Hormone Therapies and Vascular Outcomes: Who is at Risk?

Postmenopausal hormone replacement therapy (HRT), such as estrogen with a progestin (E+P), is associated with an increased risk of myocardial infarction (MI), stroke, and venous thrombosis. Subgroups of susceptible women for these clinical outcomes have not been clearly identified, although women with a prior history of venous thrombosis and women with factor V Leiden are at higher risk of venous thrombosis on HRT than others. Effects of HRT on atherosclerosis, coagulation, and inflammation have been investigated, and might improve our understanding of the pathogenesis of this drug effect. In 2 trials E+P did not alter the progression of coronary atherosclerosis, while in a third trial unopposed estradiol retarded atherosclerosis progression in the carotid arteries. HRT is associated with an increase in high-sensitivity C-reactive protein (CRP), an inflammation marker associated with arterial disease risk, and an increase in activated protein C resistance, the biochemical defect associated with factor V Leiden. Given recent data, the only current indication for E+P is the short-term treatment of symptoms of estrogen deficiency, such as hot flashes. Testing for coagulation disorders or inflammatory factors, such as factor V Leiden or CRP, for use in decision-making about HRT use would be premature in unselected patients. Further research is needed to identify pathophysiological mechanisms of vascular harm from these hormones.     

Expression of Transforming Growth Factor β1 in Bronchial Biopsies in Asthma and COPD

The role of transforming growth factor β₁ (TGF β₁) in airway remodeling in asthma and chronic obstructive pulmonary disease (COPD) has not been fully described. To evaluate the possible pathogenetic role of TGF β₁ in asthma and COPD, immunohistochemical expression of TGF β₁ was described in bronchial biopsies from patients with asthma and COPD compared with healthy individuals. Twelve subjects with asthma, 13 subjects with COPD, and 10 healthy individuals enrolled in the study. Bronchial biopsies were stained with hematoxylin and eosin and anti‐TGF β₁ antibody. As a result, immunoreactive TGF β₁ was mainly localized in association with connective tissue in all groups. The staining intensity was not statistically different among the groups in bronchial epithelium, whereas it was significantly higher in the group of asthma in the submucosa. Because there is evidence showing a significant increase of staining intensity in the submucosa from asthmatics but not from subjects with COPD, we may conclude that TGF β₁ may play a significant role in pathogenesis of asthma but not in COPD.     

Biologic Therapies for Spondyloarthritis: What Is New?

The course of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS), is strongly influenced by the degree of disease activity over time, which is mainly based on inflammation, and by the impairment of function, which is based on structural damage-mainly, new bone formation-and inflammation. In AS, nonsteroidal anti-inflammatory agents are currently recommended as the first choice of medical therapy, and there is also a clear role for regular exercise and physiotherapy in order to preserve and prevent loss of spinal mobility. For patients who have insufficiently responded to conventional medications, there are now four biologics approved for the treatment of patients with active AS in many countries, all directed against TNFα: infliximab, etanercept, adalimumab, and golimumab; studies with certolizumab are currently ongoing. Several studies with patients classified as nonradiographic axSpA have also shown a good response to TNF blockers; in patients with early disease and high CRP levels, the response rates were even better. Long-term studies with TNF blockers have shown declining retention rates over time but sustained clinical efficacy in the patients who remained on treatment. States of drug-free remission are rarely reached and only for relatively short periods of time. More studies including magnetic resonance imaging (MRI) are needed to further examine the lack of effect of anti-TNF treatment on radiographic progression in the axial skeleton. Whether the effect of an early intervention with biologics will prevent the development of bone growth in patients with nonradiographic axial SpA remains to be seen. Biologics other than TNF blockers are currently not recommended for the treatment of patients with axSpA, because of insufficient evidence of clinically relevant efficacy. The anti-IL-17a antibody secukinumab may be efficacious, on the basis of a proof-of-concept trial. Finally, first data on biosimilars of TNF blockers have recently been presented.     

Insulin Like Growth Factor—1 and Insulin—Like Growth Factor Binding Proteins: Their Possible Roles in Both Maintaining Normal Retinal Vascular Function and in Promoting Retinal Pathology

Reviews in Endocrine and Metabolic Disorders -     

OPPORTUNITY?: A Randomized Clinical Trial of Growth Hormone on Outcome in Hemodialysis Patients

