Identification and characterization of insulin-like growth factor receptors on adult rat cardiac myocytes: linkage to inositol 1,4,5-trisphosphate formation.

Cultured cardiac myocytes from adult Sprague-Dawley rats express both insulin-like growth factor-I (IGF-I) receptors and insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man6P) receptors and respond to IGF-I with a dose-dependent accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,4-bisphosphate [Ins(1,4)P2]. Specific binding of [125I]IGF-I to isolated membranes from cultured cardiac myocytes amounted to 1-1.2%. Binding of [125I]IGF-I was inhibited by unlabeled IGF-I at nanomolar concentrations and insulin at much higher concentrations. These data suggest that IGF-I binds to its own receptor on rat cardiac myocytes. Competitive binding studies using isolated membranes from cardiac myocytes and [125I]IGF-II showed 2-4% specific binding. Binding of [125I]IGF-II was inhibited by IGF-II and much less potently by IGF-I and insulin. Immunoglobulin G (IgG) 3637 (an IgG directed against the IGF-II/Man6P receptor) partially inhibited binding of [125I]IGF-II whereas nonimmune IgG did not. Affinity cross-linking studies with [125I]IGF-II and cardiac myocyte membranes and subsequent analysis of the ligand-receptor complex using SDS-PAGE and autoradiography showed a radiolabeled band of approximately 250 kilodalton (kDa). The formation of the [125I]IGF-II-receptor complex was inhibited by incubation with IGF-II and IgG 3637 but not by insulin or nonimmune IgG. Western blotting of protein extracts from cultured cardiac myocytes was performed using IgG 3637 and an immunoperoxidase technique for the visualization of the IGF-II/Man6P receptor protein. A specific band at 220 kDa under nonreducing conditions was detected on the blots, providing further evidence for the expression of the IGF-II/Man6P receptor by cardiac myocytes. The effect of IGFs on the accumulation of inositol phosphates was measured by HPLC analysis of perchloric acid extracts from myo-[3H]inositol-labeled cultured cardiac myocytes. IGF-I (50 ng/ml) stimulated the accumulation both of Ins(1,4,5)P3 and Ins(1,4)P2 after 30 sec by 43% and 63%. IGF-II (up to 500 ng/ml) had no significant effect on inositol phosphate accumulation under the same conditions. However, in the presence of millimolar concentrations of Man6P, IGF-II (500 ng/ml) also increased Ins(1,4,5)P3 accumulation by 59%. We conclude that cardiac myocytes from adult rats express IGF receptors and respond to IGFs with the accumulation of Ins(1,4,5)P3 and Ins(1,4)P2. This effect seems to be mediated by an IGF-I receptor-specific pathway

Insulin-Like Growth Factor (IGF)-I and -11 and IGFBinding Proteins-l, -2, and -3 in Children and Adolescents with Diabetes Mellitus: Correlation with Metabolic Control and Height Attainment.

The putative effects of diabetes and metabolic control on circulating levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) remain controversial. In the present study, serum levels of IGF-I and IGF-II and IGFBP-1, -2, and -3 were measured in 58 patients (age, 0.8-17 yr) with treated (51 subjects) or untreated (7 subjects) insulin-dependent diabetes mellitus (IDDM) and were compared with the levels in normal subjects. In the untreated patients IGF-I and IGF-II were decreased as compared with the healthy controls. In the treated diabetics IGF-I and IGF-II were reduced; IGFBP-2 (only in prepubertal subjects) and IGFBP-3 were increased. Furthermore, age-adjusted values of IGF-I, IGF-II, and IGFBP-3 were lower in prepubertal than in pubertal patients. Regression analysis revealed a negative correlation between hemoglobin (Hb)A1c and standard deviation scores (SDS) of IGF-I and a positive association between HbA1c and IGFBP-1 SDS or IGFBP-2 SDS. In the treated patients HbA1c was positively related to IGFBP-1 SDS and IGFBP-2 SDS when applying simple regression analysis and to IGFBP-2 SDS when using a multiple regression model. Strong correlations were observed between height SDS and IGF-I SDS, IGF-II SDS, and IGFBP-3 SDS in prepubertal subjects who had had IDDM for at least 2 yr, but not in adolescents. Such correlations have also been found in healthy children and adolescents. In conclusion; 1) IDDM is associated with alterations of the IGF-IGFBP system, which are partially accounted for by differences in metabolic control and pubertal status; 2) the lower plasma concentrations of serum IGF-I may play a role in the pathogenesis of growth impairment of poorly controlled prepubertal, but not pubertal, children and adolescents with IDDM; and 3) in addition, a potential role of the altered IGF-IGFBP system for the development of diabetic late complications is hypothesized

