of the ED visits were non-neurological. Patients with mild-to-moderate MS were more likely to present to the ED for issues directly related to MS such as acute exacerbations, while those with severe MS presented more often due to medical issues indirectly related to MS, such as urinary tract infections (p<0.0001).

Conclusions

Most MS patients seeking ED care suffer from acute non-neurological problems. The MS patients presenting to the ED tended to be underinsured, had high levels of disability, and were undertreated with disease-modifying therapies. The acute-care needs of MS patients evolve over the disease course, as do the resources that must be utilized in providing emergency care across the spectrum of MS severity. Understanding the characteristics, problems, and needs of MS patients utilizing the ED is an important step in improving care in this population from both clinical and public health perspectives.