Background: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY™ Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients.Hypothesis: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile.Design/Measurements: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 μg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V ≥1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy.Conclusions: The OPPORTUNITY™ Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.Adult end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (MHD) experience high mortality and morbidity with diminished quality of life (1,2). Death and hospitalization rates in MHD patients correlate strongly with indicators of low protein mass, as indicated by low serum albumin and decreased fat-free, edema-free body mass (i.e., lean body mass [LBM]), as well as chronic inflammation (3,4). This is an important association because protein-energy wasting (PEW) occurs in approximately 40% of MHD patients (5). The possibility that improved measures of PEW may lead to decreased mortality or morbidity was recently underscored by several cross-sectional and longitudinal evaluations of cohorts containing up to 58,000 MHD patients who were followed for up to 2 yr. These studies showed that both higher serum albumin and body weight and an increase in these measures are strongly associated with greater survival (6,7). However, there are no prospective, randomized, clinical trials (RCTs) that have confirmed or even assessed whether a pharmacologic intervention that improves indicators of PEW prolongs survival and/or reduces morbidity, including hospitalization, in MHD patients. Thus, major unmet medical needs and important questions exist concerning whether PEW causes mortality and morbidity in MHD patients and whether a treatment that reduces PEW will reduce their high mortality and morbidity.Growth hormone (GH) has extensive metabolic and, in particular, protein anabolic effects (8), a number of which have also been demonstrated in MHD or chronic peritoneal dialysis patients (9–23). Most of these studies were performed on small numbers of patients. A recent phase 2 RCT involving 139 MHD patients indicated that the GH-treated patients underwent improvement in LBM, serum transferrin, exercise capacity, and a tendency (P = 0.076) for serum albumin to rise (9). Based on these data, a decision was made to conduct a more definitive prospective RCT in hypoalbuminemic MHD patients.     

Adipose Tissue: The New Endocrine Organ? A Review Article

Fat is either white or brown, the latter being found principally in neonates. White fat, which comprises adipocytes, pre-adipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes, actively participates in hormonal and inflammatory systems. Adipokines include hormones such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidine, chemerin, omentin, and inflammatory cytokines, including tumor necrosis factor alpha (TNF), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator protein (PAI). Multiple roles in metabolic and inflammatory responses have been assigned to adipokines; this review describes the molecular actions and clinical significance of the more important adipokines. The array of adipokines evidences diverse roles for adipose tissue, which looms large in the mediators of inflammation and metabolism. For this reason, treating obesity is more than a reduction of excess fat; it is also the treatment of obesity’s comorbidities, many of which will some day be treated by drugs that counteract derangements induced by adipokine excesses.     

Behavioral Cardiology: Cardiology’s New Frontier of Action

Introduction

Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce.

Objective

To investigate the arrhythmia subtype of atrial fibrillation and flutter patients in the emergency setting and compare the clinical profile, thromboembolic risk and anticoagulants use.

Methods

Cross-sectional retrospective study, with data collection from medical records of every patient treated for atrial fibrillation and flutter in the emergency department of Instituto de Cardiologia do Rio Grande do Sul during the first trimester of 2012.

Results

We included 407 patients (356 had atrial fibrillation and 51 had flutter). Patients with paroxysmal atrial fibrillation were in average 5 years younger than those with persistent atrial fibrillation. Compared to paroxysmal atrial fibrillation patients, those with persistent atrial fibrillation and flutter had larger atrial diameter (48.6 ± 7.2 vs. 47.2 ± 6.2 vs. 42.3 ± 6.4; p < 0.01) and lower left ventricular ejection fraction (66.8 ± 11 vs. 53.9 ± 17 vs. 57.4 ± 16; p < 0.01). The prevalence of stroke and heart failure was higher in persistent atrial fibrillation and flutter patients. Those with paroxysmal atrial fibrillation and flutter had higher prevalence of CHADS2 score of zero when compared to those with persistent atrial fibrillation (27.8% vs. 18% vs. 4.9%; p < 0.01). The prevalence of anticoagulation in patients with CHA2DS2-Vasc ≤ 2 was 40%.

Conclusions

The population in our registry was similar in its comorbidities and demographic profile to those of North American and European registries. Despite the high thromboembolic risk, the use of anticoagulants was low, revealing difficulties for incorporating guideline recommendations. Public health strategies should be adopted in order to improve these rates.     

Age-Related Changes of Transforming Growth Factor β1 in Japanese Children

BackgroundTransforming growth factor β1 (TGFβ1) is an important factor in immunomodulation. The expression of TGFβ1 has been shown to be influenced by the C-509 T polymorphism in the TGFβ1 gene. We investigated age-related changes of plasma TGFβ1 levels in a birth-cohort study. In addition, the genotypes of the C-509 T polymorphism were investigated in allergic and non-allergic subjects.MethodsSixty-four neonates who met the following criteria were enrolled in this cohort study: 1) full-term vaginally delivery; 2) underwent DNA polymorphism analysis; and 3) questionnaire forms were filled out by parents at 0, 6 and 14 months of age. The umbilical cord blood at 0 months and peripheral blood at 6, and 14 months were collected. Plasma TGFβ1 levels were measured at 0, 6 and 14 months of age. Genomic DNA was extracted from their umbilical cord blood. The genotype of the subjects was examined for the presence of C- 509 T.ResultsThe plasma TGFβ1 level at 6 months was the highest of the 3 measurements (at 0, 6, and 14 months of age). The TGFβ1 levels at 14 months in allergic subjects were significantly higher than those in non-allergic subjects (p = 0.03). All subjects with bronchial asthma (n = 3) had the TT genotype of the C-509 T polymorphism.ConclusionsThe plasma TGFβ1 levels change with age. In addition, TGFβ1 may play a role in the pathogenesis of bronchial asthma.     

