Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

Intense immune responses are observed during human or experimental infection with the digenetic protozoan parasite Trypanosoma cruzi. The reasons why such immune responses are unable to completely eliminate the parasites are unknown. The survival of the parasite leads to a parasite-host equilibrium found during the chronic phase of chagasic infection in most individuals. Parasite persistence is recognized as the most likely cause of the chagasic chronic pathologies. Therefore, a key question in Chagas' disease is to understand how this equilibrium is established and maintained for a long period. Understanding the basis for this equilibrium may lead to new approaches to interventions that could help millions of individuals at risk for infection or who are already infected with T. cruzi. Here, we propose that the phenomenon of immunodominance may be significant in terms of regulating the host-parasite equilibrium observed in Chagas' disease. T. cruzi infection restricts the repertoire of specific T cells generating, in some cases, an intense immunodominant phenotype and in others causing a dramatic interference in the response to distinct epitopes. This immune response is sufficiently strong to maintain the host alive during the acute phase carrying them to the chronic phase where transmission usually occurs. At the same time, immunodominance interferes with the development of a higher and broader immune response that could be able to completely eliminate the parasite. Based on this, we discuss how we can interfere with or take advantage of immunodominance in order to provide an immunotherapeutic alternative for chagasic individuals.

Tracheal instillation of urban PM2.5 suspension promotes acute cardiac polarization changes in rats

The mechanisms by which PM2.5 increases cardiovascular mortality are not fully identified. Autonomic alterations are the current main hypotheses. Our objective was to determine if PM2.5 induces acute cardiac polarization alterations in healthy Wistar rats. PM2.5 samples were collected on polycarbonate filters. Solutions containing 10, 20, and 50 µg PM2.5 were administered by tracheal instillation. P wave duration decreased significantly at 20 µg (0.99 ± 0.06, 0.95 ± 0.06, and 0.96 ± 0.07; P < 0.001), and 50 µg (0.98 ± 0.06, 0.98 ± 0.07, and 0.96 ± 0.08; 60, 90 and 120 min, respectively) compared to blank filter solution (P < 0.001). PR interval duration decreased significantly at 20 µg (0.99 ± 0.06, 0.98 ± 0.07, and 0.97 ± 0.08) and 50 µg (0.99 ± 0.05, 0.97 ± 0.0, and 0.95 ± 0.05; 60, 90, and 120 min, respectively) compared to blank filter and 10 µg (P < 0.001). QRS interval duration decreased at 20 and 50 µg in relation to blank filter solution and 10 µg (P < 0.001). QT interval duration decreased significantly (P < 0.001) with time in animals receiving 20 µg (0.94 ± 0.12, 0.88 ± 0.14, and 0.88 ± 0.11) and 50 µg (1.00 ± 0.13; 0.97 ± 0.11 and 0.98 ± 0.16; 60, 90 and 120 min, respectively) compared to blank filter solution and 10 µg (P < 0.001). PM2.5 induced reduced cardiac conduction time, within a short period, indicating that depolarization occurs more rapidly across ventricular tissue.

Detection of caliciviruses associated with acute infantile gastroenteritis in Salvador, an urban center in Northeast Brazil

Acute gastroenteritis caused by viruses is one of the leading causes of infantile morbidity. The aim of the present study was to investigate the presence of human caliciviruses of the genera norovirus and sapovirus in children up to 3 years of age with acute gastroenteritis from low-income communities in the city of Salvador, Brazil. This study is an extension of previous work carried out to establish the profile of the most prevalent enteric pathogens present in these communities. In this report, 139 fecal samples, collected from July 2001 to January 2002 were analyzed by RT-PCR and 13 (9%) were positive for human caliciviruses. By sequencing, seven isolates were characterized as norovirus genogroup GII and one as sapovirus genotype GII/1. Sequencing of the previously detected group-A rotaviruses and human astroviruses was also performed and revealed the circulation of rotavirus group A genotypes G1P[8] and G9P[8], and human astrovirus genotypes 6, 7, and 8. No mixed infection was observed. Community-based studies provide geographically representative information on disease burden. However, there are only a few reports in developing countries concerning the genotypes of the most important gastroenteric viruses detected in such communities. The present findings demonstrate the wide diversity of genotypes of the most important viruses responsible for acute gastroenteritis circulating in low-income communities.

Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 ± 45 vs post: 235 ± 47; P = 0.003) but not during 400-ms (pre: 275 ± 28 vs post: 248 ± 32; P = 0.490) or 600-ms (pre: 252 ± 42 vs post: 179 ± 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 ± 7 vs post: 245 ± 9; P = 0.028) but not during the 500-ms (pre: 248 ± 7 vs post: 253 ± 9; P = 0.150) or 600-ms (pre: 254 ± 8 vs post: 259 ± 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.

