Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease

Biomarkers have been identified for pulmonary arterial hypertension, but are less well defined for specific etiologies such as congenital heart disease-associated pulmonary arterial hypertension (CHDPAH). We measured plasma levels of eight microvascular dysfunction markers in CHDPAH, and tested for associations with survival. A cohort of 46 inoperable CHDPAH patients (age 15.0 to 60.2 years, median 33.5 years, female:male 29:17) was prospectively followed for 0.7 to 4.0 years (median 3.6 years). Plasma levels of von Willebrand factor antigen (VWF:Ag), tissue plasminogen activator (t-PA) and its inhibitor (PAI-1), P-selectin, reactive C-protein, tumor necrosis factor alpha, and interleukin-6 and -10 were measured at baseline, and at 30, 90, and 180 days in all subjects. Levels of six of the eight proteins were significantly increased in patients versus controls (13 to 106% increase, P < 0.003). Interleukin-10 level was 2.06 times normal (P = 0.0003; Th2 cytokine response). Increased levels of four proteins (t-PA, PAI-1, P-selectin, and interleukin-6) correlated with disease severity indices (P < 0.05). Seven patients died during follow-up. An average VWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was independently associated with a high risk of death (hazard ratio = 6.56, 95%CI = 1.46 to 29.4, P = 0.014). Thus, in CHDPAH, microvascular dysfunction appears to involve Th2 inflammatory response. Of the biomarkers studied, plasma vWF:Ag was independently associated with survival.

The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto’s thyroiditis but not in Graves’ disease

Hashimoto’s thyroiditis (HT) is considered to be mediated mainly by Th1 cells, but it is not known whether Graves’ disease (GD) is associated with Th1 or Th2 predominance. Th17 cells, a novel subset of Th cells, play a crucial role in the pathogenesis of various autoimmune disorders. In the present study, the expression of IL-17A and IFN-γ was investigated in patients with HT or GD. mRNA expression of IL-17A and IFN-γ in peripheral blood mononuclear cells (PBMC) from 43 patients with autoimmune thyroid disease (AITD) and in thyroid tissues from 40 AITD patients were measured by real-time qRT-PCR. The protein expression of IL-17A and IL-23p19 was examined by immunohistochemistry in thyroid tissues from 28 AITD patients. The mRNA levels of IL-17A and IFN-γ were higher in both PBMC and thyroid tissues of HT patients than in controls (mRNA levels are reported as the cytokine/β-actin ratio: IL-17 = 13.58- and 2.88-fold change and IFN-γ = 16.54- and 2.74-fold change, respectively, P < 0.05). Also, the mRNA levels of IL-17A and IFN-γ did not differ significantly in GD patients (P > 0.05). The high protein expression of IL-17A (IOD = 15.17 ± 4.8) and IL-23p19 (IOD = 16.84 ± 7.87) in HT was confirmed by immunohistochemistry (P < 0.05). The similar high levels of IL-17A and IFN-γ suggest a mixed response of Th17 and Th1 in HT, where both cells may play important roles in the destruction procedure by cell-mediated cytotoxicity.

Clinical outcome of protein-energy malnourished patients in a Brazilian university hospital

Protein-energy malnutrition (PEM) is a treatable disease with high prevalence among hospitalized patients. It can cause significant increases in the duration of hospitalization and costs. PEM is especially important for health systems since malnourished patients present higher morbidity and mortality. The objective of the present study was to assess the evolution of nutritional status (NS) and the effect of malnutrition on clinical outcome of patients at a public university hospital of high complexity in Brazil. Patients hospitalized in internal medicine (n = 54), oncology (n = 43), and infectious diseases (n = 12) wards were included. NS was evaluated using subjective global assessment up to 48 h after admission, and thereafter at intervals of 4-6 days. On admission, patients (n = 109) were classified as well-nourished (n = 73), moderately malnourished or at risk of malnutrition (n = 28), and severely malnourished (n = 8). During hospitalization, malnutrition developed or worsened in 11 patients. Malnutrition was included in the clinical diagnosis of only 5/36 records (13.9% of the cases, P = 0.000). Nutritional therapy was administered to only 22/36 of the malnourished patients; however, unexpectedly, 6/73 well-nourished patients also received commercial enteral diets. Complications were diagnosed in 28/36 malnourished and 9/73 well-nourished patients (P = 0.000). Death occurred in 12/36 malnourished and 3/73 well-nourished patients (P = 0.001). A total of 24/36 malnourished patients were discharged regardless of NS. In summary, malnutrition remains a real problem, often unrecognized, unappreciated, and only sporadically treated, even though its effects can be detrimental to the clinical course and prognosis of patients. The amount of public and private funds unnecessarily dispersed because of hospital malnutrition is significant.

Alzheimer's disease: is a vaccine possible?

The cause of Alzheimer's disease is still unknown, but the disease is distinctively characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. These features have become the primary focus of much of the research looking for new treatments for the disease, including immunotherapy and vaccines targeting β-amyloid in the brain. Adverse effects observed in a clinical trial based on the β-amyloid protein were attributed to the presence of the target antigen and emphasized the relevance of finding safer antigen candidates for active immunization. For this kind of approach, different vaccine formulations using DNA, peptide, and heterologous prime-boost immunization regimens have been proposed. Promising results are expected from different vaccine candidates encompassing B-cell epitopes of the β-amyloid protein. In addition, recent results indicate that targeting another protein involved in the etiology of the disease has opened new perspectives for the effective prevention of the illness. Collectively, the evidence indicates that the idea of finding an effective vaccine for the control of Alzheimer's disease, although not without challenges, is a possibility.

Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume

Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication.

Elevated levels of plasma osteoprotegerin are associated with all-cause mortality risk and atherosclerosis in patients with stages 3 to 5 chronic kidney disease

Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and plays a role in vascular calcification. We evaluated the relationship between osteoprotegerin levels and inflammatory markers, atherosclerosis, and mortality in patients with stages 3-5 chronic kidney disease. A total of 145 subjects (median age 61 years, 61% men; 36 patients on hemodialysis, 55 patients on peritoneal dialysis, and 54 patients with stages 3-5 chronic kidney disease) were studied. Clinical characteristics, markers of mineral metabolism (including fibroblast growth factor-23 [FGF-23]) and inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]), and the intima-media thickness (IMT) in the common carotid arteries were measured at baseline. Cardiac function was assessed by color tissue Doppler echocardiography. After 36 months follow-up, the survival rate by Kaplan-Meier analysis was significantly different according to OPG levels (χ2=14.33; P=0.002). Increased OPG levels were positively associated with IL-6 (r=0.38, P<0.001), FGF-23 (r=0.26, P<0.001) and hsCRP (r=0.0.24, P=0.003). In addition, OPG was positively associated with troponin I (r=0.54, P<0.001) and IMT (r=0.39, P<0.0001). Finally, in Cox analysis, only OPG (HR=1.07, 95%CI=1.02-1.13) and hsCRP (HR=1.02, 95%CI=1.01-1.04) were independently associated with increased risk of death. These results suggested that elevated levels of serum OPG might be associated with atherosclerosis and all-cause mortality in patients with chronic kidney disease.

Association of body mass index with disease severity and prognosis in patients with non-cystic fibrosis bronchiectasis

The objective of this observational, multicenter study was to evaluate the association of body mass index (BMI) with disease severity and prognosis in patients with non-cystic fibrosis bronchiectasis. A total of 339 patients (197 females, 142 males) diagnosed with non-cystic fibrosis bronchiectasis by high-resolution computed tomography were classified into four groups: underweight (BMI<18.5 kg/m2), normal weight (18.5≤BMI<25.0 kg/m2), overweight (25.0≤BMI<30.0 kg/m2), and obese (BMI≥30.0 kg/m2). Clinical variables expressing disease severity were recorded, and acute exacerbations, hospitalizations, and survival rates were estimated during the follow-up period. The mean BMI was 21.90 kg/m2. The underweight group comprised 28.61% of all patients. BMI was negatively correlated with acute exacerbations, C-reactive protein, erythrocyte sedimentation rate, radiographic extent of bronchiectasis, and chronic colonization by P. aeruginosa and positively correlated with pulmonary function indices. BMI was a significant predictor of hospitalization risk independent of relevant covariates. The 1-, 2-, 3-, and 4-year cumulative survival rates were 94%, 86%, 81%, and 73%, respectively. Survival rates decreased with decreasing BMI (χ2=35.16, P<0.001). The arterial carbon dioxide partial pressure, inspiratory capacity, age, BMI, and predicted percentage of forced expiratory volume in 1 s independently predicted survival in the Cox proportional hazard model. In conclusion, an underweight status was highly prevalent among patients with non-cystic fibrosis bronchiectasis. Patients with a lower BMI were prone to developing more acute exacerbations, worse pulmonary function, amplified systemic inflammation, and chronic colonization by P. aeruginosa. BMI was a major determinant of hospitalization and death risks. BMI should be considered in the routine assessment of patients with non-cystic fibrosis bronchiectasis.

Association between indoxyl sulfate and bone histomorphometry in pre-dialysis chronic kidney disease patients

Introduction: Experimental studies have suggested that indoxyl sulfate (IS), a protein-bound uremic toxin, may be involved in the development of renal osteodystrophy. Objective: evaluate the association between IS levels and biochemical parameters related to mineral metabolism and bone histomorphometry in a cohort of pre-dialysis chronic kidney disease (CKD) patients. Methods: This is a post-hoc analysis of an observational study evaluating the association between coronary calcification and bone biopsy findings in 49 patients (age: 52 ± 10 years; 67% male; estimated glomerular filtration rate: 36 ± 17 ml/min). Serum levels of IS were measured. Results: Patients at CKD stages 2 and 3 presented remarkably low bone formation rate. Patients at CKD stages 4 and 5 presented significantly higher osteoid volume, osteoblast and osteoclast surface, bone fibrosis volume and bone formation rate and a lower mineralization lag time than CKD stage 2 and 3 patients. We observed a positive association between IS levels on one hand and the bone formation rate, osteoid volume, osteoblast surface and bone fibrosis volume on the other. Multivariate regression models confirmed that the associations between IS levels and osteoblast surface and bone fibrosis volume were both independent of demographic and biochemical characteristics of the study population. A similar trend was observed for the bone formation rate. Conclusion: Our findings demonstrated that IS is positively associated with bone formation rate in pre-dialysis CKD patients.