Immunolocalization of Transforming Growth Factor-α and Epidermal Growth Factor Receptor in the Rat Gastroduodenal Area

The maintenance of gastrointestinal epitheliumintegrity requires a fine balance between proliferationand differentiation as well as protection againstgastric acid secretion. Transforming growthfactor- (TGF-) regulates these functions bybinding to epidermal growth factor receptor (EGF-R).This study was designed to identify the localization ofTGF- and EGF-R in the rat gastroduodenal region. In the stomach, the surface and gastric pitcells showed staining for TGF- antibodies in thecytoplasm and basolateral and apical membranes.TGF- and EGF-R were observed in the supranuclearregion of the cells lining the gland. In the duodenum,the enterocytes coexpressed both TGF- and EGF-Rin the supranuclear area. The EGF-R was also observed inthe apical membrane. Brunner's glands were positive for both TGF- and EGF-R antibodies. Ourresults demonstrate the coexpression of TGF- andEGF-R in the rat gastroduodenal area, which suggests afunctional role for them in the establishment and maintenance of the epithelialrenewal.     

Growth Assessment in Clinical Practice: Whose Growth Curve?

Differences in growth curves can influence the diagnosis of under- and overnutrition, and the interpretation of adequate growth following nutrition intervention. This effect is notable when comparing the World Health Organization (WHO) 2006 Growth Standard and the Centers for Disease Control and Prevention (CDC) 2000 Growth Reference for infants and children to 59 months of age. Important differences relate to conceptual approaches for generating growth standards to describe what population growth should be, compared to a reference of what growth is. WHO included only term infants exclusively or predominantly breast-fed beyond 4 months, and data for infants and children indicative of excess adiposity and growth failure were removed. Thus, fewer children are diagnosed with poor weight gain, and more with excess adiposity, using the WHO Growth Standard than when using the CDC Growth Reference. Adequate growth is based on proportional height and weight gains that track along growth curve trajectories. Use of the WHO curves should assist in prevention of inappropriate intervention or overfeeding in young children.     

Transforming Growth Factor β1 and Coronary Intimal Hyperplasia in Pediatric Patients With Congenital Heart Disease

Background

Congenital heart defects or the process of their repair leads to an increased risk for adult cardiovascular disease compared with the general population. Intimal hyperplasia is a preatherosclerotic lesion that may be produced as a consequence of transforming growth factor β1 (TGF-β1) pathway activation. We studied the presence of intimal hyperplasia in arteries from a pediatric population with congenital heart disease (CHD) and TGF-β1 expression to enlighten its possible role in the genesis of these lesions.

Methods

Coronary arteries from 10 controls and 98 CHD patients (54% cyanotic type, 32% surgically repaired) were stained, and the presence and degree of intimal thickening were analyzed. The expression of TGF-β1 was studied by immunohistochemistry.

Results

The difference between the presence of coronary intimal hyperplasia in patients with cyanotic (35; 66.1%) and noncyanotic CHD (29; 64.3%) was not significant. However, surgically repaired CHD presented a higher rate of coronary intimal hyperplasia (80%) than did the group without surgical intervention (47.3%), P = 0.0002. The immunostaining for TGF-β1 analyzed in samples of patients with cyanotic and noncyanotic CHD showed no significant differences. However, TGF-β1 expression was more intense on the intimal layer of patients with surgically repaired CHD than on that of those without surgery (intimal area positive for TGF-β1, 50.43% vs 15.91%, respectively; Mann-Whitney U test P = 0.0005).

Conclusion

The high incidence of intimal hyperplasia in patients with surgically repaired CHD is correlated with TGF-β1 expression and may contribute to the development of atherosclerotic coronary artery disease in CHD patients.     

Melnick?Needles Syndrome Associated with Growth Hormone Deficiency: A Case Report

Melnick-Needles syndrome is an X-linked dominant bone dysplasia characterized by a typical facies (exophthalmos, full cheeks, micrognathia, and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of the lower extremities, irregular constriction in the ribs, and sclerosis of base of the skull. The phenotype of affected individuals varies, even within families. About fifty cases of Melnick-Needles syndrome have been reported to date. Short stature is not a well-known component of the disorder. There is only one reported case of Melnick-Needles syndrome associated with growth hormone deficiency. A six-year-old girl who presented to our clinic with short stature was diagnosed as Melnick-Needles syndrome based upon characteristic clinical and radiological findings. Two different stimulation tests demonstrated growth hormone deficiency. Presenting this second case of Melnick-Needles syndrome associated with growth hormone deficiency, we suggest that this association may be coincidental, but that it may also be a consequence of craniofacial abnormalities or an independent component of the disorder.