Acute kidney injury in AIDS: frequency, RIFLE classification and outcome

The objective of the present study was to evaluate the characteristics of acute kidney injury (AKI) in AIDS patients and the value of RIFLE classification for predicting outcome. The study was conducted on AIDS patients admitted to an infectious diseases hospital inBrazil. The patients with AKI were classified according to the RIFLE classification: R (risk), I (injury), F (failure), L (loss), and E (end-stage renal disease). Univariate and multivariate analyses were used to evaluate the factors associated with AKI. A total of 532 patients with a mean age of 35 ± 8.5 years were included in this study. AKI was observed in 37% of the cases. Patients were classified as "R" (18%), "I" (7.7%) and "F" (11%). Independent risk factors for AKI were thrombocytopenia (OR = 2.9, 95%CI = 1.5-5.6, P < 0.001) and elevation of aspartate aminotransferase (AST) (OR = 3.5, 95%CI = 1.8-6.6, P < 0.001). General mortality was 25.7% and was higher among patients with AKI (40.2 vs17%, P < 0.001). AKI was associated with death and mortality increased according to RIFLE classification - "R" (OR 2.4), "I" (OR 3.0) and "F" (OR 5.1), P < 0.001. AKI is a frequent complication in AIDS patients, which is associated with increased mortality. RIFLE classification is an important indicator of poor outcome for AIDS patients.

Evasion of immune responses by Trypanosoma cruzi, the etiological agent of Chagas disease

Infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects millions of people in Latin America. Infection with T. cruzi cannot be eliminated by the immune system. A better understanding of immune evasion mechanisms is required in order to develop more effective vaccines. During the acute phase, parasites replicate extensively and release immunomodulatory molecules that delay parasite-specific responses mediated by T cells. This immune evasion allows the parasite to spread in the host. In the chronic phase, parasite evasion relies on its replication strategy of hijacking the TGF-β signaling pathway involved in inflammation and tissue regeneration. In this article, the mechanisms of immune evasion described for T. cruzi are reviewed.

Characterization and analysis of the outcome of adults with acute myeloid leukemia treated in a Brazilian University hospital over three decades

We evaluated the outcome of 227 patients with acute myeloid leukemia during three decades (period 1 - 1980’s, N = 89; period 2 - 1990’s, N = 73; period 3 - 2000’s, N = 65) at a single institution. Major differences between the three groups included a higher median age, rates of multilineage dysplasia and co-morbidities, and a lower rate of clinical manifestations of advanced leukemia in recent years. The proportion of patients who received induction remission chemotherapy was 66, 75, and 85% for periods 1, 2, and 3, respectively (P = 0.04). The median survival was 40, 77, and 112 days, and the 5-year overall survival was 7, 13, and 22%, respectively (P = 0.01). The median disease-free survival was 266, 278, and 386 days (P = 0.049). Survival expectation for patients with acute myeloid leukemia has substantially improved during this 30-year period, due to a combination of lower tumor burden and a more efficient use of chemotherapy and supportive care.

Lymphatic fluctuation in the parenchymal remodeling stage of acute interstitial pneumonia, organizing pneumonia, nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis

Because the superficial lymphatics in the lungs are distributed in the subpleural, interlobular and peribroncovascular interstitium, lymphatic impairment may occur in the lungs of patients with idiopathic interstitial pneumonias (IIPs) and increase their severity. We investigated the distribution of lymphatics in different remodeling stages of IIPs by immunohistochemistry using the D2-40 antibody. Pulmonary tissue was obtained from 69 patients with acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD, N = 24), cryptogenic organizing pneumonia/organizing pneumonia (COP/OP, N = 6), nonspecific interstitial pneumonia (NSIP/NSIP, N = 20), and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP, N = 19). D2-40+ lymphatic in the lesions was quantitatively determined and associated with remodeling stage score. We observed an increase in the D2-40+ percent from DAD (6.66 ± 1.11) to UIP (23.45 ± 5.24, P = 0.008) with the advanced process of remodeling stage of the lesions. Kaplan-Meier survival curves showed a better survival for patients with higher lymphatic D2-40+ expression than 9.3%. Lymphatic impairment occurs in the lungs of IIPs and its severity increases according to remodeling stage. The results suggest that disruption of the superficial lymphatics may impair alveolar clearance, delay organ repair and cause severe disease progress mainly in patients with AIP/DAD. Therefore, lymphatic distribution may serve as a surrogate marker for the identification of patients at greatest risk for death due to IIPs.

