Plasma stem cell factor levels are associated with risk of cardiovascular disease and death.

OBJECTIVE: Stem cell factor (SCF) is a key growth factor for several types of stem and progenitor cells. There is experimental evidence that such cells are of importance for maintaining the integrity of the cardiovascular system. We investigated the association between circulating levels of SCF and risk for development of cardiovascular events and death. METHODS: SCF was analysed by the proximity extension assay technique in plasma from 4742 subjects participating in the Malmö Diet and Cancer Study. Cardiovascular events and death were monitored through national registers with a mean follow-up time of 19.2 years. RESULTS: Subjects with high baseline levels of SCF had lower cardiovascular (n = 340) and all-cause mortality (n = 1159) as well as a lower risk of heart failure (n = 177), stroke (n = 318) and myocardial infarction (n = 452). Smoking, diabetes and high alcohol consumption were associated with lower levels of SCF. Single nucleotide polymorphisms in the gene region encoding PDX1 C-terminal inhibiting factor 1 (PCIF1) and matrix metalloproteinase-9 were associated with plasma SCF levels. The highest SCF quartile remained independently associated with a lower risk of a lower risk of cardiovascular [hazard ratio and 95% confidence interval 0.59 (0.43-0.81)] and all-cause mortality [0.68 (0.57-0.81)], heart failure [0.50 (0.31-0.80)] and stroke [0.66 (0.47-0.92)], but not with MI [0.96 (0.72-1.27)] as compared with the lowest quartile when adjusting for traditional cardiovascular risk factors in Cox proportional hazard regression models. CONCLUSIONS: This prospective population-based study demonstrates that subjects with high levels of SCF have a lower risk of cardiovascular events and death. The findings provide clinical support for a protective role of SCF in maintaining cardiovascular integrity.

Decreased levels of stem cell factor in subjects with incident coronary events.

BACKGROUND: It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs). METHODS: Levels of the three growth factors were measured using the proximity extension assay technique in baseline plasma samples from 384 subjects with a first CE (mean follow-up 14.0 ± 4.3 years) and 409 event-free control subjects matched by sex and age, as well as in homogenates from 201 endarterectomy specimens. RESULTS: After controlling for known cardiovascular disease risk factors in a Cox regression model, subjects in the lowest SCF tertile had a hazard ratio of 1.70 (95% confidence interval 1.14-2.54) compared with subjects in the highest SCF tertile. Lower SCF levels were also associated with more severe carotid disease, less fibrous atherosclerotic plaques and an increased incidence of heart failure. Expression of the SCF receptor c-kit was demonstrated in the subendothelial layer and fibrous cap of human atherosclerotic plaques. Smokers and subjects with diabetes had decreased levels of SCF compared with control subjects. CONCLUSION: To our knowledge, this is the first clinical study to provide evidence to support a key role for SCF and progenitor cells in vascular repair. We suggest that the SCF-c-kit pathway may be a promising biomarker and therapeutic target in cardiovascular disease.

CD4+ CD56+ natural killer T-like cells secreting interferon-γ are associated with incident coronary events.

BACKGROUND: CD3(+) CD56(+) natural killer T (NKT)-like cells are a subset of T cells characterized by expression of NK receptors and potent antitumour activity. It has also been suggested that they have a role in autoimmune disease, and levels of NKT-like cells are elevated in patients with coronary disease. OBJECTIVES: To investigate whether high levels of CD3(+) CD56(+) NKT-like cells are associated with an increased incidence of cardiovascular disease and a lower incidence of cancer. METHODS: This was a prospective study including 700 subjects participating in the baseline investigation of the Malmö Diet and Cancer study between 1991 and 1994. Leucocytes obtained at the baseline investigation and stored at -140 °C were thawed and CD3(+) CD56(+) cells analysed by flow cytometry. The incidence rates of cancer and coronary events during a mean follow-up of 15 years were determined through national registers. RESULTS: Subjects in the lowest tertile of interferon (IFN)-γ-expressing CD4(+) CD56(+) cells were found to have an increased risk of incidence of coronary events (log-rank test: P < 0.05). This association remained significant after controlling for age, sex, smoking, body mass index, hypertension, diabetes and the Th1/Th2 and Th1/Treg cell ratios in a Cox proportional hazards regression model (hazard ratio 1.98, 95% confidence interval 1.24-3.16), but not when the LDL/HDL ratio was included in the model. There were no associations between CD3(+) CD56(+) NKT-like cells and incident cancer. CONCLUSIONS: The present results could not confirm the hypothesis that low levels of CD3(+) CD56(+) NKT-like cells are associated with a higher incidence of cancer and a lower incidence of cardiovascular disease. However, we found that low levels of IFN-γ-expressing CD3(+) CD4(+) CD56(+) NKT-like cells were associated with an increased incidence of coronary events and that this association may be dependent on lipoproteins.

Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T-cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine.

OBJECTIVES: Autoimmune responses against oxidized low-density lipoprotein are considered to play an important pro-inflammatory role in atherosclerosis and to promote disease progression. T-regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self-tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. DESIGN: Six-week-old Apoe(-/-) mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. RESULTS: At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)-induced interferon-γ, interleukin (IL)-4, and IL-10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A-induced splenic T-cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210-induced Treg activation as well as the reduction of atherosclerosis. CONCLUSIONS: The present findings demonstrate that immunization of Apoe(-/-) mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis-related autoimmunity by antigen-specific activation of Tregs represents a novel approach for treatment of atherosclerosis.

ADHD symptoms and insistence on sameness in Prader-Willi syndrome.

BACKGROUND: Apart from a pervasive eating disorder, the Prader-Willi (PWS) syndrome is characterized by a distinct behavioural profile comprising maladaptive behaviours, obsessive-compulsive traits and skin picking, all included in the PWS behavioural phenotype. In this study, we present a further delineation of this characteristic behavioural profile by screening for indices of executive dysfunctions related to attention-deficit/hyperactivity disorder (ADHD), immature compulsive-like adherence to sameness and skin picking, and how these features aggregate into symptom constellations in children and adolescents with PWS. METHOD: Parents of 58 individuals with PWS (aged 5-18 years) participated by completing Childhood Routines Inventory (CRI) and Conners' Parent Rating Scale (CPRS-48). RESULTS: Results showed that indices of ADHD and excessive insistence on sameness were common, comorbid and of early onset. They were both associated with conduct problems. Skin picking, appearing as a single and comorbid symptom, was less associated with childlike compulsions and ADHD-related problems. CONCLUSIONS: Findings are discussed in terms of further research in executive dysfunctions in PWS.

Prader-Willi syndrome: clinical picture, psychosocial support and current management.

AIM: Prader-Willi syndrome (PWS) is a rare, genetically based disorder that occurs in about 1 of 15 000 live-born children. To raise a child with PWS is challenging for parents and requires support from multiprofessional habilitation services. This paper maps the need for psychosocial support and current management of children and adolescents with PWS. METHOD: Parents to 58 children with PWS (aged 5-18 years) completed questionnaires covering clinical, diagnostic and psychosocial issues. RESULTS: The children received their diagnosis at a mean age of 2.5 year. Growth hormone treatment was given to 72%. Sixty-three per cent of the sample was not overweight. Neuropsychiatric symptoms were common from early age and some were related to obesity. Most parents wanted information as to availability of external resources and future child needs. Few parents needed family-directed support. CONCLUSION: The overall impression is that the eating disorder is managed relatively well. Even so PWS symptoms typically exacerbate over time and consequently parents need continuous support throughout childhood and adolescence. Greater attention should be paid to idiosyncrasies in cognitive functioning and to clinical markers of neuropsychiatric problems.

Rituals and compulsivity in Prader-Willi syndrome: profile and stability.

BACKGROUND: Prader-Willi syndrome (PWS) is characterized by an increased risk for obsessive-compulsive disorder. This study investigated the nature of compulsive-like behaviours in the PWS. METHOD: Parents of 50 individuals with PWS (aged 5-18 years) and 50 typically developing 4-year-old children completed the Childhood Routines Inventory. This instrument measures compulsive-like behaviours in normative childhood. RESULTS: Many childhood compulsive behaviours are prevalent among older children and adolescents with PWS. Group differences were observed in that the PWS group, independent of age, gender and cognitive dysfunctions, exhibited more intense compulsive behaviours related to insistence on sameness in many daily activities and social contexts. Findings also revealed an age-independent low-prevalent pattern of PWS compulsivity, probably related to other features in the PWS symptomatology. CONCLUSIONS: Compulsions of childhood do not subside with age in adolescents with PWS. The findings indicate that the differentiation between delayed childhood rituals and pathological manifestations of compulsive features is complex in PWS populations.

A national survey of attitudes and practices of primary-care physicians relating to nutrition: strategies for enhancing the use of clinical nutrition in medical practice.

A nationwide mail survey was used to determine the degree to which primary-care physicians indicated that they practice the "core competencies" in clinical nutrition identified by Young et al (Am J Clin Nutr 1983;38:800-10). We also surveyed the nutrition-related attitudes of these physicians. Although the 3416 physicians who responded to the survey tended to report favorable attitudes toward using nutrition in their practice, these favorable attitudes were not consistent with their own reports of clinical performance. Neither the positive- or negative-attitude score correlated highly with the reported behavior-practice score. The clinical practices reported by those surveyed are well below the minimum level defined by the Young et al essential core competencies in clinical nutrition. The attitudes, practices, and demographic characteristics associated with the clinical performance variables suggest educational strategies for improving the competence of primary-care physicians and medical students in clinical nutrition.