results of the sifap1 study

Objectives The present study aimed to evaluate the frequency of warning signs in younger patients with stroke with a special regard to the ‘FAST’ scheme, a public stroke recognition instrument (face, arm, speech, timely). Setting Primary stroke care in participating centres of a multinational European prospective cross-sectional study (Stroke in Young Fabry Patients; sifap1). Forty-seven centres from 15 European countries participate in sifap1. Participants 5023 acute patients with stroke (aged 18–55 years) patients (96.5% Caucasians) were enrolled in the study between April 2007 and January 2010. Primary and secondary outcome measures sifap1 was originally designed to investigate the relation of juvenile stroke and Fabry disease. A secondary aim of sifap1 was to investigate stroke patterns in this specific group of patients. The present investigation is a secondary analysis addressing stroke presenting symptoms with a special regard to signs included in the FAST scheme. Results 4535 patients with transient ischaemic attack (TIA; n=1071), ischaemic stroke (n=3396) or other (n=68) were considered in the presented analysis. FAST symptoms could be traced in 76.5% of all cases. 35% of those with at least one FAST symptom had all three symptoms. At least one FAST symptom could be recognised in 69.1% of 18–24 years-old patients, in 74% of those aged 25–34 years, in 75.4% of those aged 35–44 years, and 77.8% in 45–55 years-old patients. With increasing stroke severity signs included in the FAST scheme were more prevalent (National Institute of Health Stroke Scale, NIHSS15: 100%). Clustering clinical signs according to FAST lower percentages of strokes in the posterior circulation (65.2%) and in patients with TIA (62.3%) were identified. Conclusions FAST may be applied as a useful and rapid tool to identify stroke symptoms in young individuals aged 18–55 years. Especially in patients eligible for thrombolysis FAST might address the majority of individuals

Psychosocial primary care – what patients expect from their General Practitioners A cross-sectional trial

BACKGROUND: Psychosocial Primary Care (PPC) is a model of service delivery for patients with mental disorders and psychosocial problems which was established in Germany in 1987. This study was performed as part of the evaluation of a PPC training program. We investigated patients' expectations of the psychosocial treatment offered by GPs trained in PPC. METHODS: Ten general practitioners trained in PPC were randomly selected. Two hundred and twenty patients were surveyed in the waiting room regarding their expectations concerning psychological treatment. RESULTS: Eighty-five per cent of patients could envisage making use of psychosocial treatments. Counselling by the GP was considered most important (65%). Fifty-four per cent of patients indicated that there was sufficient counselling, but further distinctions revealed dissatisfaction with both the extent and content of the counselling. Lack of time was the most frequent reason (53%) cited for insufficient counselling. A willingness to discuss the psychological aspects of illness was exhibited by between 55% (current illness) and 79% of patients. Two-thirds of patients believed that discussing psychological aspects and counselling by the doctor could exert a healing effect or contribute to symptomatic improvement in physical illnesses. Younger patients and patients with experience in psychotherapy expected referral to mental health services. CONCLUSIONS: Primary care patients desire and accept psychological treatment from their GP. Training in psychosocial competence in primary care should be offered more frequently

Clinical signs in young patients with stroke related to FAST : results of the sifap1 study

Peer reviewe

Cervical Artery Dissection in Young Adults in the Stroke in Young Fabry Patients (sifap1) Study

Background: Patients with carotid artery dissection (CAD) have been reported to have different vascular risk factor profiles and clinical outcomes to those with vertebral artery dissection (VAD). However, there are limited data from recent, large international studies comparing risk factors and clinical features in patients with cervical artery dissection (CeAD) with other TIA or ischemic stroke (IS) patients of similar age and sex. Methods: We analysed demographic, clinical and risk factor profiles in TIA and IS patients ≤55 years of age with and without CeAD in the large European, multi-centre, Stroke In young FAbry Patients 1 (sifap1) study. Patients were further categorised according to age (younger: 18-44 years; middle-aged: 45-55 years), sex, and site of dissection. Results: Data on the presence of dissection were available in 4,208 TIA and IS patients of whom 439 (10.4%) had CeAD: 196 (50.1%) had CAD, 195 (49.9%) had VAD, and 48 had multiple artery dissections or no information regarding the dissected artery. The prevalence of CAD was higher in women than in men (5.9 vs. 3.8%, p < 0.01), whereas the prevalence of VAD was similar in women and men (4.6 vs. 4.7%, n.s.). Patients with VAD were younger than patients with CAD (median = 41 years (IQR = 35-47 years) versus median = 45 years (IQR = 39-49 years); p < 0.01). At stroke onset, about twice as many patients with either CAD (54.0 vs. 23.1%, p < 0.001) or VAD (63.4 vs. 36.6%, p < 0.001) had headache than patients without CeAD and stroke in the anterior or posterior circulation, respectively. Compared to patients without CeAD, hypertension, concomitant cardiovascular diseases and a patent foramen ovale were significantly less prevalent in both CAD and VAD patients, whereas tobacco smoking, physical inactivity, obesity and a family history of cerebrovascular diseases were found less frequently in CAD patients, but not in VAD patients. A history of migraine was observed at a similar frequency in patients with CAD (31%), VAD (27.8%) and in those without CeAD (25.8%). Conclusions: We identified clinical features and risk factor profiles that are specific to young patients with CeAD, and to subgroups with either CAD or VAD compared to patients without CeAD. Therefore, our data support the concept that certain vascular risk factors differentially affect the risk of CAD and VAD

Acute Cerebrovascular Disease in the Young The Stroke in Young Fabry Patients Study

Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Results-Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Conclusions-Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies