One of the main challenges for neurodegenerative disorders that are principally incurable is the development of new therapeutic strategies, which raises important medical, scientific and societal issues. Creutzfeldt-Jakob diseases are rare neurodegenerative fatal disorders which today remain incurable. The objective of this study was to evaluate the efficacy of the down-regulation of the prion protein (PrP) expression using siRNA delivered by, a water-in-oil microemulsion, as a therapeutic candidate in a preclinical study. After 12 days rectal mucosa administration of Aonys/PrP-siRNA in mice, we observed a decrease of about 28% of the brain PrPC level. The effect of Aonys/PrP-siRNA was then evaluated on prion infected mice. Several mice presented a delay in the incubation and survival time compared to the control groups and a significant impact was observed on astrocyte reaction and neuronal survival in the PrP-siRNA treated groups. These results suggest that a new therapeutic scheme based an innovative delivery system of PrP-siRNA can be envisioned in prion disorders.
It has been well documented that the maturing oocyte is very vulnerable to changes in its micro-environment, the follicular fluid (FF). Recent research has focused on different components within this FF, like hormones, growth factors and metabolites, and how their concentrations are altered by diet and the metabolic health of the mother. It has been proposed that fatty acids (FAs) are potential factors that influence oocyte maturation and subsequent embryo development. However, a thorough study of the specific FF FA composition per lipid fraction and how this may be affected by BMI is currently lacking. Therefore, we investigated the BMI-related concentration of FAs in the phospholipid (PL), cholesteryl-ester (CHE), triglyceride (TG) and non-esterified (NE) lipid fraction in the FF of women undergoing assisted reproductive treatment (ART).
In this descriptive cross-sectional study, the FF of normal weight (18.5 ≤ BMI < 25.0 kg/m(2), n = 10), overweight (25.0 ≤ BMI < 30.0 kg/m(2), n = 10) and obese (BMI ≥ 30.0 kg/m(2), n = 10) women, undergoing ART, was sampled and analyzed for 23 specific FAs in the PL, CHE, TG and NEFA fraction, using a gas chromatographic analysis method. Differences between BMI-groups were studied by means of univariate general linear models and post hoc Sheffé tests.
Total FA concentrations in the PL and CHE fraction did not differ between BMI groups. Total TG concentrations tended to differ and total NEFA concentrations differed significantly between BMI groups. Interestingly, 42% and 34% of the total FAs was esterified in the PL and CHE fraction, respectively, while only 10% were present in both the TG and NEFA fraction. Only few individual FA concentrations differed in the PL, CHE and TG fraction between BMI groups, whereas abundant BMI-related differences were found in the NEFA fraction.
Our data show that differences in BMI are associated with alterations in the FA composition of the FF, an effect most pronounced in the NEFA fraction. These BMI-related variations could possibly affect granulosa cell viability, oocyte developmental competence and subsequent embryo quality possibly explaining differences in oocyte quality in obese patients described by others.
Follicular fluid; Fatty acid; NEFA; BMI; Obesity; ART
The objective of this study was to evaluate total antioxidant capacity (TAC), total phenolic content (TPH), and the identification of anthocyanidin and polyphenolic compounds in 13 colored potatoes collected from the Andean region of Bolivia, and understand how the chemical composition correlated with the botanical classification and molecular characterization of genes, ans (anthocyanidin synthase) and stan1 (Solanum tuberosum anthocyanidin synthase), associated with the synthesis of anthocyanidins. The results show the existence of a limited correlation between botanical classification, based on morphological identification and polyphenol composition. No association between genetic grouping of the ans and stan genes and botanical classification was found. However, it was possible to identify a correlation between the ans gene clades and the levels of anthocyanidins as well as of other polyphenols. Thus, this result confirms the concept that potato color can be used in the search for high polyphenol potato cultivars.
