Immunopathology of Chagas disease

The main clinical forms of Chagas disease (acute, indeterminate and chronic cardiac) present strong evidences for the participation of the immune system on pathogenesis. Although parasite multiplication is evident during acute infection, the intense acute myocarditis of this phase exhibits clear ultrastructural signs of cell-mediated immune damage, inflicted to parasitized and non-parasitized myocardiocytes and to the endothelium of myocardial capillaries (microangiopathy). Inflammation subsides almost completely when immunity decreases parasite load and suppressor factors modulate host reaction, but inflammation does not disappear when the disease enters the indeterminate phase. Inflammation becomes mild and focal and undergoes cyclic changes leading to complete resolution. However, the process is maintained because the disappearance of old focal lesions is balanced by the upsurge of new ones. This equilibrium allows for prolonged host survival in the absence of symptoms or signs of disease. The chronic cardiac form is represented by a delayed-type, cell-mediated diffuse myocarditis, that probably ensues when the suppressive mechanisms, operative during the indeterminate phase, become defaulted. The mechanism responsible for the transition from the indeterminate to the cardiac form, is poorly understood.

Vectorial competence of Aedes aegypti (Linnaeus 1762) Rio de Janeiro Strain, to Dirofilaria immitis (Leidy 1856)

Dirofilaria immitis (Leidy 1856), a nematode parasite, is the etiologic agent of canine heartworm disease and mosquitoes are essential intermediate hosts. Mosquito susceptibility to the worms differ with species, strains and also among individuals of the same strain. To evaluate the degree of susceptibility of Rio de Janeiro laboratory raised strain of Aedes aegypti, we fed mosquitoes on canine blood with different densities of microfilariae (mf). There was no significant difference in the rate of development among the three different densities of mf. Infective larvae were found in the head and proboscis of all mosquitoes provided bloodmeals with different densities of mf after the 11th day post-infection. The infection rate of mosquitoes after ingestion of blood containing 3,000 mf/ml, 5,000 mf/ml and 7,000 mf/ml were 55.3%, 66.7% and 100%, respectively. The vector efficiency indices ranged from 1.6 to 9.3. The finding of L3 stage larvae, high infection rates and vector efficiency indices suggest that Ae. aegypti, Rio de Janeiro laboratory strain, is a potential vector of D. immitis, although of low efficiency.

The impact of Chagas disease control in Latin America: a review

Discovered in 1909, Chagas disease was progressively shown to be widespread throughout Latin America, affecting millions of rural people with a high impact on morbidity and mortality. With no vaccine or specific treatment available for large-scale public health interventions, the main control strategy relies on prevention of transmission, principally by eliminating the domestic insect vectors and control of transmission by blood transfusion. Vector control activities began in the 1940s, initially by means of housing improvement and then through insecticide spraying following successful field trials in Brazil (Bambui Research Centre), with similar results soon reproduced in São Paulo, Argentina, Venezuela and Chile. But national control programmes only began to be implemented after the 1970s, when technical questions were overcome and the scientific demonstration of the high social impact of Chagas disease was used to encourage political determination in favour of national campaigns (mainly in Brazil). Similarly, large-scale screening of infected blood donors in Latin America only began in the 1980s following the emergence of AIDS. By the end of the last century it became clear that continuous control in contiguous endemic areas could lead to the elimination of the most highly domestic vector populations - especially Triatoma infestans and Rhodnius prolixus - as well as substantial reductions of other widespread species such as T. brasiliensis, T. sordida, and T. dimidiata, leading in turn to interruption of disease transmission to rural people. The social impact of Chagas disease control can now be readily demonstrated by the disappearance of acute cases and of new infections in younger age groups, as well as progressive reductions of mortality and morbidity rates in controlled areas. In economic terms, the cost-benefit relationship between intervention (insecticide spraying, serology in blood banks) and the reduction of Chagas disease (in terms of medical and social care and improved productivity) is highly positive. Effective control of Chagas disease is now seen as an attainable goal that depends primarily on maintaining political will, so that the major constraints involve problems associated with the decentralisation of public health services and the progressive political disinterest in Chagas disease. Counterbalancing this are the political and technical cooperation strategies such as the "Southern Cone Initiative" launched in 1991. This international approach, coordinated by PAHO, has been highly successful, already reaching elimination of Chagas disease transmission in Uruguay, Chile, and large parts of Brazil and Argentina. The Southern Cone Initiative also helped to stimulate control campaigns in other countries of the region (Paraguay, Bolivia, Peru) which have also reached tangible regional successes. This model of international activity has been shown to be feasible and effective, with similar initiatives developed since 1997 in the Andean Region and in Central America. At present, Mexico and the Amazon Region remain as the next major challenges. With consolidation of operational programmes in all endemic countries, the future focus will be on epidemiological surveillance and care of those people already infected. In political terms, the control of Chagas disease in Latin America can be considered, so far, as a victory for international scientific cooperation, but will require continuing political commitment for sustained success.

Telephone Survey of Infectious Intestinal Disease in the Republic of Ireland

Infectious intestinal disease is a disease of the digestive system caused by infectious agents. Most infectious intestinal disease (IID) is self-limiting, requiring no clinical intervention, but it causes a substantial burden to the population through healthcare usage and absenteeism. Understanding the magnitude, distribution and demographic factors associated with IID is key to its mitigation. The cases and outbreaks of human disease detected via surveillance represent but a small proportion of the true burden of disease in the population, and special studies are needed periodically in order to be able to extrapolate true population experience from what is reported via surveillance. One way to identify the true extent of IID is to estimate illness in the community, and not just at the point where the individual has made contact with the health services.

Blood transfusion and iatrogenic risks in Mexico city: anti-Trypanosoma cruzi seroprevalence in 43,048 blood donors, evaluation of parasitemia, and electrocardiogram findings in seropositive

Iatrogenous transmission of Trypanosoma cruziby blood transfusion was suggested as a potential risk by Pellegrino (1949). Seropositive blood donors in Mexico were first reported in 1978, however, limited information is available due to small sampling, the use of heterogeneous serologic assays, and geographically limited studies. A wide survey carried out in 18 out of the 32 states of Mexico, showed a national mean of 1.6% seropositive among 64,969 donors, ranging from 0.2 to 2.8%. In the present study, we have screened 43,048 voluntary blood donors in a period of five years at the Instituto Nacional de Cardiología I. Chávez, a concentration hospital located in Mexico city which serves mainly the metropolitan area and accepts from all over the country. Standardized ELISA and IIF were used to identify seropositive individuals in addition to hemoculture, PCR and standard 12 lead ECG tests that were applied to a group of seropositive patients (29/161). The result showed a seropositivity of 0.37% (161/43,048). From the group of seropositive individuals 40% (12/29) were potential carriers of T. cruzi at the donation time and 5/29 had subclinical ECG abnormalities. Parasitological tests performed in 70 erythrocyte and platelet fractions from seropositive units (70/161) showed negative results. Our findings strongly support T. cruzi screening in the transfusion medicine practice and identify subclinical heart disease among seropositive blood donors.

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment.

BACKGROUND: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. METHODS: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. FINDINGS: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. INTERPRETATION: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. FUNDING: UK Medical Research Council, US National Institutes of Health.