Relationship between genetic mutation variations and acute-phase reactants in the attack-free period of children diagnosed with familial Mediterranean fever

Familial Mediterranean fever (FMF) is a periodic autoinflammatory disease characterized by chronic inflammation. This study investigated the relationship between acute-phase reactants and gene mutations in attack-free periods of childhood FMF. Patients diagnosed with FMF were divided into four groups based on genetic features: no mutation, homozygous, heterozygous, and compound heterozygous. These groups were monitored for 2 years, and blood samples were collected every 6 months during attack-free periods. Erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and white blood cell count were measured. A disease severity score was determined for each patient. Mean values for erythrocyte sedimentation rate and fibrinogen were significantly different in the homozygous group. White blood cell count and C-reactive protein were similar between the groups. Disease severity score was higher in patients with the M694V mutation than in individuals without the mutation, as well as in those with other mutation groups. Periodic follow-up of patients with FMF MEFV mutations in subjects with acute-phase reactants may be useful in the prevention of morbidity.

A time series analysis of meteorological factors and hospital outpatient admissions for cardiovascular disease in the Northern district of Guizhou Province, China

Findings on the effects of weather on health, especially the effects of ambient temperature on overall morbidity, remain inconsistent. We conducted a time series study to examine the acute effects of meteorological factors (mainly air temperature) on daily hospital outpatient admissions for cardiovascular disease (CVD) in Zunyi City, China, from January 1, 2007 to November 30, 2009. We used the generalized additive model with penalized splines to analyze hospital outpatient admissions, climatic parameters, and covariate data. Results show that, in Zunyi, air temperature was associated with hospital outpatient admission for CVD. When air temperature was less than 10°C, hospital outpatient admissions for CVD increased 1.07-fold with each increase of 1°C, and when air temperature was more than 10°C, an increase in air temperature by 1°C was associated with a 0.99-fold decrease in hospital outpatient admissions for CVD over the previous year. Our analyses provided statistically significant evidence that in China meteorological factors have adverse effects on the health of the general population. Further research with consistent methodology is needed to clarify the magnitude of these effects and to show which populations and individuals are vulnerable.

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.

Multiple facets of HIV-associated renal disease

HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥200 cells/mm3 was associated with better renal function after 2 years of follow-up.

Averting the legacy of kidney disease - focus on childhood

World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, in that the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease as a consequence of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for-date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, although only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that the World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood.

Promoting inflammatory lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) aggravated intestinal inflammation in mice with experimental acute colitis

Angiogenesis and lymphangiogenesis are thought to play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, it is not understood if inflammatory lymphangiogenesis is a pathological consequence or a productive attempt to resolve the inflammation. This study investigated the effect of lymphangiogenesis on intestinal inflammation by overexpressing a lymphangiogenesis factor, vascular endothelial growth factor-C (VEGF-C), in a mouse model of acute colitis. Forty eight-week-old female C57BL/6 mice were treated with recombinant adenovirus overexpressing VEGF-C or with recombinant VEGF-C156S protein. Acute colitis was then established by exposing the mice to 5% dextran sodium sulfate (DSS) for 7 days. Mice were evaluated for disease activity index (DAI), colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), and VEGFR-3mRNA expression in colon tissue. When acute colitis was induced in mice overexpressing VEGF-C, there was a significant increase in colonic epithelial damage, inflammatory edema, microvessel density, and neutrophil infiltration compared to control mice. These mice also exhibited increased lymphatic vessel density (73.0±3.9 vs 38.2±1.9, P<0.001) and lymphatic vessel size (1974.6±104.3 vs 1639.0±91.5, P<0.001) compared to control mice. Additionally, the expression of VEGFR-3 mRNA was significantly upregulated in VEGF-C156S mice compared to DSS-treated mice after induction of colitis (42.0±1.4 vs 3.5±0.4, P<0.001). Stimulation of lymphangiogenesis by VEGF-C during acute colitis promoted inflammatory lymphangiogenesis in the colon and aggravated intestinal inflammation. Inflammatory lymphangiogenesis may have pleiotropic effects at different stages of IBD.

The long-term outcome after acute kidney injury: a narrative review

This review will focus on long-term outcomes after acute kidney injury (AKI). Surviving AKI patients have a higher late mortality compared with those admitted without AKI. Recent studies have claimed that long-term mortality in patients after AKI varied from 15% to 74% and older age, presence of previous co-morbidities, and the incomplete recovery of renal function have been identified as risk factors for reduced survival. AKI is also associated with progression to chronic kidney (CKD) disease and the decline of renal function at hospital discharge and the number and severity of AKI episodes have been associated with progression to CKD. IN the most studies, recovery of renal function is defined as non-dependence on renal replacement therapy which is probably too simplistic and it is expected in 60-70% of survivors by 90 days. Further studies are needed to explore the long-term prognosis of AKI patients.