Reduced neointima in vein grafts following a blockage of cell recruitment from the vein and the surrounding tissue

OBJECTIVE: Accumulation of intimal smooth muscle cells (SMC) is an important event in vein graft-stenosis. Different SMC sources have been reported, but their interrelations have been poorly studied. In a mouse vein graft model we investigated whether recipient-derived intimal SMCs are recruited from the surrounding tissue and whether blockage of SMC recruitment from the surrounding tissue and/or the donor vein will reduce neointimal formation. METHODS: To detect recipient-derived cells, wild-type veins were implanted into ROSA26 transgenic mice. To block cell recruitment from the surrounding tissue, implanted veins were isolated with a tube-shaped plastic film. To exclude vein-derived cells in the neointimal formation, acellular veins were implanted. RESULTS: In vein grafts isolated from the surrounding tissue the recipient contribution became minimal, but the total number of SMCs was not decreased. Acellular grafts contained an equal number of intimal SMCs as cellular controls after 4 weeks. Isolation of acellular grafts from the surrounding tissue decreased the number of intimal SMCs by 90%. CONCLUSIONS: Recipient-derived SMCs are mainly recruited from the surrounding tissue. Cell recruitment from either the vein or the surrounding tissue is enough to form a neointima. Therefore, a simultaneous inhibition of both these sources is needed to reduce accumulation of intimal SMCs.     

Impact of obesity on long-term prognosis following acute myocardial infarction

OBJECTIVE: To evaluate the impact of obesity on mortality in patients with acute myocardial infarction. METHODS: This study comprises 6676 consecutive patients with acute myocardial infarction screened for entry into the Danish Trandolapril Cardiac Evaluation (TRACE) study. At baseline, body mass index (BMI) and waist to hip ratio (WHR) were measured. Survival status was determined after 8-10 years. RESULTS: BMI was used to divide patients into 4 groups: underweight, normal weight, overweight and obese. The normal weight group was used as reference for the other groups. WHR was divided in quartiles and the lowest quartile was used as reference for the three other quartiles. The prevalence of overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI>30 kg/m(2)) were 48% and 13% in males and 31% and 13% in females. Obese patients were younger, less often smokers and more frequently suffered from diabetes and hypertension. In both men and women, there was no association between obesity assessed as BMI and mortality [men: adjusted RR=0.99 (0.85-1.14, p=0.3); women: adjusted RR=0.90 (0.74-1.10, p=0.2)]. Men with WHR in the upper quartile had an increased mortality [adjusted RR=1.21 (1.07-1.37, p<0.01)]. Increasing WHR in women showed a trend of increased mortality, although this was not significant [adjusted RR=1.13 (0.95-1.34, p=0.2)]. CONCLUSION: In patients with acute myocardial infarction overall obesity as assessed by body mass index is inversely related to mortality. However, abdominal obesity appears to be an independent predictor of all-cause mortality in men and perhaps also in women.     

The quantitative genetics of sex differences in parenting

Sex differences in parenting are common in species where both males and females provide care. Although there is a considerable body of game and optimality theory for why the sexes should differ in parental care, genetics can also play a role, and no study has examined how genetic influences might influence differences in parenting. We investigated the extent that genetic variation influenced differences in parenting, whether the evolution of differences could be constrained by shared genetic influences, and how sex-specific patterns of genetic variation underlying parental care might dictate which behaviors are free to evolve in the burying beetle Nicrophorus vespilloides. Females provided more direct care than males but did not differ in levels of indirect care or the number of offspring they were willing to rear. We found low to moderate levels of heritability and evolvability for all 3 parenting traits in both sexes. Intralocus sexual conflict was indicated by moderately strong intersex genetic correlations, but these were not so strong as to represent an absolute constraint to the evolution of sexual dimorphism in care behavior. Instead, the pattern of genetic correlations between parental behaviors showed sex-specific tradeoffs. Thus, differences in the genetic correlations between parental traits within a sex create sex-specific lines of least evolutionary resistance, which in turn produce the specific patterns of sex differences in parental care. Our results therefore suggest a mechanism for the evolution of behavioral specialization during biparental care if uniparental and biparental care behaviors share the same genetic influences.     

The potential benefits of treatment of sleep apnea in heart failure

At least half of patients with heart failure (HF) suffer from sleep apnea. Growing evidence suggests that there may be a strong pathophysiological link between chronic HF and sleep apnea due to nocturnal oxygen desaturation and sympathetic activation. It seems that sleep apnea contributes to systolic and diastolic HF, reduced left and right ventricular function, and arrhythmia (e.g. atrial fibrillation, bradycardia, or ventricular ectopy). Therefore, treatment of sleep apnea might alleviate cardiac symptoms and improve cardiac function. Nevertheless, the exact role of long-term treatment of sleep apnea in HF patients remains to be elucidated, as important clinical endpoints (e.g mortality) have been assessed in only a few studies. Heart Fail Monit 2008;5(4):106-11.     

Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism

Parkinson's disease (PD) is characterized by a progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes prominent side effects. There is a strong serotonin innervation of the striatum by serotonergic neurons that remains relatively preserved in PD. The study of this innervation has been largely neglected. Here, we demonstrate that chronic L-DOPA administration to 6-OHDA-lesioned rodents increases, via D1 receptors, the levels of the 5-HT1B receptor and its adaptor protein, p11, in dopamine-denervated striatonigral neurons. Using unilaterally 6-OHDA-lesioned p11 WT and KO mice, it was found that administration of a selective 5-HT1B receptor agonist, CP94253, inhibited L-DOPA-induced rotational behavior and abnormal involuntary movements in a p11-dependent manner. These data reveal an L-DOPA-induced negative-feedback mechanism, whereby the serotonin system may influence the symptomatology of Parkinsonism.     