Morphobiological aspects of Rhodnius brethesi Matta, 1919 (Hemiptera:Reduviidae) from the Upper and Middle Negro River, Amazon region of Brazil: I - scanning electron microscopy

The occurrence of autochthonous cases of Chagas disease in the Amazon region of Brazil over recent decades has motivated an intensification of studies in this area. Different species of triatomines have been identified, and ten of these have be proven to be carriers of the parasite Trypanosoma cruzi or " cruzi-like " parasites. Studies conducted in the municipalities of Santa Isabel do Rio Negro and Barcelos, located on the Upper and Middle of the Negro River, microregion of Negro River, state of Amazonas have confirmed not only that Rhodnius brethesi is present in the palm tree Leopoldinia piassaba, but also that this insect was recognized by palm fiber collectors. A morphological study of eyes, inter-ocular and inter-ocellar regions, antennae, buccula, labrum, rostrum, stridulatory sulcus and feet, including the apex of the tibia, spongy fossette and ctenidium was conducted by scanning electron microscopy. The buccula and the stridulatory sulcus presented notable differences in specimens of different genera and also of different species. These data make it possible to suggest that the details presented in these structures can be included as diagnostic characteristics to be used in new dichotomous keys, thereby contributing towards studies of taxonomy and systematics and furnishing backing for comparative analysis of specimens collected from different localities.

Chagas disease in Mexico: an analysis of geographical distribution during the past 76 years - A review

Literature from 1928 through 2004 was compiled from different document sources published in Mexico or elsewhere. From these 907 publications, we found 19 different topics of Chagas disease study in Mexico. The publications were arranged by decade and also by state. This information was used to construct maps describing the distribution of Chagas disease according to different criteria: the disease, vectors, reservoirs, and strains. One of the major problems confronting study of this zoonotic disease is the great biodiversity of the vector species; there are 30 different species, with at least 10 playing a major role in human infection. The high variability of climates and biogeographic regions further complicate study and understanding of the dynamics of this disease in each region of the country. We used a desktop Genetic Algorithm for Rule-Set Prediction procedure to provide ecological models of organism niches, offering improved flexibility for choosing predictive environmental and ecological data. This approach may help to identify regions at risk of disease, plan vector-control programs, and explore parasitic reservoir association. With this collected information, we have constructed a data base: CHAGMEX, available online in html format.

Polymorphisms of CD16A and CD32 Fcgamma receptors and circulating immune complexes in Meniere's disease: a case-control study.

BACKGROUND: Autoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménière's disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC. METHODS: The functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ2 with Fisher's exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC. RESULTS: Elevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fisher's test, corrected p = 6.9 × 10-4 for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fisher's test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11). CONCLUSIONS: Elevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.

Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.

Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study.

BACKGROUND Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. METHODS A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG > or = 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. RESULTS We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-epsilon4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG. CONCLUSION Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the epsilon4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.

Dispersal of Triatoma infestans and other Triatominae species in the arid Chaco of Argentina: Flying, walking or passive carriage? The importance of walking females

The aim of this paper was to analyse the active dispersal of Triatoma infestans and the role of chickens as passive carriers of this insect in peridomestic areas of La Rioja, Argentina. To measure active dispersal, monthly catches were made on six consecutive nights for five months (in the warm season) using light traps (for flying insects) and sticky dispersal barriers (for walking insects). The nutritional and reproductive states of adults were evaluated. Over the course of the sampling period, a total of eight flying adults, six walking nymphs and 10 walking adults of the species T. infestans were captured, as well as specimens of Triatoma guasayana, Triatoma eratyrusiformis and Triatoma platensis. Our data demonstrate for the first time that females of T. infestans can disperse by walking. This may be an adaptive strategy because it allows them to move with eggs and/or with good blood reserves, which are not possible when flying. All flying and walking individuals of both genders were of an appropriate physiological state that would allow for colonisation of the target habitat. However, manual inspection of 122 chickens suggests that it is unlikely that these animals passively transport T. infestans. Finally, the dispersal activity of T. infestans was compared with other triatomines using a dispersion index.

Ocular toxoplasmosis: evaluation of lacrimal - specific secretory IgA levels in both patients with active and inactive phases of the disease

Ocular toxoplasmosis can result in recurrent uveitis. Studies have shown that a correlation between active ocular toxoplasmosis and the presence of anti-Toxoplasma gondii secretory IgA (SIgA) in tears. This study compares anti-T. gondii SIgA levels in patients' tears during the acute and inactive phases of toxoplasmic uveitis. Twenty-nine positive tear specific SIgA for T. gondii patients with acute toxoplasmic uveitis were selected and were followed-up for at least two years, when the anti-T. gondii SIgA tears levels were determined. Specific SIgA for T. gondii was negative in 22 patients (75.86%) and positive in seven patients (24.13%) of whom six (85.7%) were followed over three years. Average SIgA levels during the acute phase are 1.54 and decrease significantly to 0.72 (p = 0.0001) during the inactive phase of disease. Because anti-T. gondii SIgA in the tear is negative in 75.86% of patients after the acute phase of infection, T. gondii SIgA levels may be used as a complementary diagnostic marker for active ocular toxoplasmosis.

HLA-Bw4 identifies a population of HIV-infected patients with an increased capacity to control viral replication after structured treatment interruption.

OBJECTIVES: After structured treatment interruption (STI) of treatment for HIV-1, a fraction of patients maintain suppressed viral loads. Prospective identification of such patients might improve HIV-1 treatment, if selected patients are offered STI. METHODS: We analysed the effect of previously identified genetic modulators of HIV-1 disease progression on patients' ability to suppress viral replication after STI. Polymorphisms in the genes killer cell immunoglobulin-like receptor 3DLI (KIR3DL1)/KIR3DS1, human leucocyte antigen B (HLA-B) and HLA Complex P5 (HCP5), and a polymorphism affecting HLA-C surface expression were analysed in 130 Swiss HIV Cohort Study patients undergoing STI. Genotypes were correlated with viral load levels after STI. RESULTS: We observed a statistically significant reduction in viral load after STI in carriers of HLA-B alleles containing either the Bw480Thr or the Bw480Ile epitope (mean adjusted effect on post-STI viral load: -0.82 log HIV-1 RNA copies/ml, P < 0.001; and -1.12 log copies/ml, P < 0.001, respectively). No significant effects were detected for the other polymorphisms analysed. The likelihood of being able to control HIV-1 replication using a prespecified cut-off (viral load increase < 1000 copies/ml) increased from 39% in Bw4-negative patients to 53% in patients carrying Bw4-80Thr, and to 65% in patients carrying Bw4-80Ile (P = 0.02). CONCLUSIONS: These data establish a significant impact of HLA-Bw4 on the control of viral replication after STI.

Effects of social support on the clinical course of Crohn's disease.

BACKGROUND: Social support has been found to be protective from adverse health effects of psychological stress. We hypothesized that higher social support would predict a more favorable course of Crohn's disease (CD) directly (main effect hypothesis) and via moderating other prognostic factors (buffer hypothesis). METHODS: Within a multicenter cohort study we observed 597 adults with CD for 18 months. We assessed social support using the ENRICHD Social Support Inventory. Flares, nonresponse to therapy, complications, and extraintestinal manifestations were recorded as a combined endpoint indicating disease deterioration. We controlled for several demographic, psychosocial, and clinical variables of potential prognostic importance. We used multivariate binary logistic regression to estimate the overall effect of social support on the odds of disease deterioration and to explore main and moderator effects of social support by probing interactions with other predictors. RESULTS: The odds of disease deterioration decreased by 1.5 times (95% confidence interval [CI]: 1.2-1.9) for an increase of one standard deviation (SD) of social support. In case of low body mass index (BMI) (i.e., 1 SD below the mean or <19 kg/m(2)), the odds decreased by 1.8 times for an increase of 1 SD of social support. In case of low social support, the odds increased by 2.1 times for a decrease of 1 SD of BMI. Low BMI was not predictive under high social support. CONCLUSIONS: The findings suggest that elevated social support may favorably affect the clinical course of CD, particularly in patients with low BMI. (Inflamm Bowel Dis 2010;).