Association between Gm allotypes and asthma severity from childhood to young middle age

Immunoglobulin constant heavy G chain (IGHG) gene polymorphisms are associated with atopy and can be determined by the serum Gm allotypes. We studied whether certain polymorphisms are related to asthma severity and to the extent or intensity of allergic sensitization in asthmatic subjects followed from childhood to young middle age. Fifty-five subjects (28 males) with childhood asthma were all followed-up prospectively on six occasions from a mean age of 9 to 35 years in a study including asthma severity scoring, spirometry, skin prick, and specific serum IgE antibody testing. At the last visit, extended lung function tests and a cold air challenge were performed, and IGHG gene polymorphisms were identified by the alternative serum IgG subclass allotypes, employing ELISA and double immunodiffusion. The 19 subjects with the homozygous IGHG*bf/*bf genotype (originating from the IGHG3*b and the IGHG1*f alleles, which are in strong linkage disequilibrium), showed significantly higher asthma scores, lower airway function, and greater bronchodilator responses from childhood to adulthood, and in middle age greater airway hyperresponsiveness, compared to the subjects with the IGHG*bf/*ga or IGHG*ga/*ga genotypes. Among the subjects sensitized to animal danders, those with the IGHG*bf/*bf genotype showed the highest specific IgE levels. In conclusion, IGHG gene polymorphisms were associated with the severity and outcome of childhood asthma, and with the intensity of allergic sensitization.     

Initiating or Switching to Biphasic Insulin Aspart 30/70 Therapy in Subjects with Type 2 Diabetes Mellitus. An Observational Study

OBJECTIVE: To investigate tolerability and glycemic control over 26 weeks in patients with type 2 diabetes (T2D) who initiated insulin with, or switched to, biphasic insulin aspart 30/70 (BIAsp 30) in routine clinical care. METHODS: This was a non-randomized, non-interventional, open-label, observational study involving patients under the care of approximately 150 insulin-prescribing physicians in Denmark. All patients enrolled were prescribed BIAsp 30 in routine care. Starting dose, dose titration and injection frequency were determined individually by each physician. Information on serious adverse drug reactions (SADR), glycemic parameters and hypoglycemic events were obtained from patients’ notes, patients’ diaries and recall, and transferred to case report forms by physicians at baseline (during 4 weeks prior to BIAsp 30 therapy) and after 12 and 26 weeks of treatment. RESULTS: 421 subjects were recruited and 392 provided safety data. The age (mean ± SD) was 62.0 ± 11.4 years, body mass index (BMI) 30.4 ± 6.4 kg/m², duration of diabetes 9.1 ± 8.1 years and HbA1c (%) 9.4 ± 1.7. 199 subjects were prior insulin users and 193 were insulin-naïve patients. Four patients reported a SADR (3 hypoglycemia, 1 severe hypoglycemia). HbA1c was significantly reduced after 26 weeks of BIAsp 30 therapy: prior insulin users -1.2%, insulin-naïve patients -2.2% (both p < 0.001). 28% and 41% of patients, respectively, reached target HbA1c < 7%. Overall the hypoglycemia rate was lower for insulin-naïve patients than for prior insulin users: 5.0 vs. 6.6 episodes/patient-year (p < 0.05). CONCLUSION: Initiating insulin with, or switching insulin to, BIAsp 30 in routine care was safe and effective in patients with T2D.     

Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin's lymphoma--a population-based study

Objective: Classical Hodgkin’s lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype. Methods: In a population‐based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n = 448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein‐x (EPX) gene polymorphisms were determined. Associations were assessed in regression models. Results: Self‐reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR) = 2.22, 95% CI 1.06–4.64, P = 0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs) = 1.84, 95% CI 1.02–3.30, P = 0.04]. Lower number of eosinophils was seen in Epstein–Barr virus (EBV)‐positive tumours (univariate RL = 0.52, 95% CI 0.3–0.9, P = 0.02) and in older patients (univariate RL = 0.85, 95% CI 0.73–0.99, P = 0.03). Well‐known factors such as young age, female sex and EBV‐negative status predicted nodular sclerosis histology. Conclusion: The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.     

Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8(+) T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO(+) suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)-producing CD4(+) T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-α while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosine-phosphate-guanosine, soluble cytotoxic T lymphocyte-associated antigen 4, or interferon γ) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells."     

The association of inherited thrombophilia and intrauterine fetal death: a case-control study

Inherited thrombophilias are probably associated with placenta-mediated pregnancy complications, but the strength of the association between inherited thrombophilias and intrauterine fetal death after 22 gestational weeks varies due to small sample size and different methodologies used across studies. The objective of the present study was to investigate the association of inherited thrombophilia and intrauterine fetal death in a case-control design. We studied 105 women with a history of intrauterine fetal death after 22 gestational weeks and 262 controls with live births. We investigated the prevalence of the factor V Leiden (F5 rs6025) and prothrombin gene G20210A (F2 rs1799963) polymorphisms, and antithrombin, protein C and protein S deficiencies, and their association with intrauterine fetal death. Results were presented as percentages and odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18.4% of cases and 11.8% of controls were positive for at least one inherited thrombophilia (OR 1.7; 95% CI 0.9-3.1). The prothrombin gene G20210A polymorphism (OR 4.0; 95% CI 1.1-14.4), but not the factor V Leiden polymorphism, or antithrombin, protein C or protein S deficiencies, was associated with intrauterine fetal death after 22 weeks of gestation. Compared with women with live births only, women with a history of intrauterine fetal death after 22 gestational weeks were significantly more often carriers of the prothrombin gene G20210A polymorphism.