Ans and stan genes; anthocyanidins; antioxidant capacity; polyphenolic compounds and purple potatoes
Acute schistosomiasis is associated with a primary exposure and is more commonly seen in nonimmune individuals traveling through endemic regions. In this study, we have focused on the cytokine profile of T lymphocytes evaluated in circulating leukocytes of acute Schistosomiasis mansoni-infected patients (ACT group) before and after praziquantel treatment (ACT-TR group). Our data demonstrated increased values of total leukocytes, eosinophils, and monocytes in both groups. Interestingly, we have observed that patients treated with praziquantel showed increased values of lymphocytes as compared with noninfected group (NI) or ACT groups. Furthermore, a decrease of neutrophils in ACT-TR was observed when compared to ACT group. Analyses of short-term in vitro whole blood stimulation demonstrated that, regardless of the presence of soluble Schistosoma mansoni eggs antigen (SEA), increased synthesis of IFN-γ and IL-4 by T-cells was observed in the ACT group. Analyses of cytokine profile in CD8 T cells demonstrated higher percentage of IFN-γ and IL-4 cells in both ACT and ACT-TR groups apart from increased percentage of IL-10 cells only in the ACT group. This study is the first one to point out the relevance of CD8 T lymphocytes in the immune response induced during the acute phase of schistosomiasis.
The lifetime prevalence of self-reported asthma among Puerto Ricans is very high, with increased asthma hospitalizations, emergency department visits, and mortality rates. Differences in asthma severity between the mainland and island, however, remain largely unknown.
We sought to characterize differences in asthma severity and control among 4 groups: (1) Island Puerto Ricans, (2) Rhode Island (RI) Puerto Ricans, (3) RI Dominicans, and (4) RI whites.
Eight hundred five children aged 7 to 15 years completed a diagnostic clinic session, including a formal interview, physical examination, spirometry, and allergy testing. Using a visual grid adapted from the Global Initiative for Asthma, asthma specialists practicing in each site determined an asthma severity rating. A corresponding level of asthma control was determined by using a computer algorithm.
Island Puerto Ricans had significantly milder asthma severity compared with RI Puerto Ricans, Dominicans, and whites (P < .001). Island Puerto Ricans were not significantly different from RI whites in asthma control. RI Puerto Ricans showed a trend toward less control compared with island Puerto Ricans (P = .061). RI Dominicans had the lowest rate of controlled asthma. Paradoxically, island Puerto Ricans had more emergency department visits in the past 12 months (P < .001) compared with the 3 RI groups.
Potential explanations for the paradoxic finding of milder asthma in island Puerto Ricans in the face of high health care use are discussed. Difficulties in determining guideline-based composite ratings for severity versus control are explored in the context of disparate groups.
Asthma; severity; control; clinical guidelines; Global Initiative for Asthma; Latino; Puerto Rican; Dominican; Rhode Island; health care use
Epidemiologic studies have documented higher rates of asthma prevalence and morbidity in minority children compared to non-Latino white (NLW) children. Few studies focus on the mechanisms involved in explaining this disparity, and fewer still on the methodological challenges involved in rigorous disparities research.
Objectives and Methods
This article provides an overview of challenges and potential solutions to research design for studies of health disparities. The methodological issues described in this article were framed on an empirical model of asthma health disparities that views disparities as resulting from several factors related to the healthcare system and the individual/community system. The methods used in the Rhode Island–Puerto Rico Asthma Center are provided as examples, illustrating the challenges in executing disparities research.
Several methods are described: distinguishing ethnic/racial differences from methodological artifacts, identifying and adapting culturally sensitive measures to explain disparities, and addressing the challenges involved in determining asthma and its severity in Latino and other minority children. The measures employed are framed within each of the components of the conceptual model presented.
Understanding ethnic and/or cultural disparities in asthma morbidity is a complicated process. Methodologic approaches to studying the problem must reflect this complexity, allowing us to move from documenting disparities to understanding them, and ultimately to reducing them.
asthma; health disparities; Latino; Puerto Rican; children; research methods
Disease-specific estimates of medical costs are important for health policy decision making.
To identify predictors of health care costs associated with hepatitis C virus (HCV) seropositivity across disease phases.
HCV laboratory tests from the BC Centre for Disease Control were linked to administrative data pertaining to health services and drugs dispensed to estimate costs among case subjects and controls. The case group comprised HCV seropositive individuals (n=20,001), and the control group comprised single-tested, HCV seronegative persons (n=70,752) identified between January 1997 and December 2004. Subject observation time was assigned to the three following disease phases: initial phase (after diagnosis), late phase (late-stage liver disease) and predeath phase (12 months before death). Case subjects and controls were matched for age, sex and a propensity score within each phase to determine the net cost attributable to HCV seropositivity, and were adjusted for demographic and clinical factors.
Costs increased with disease progression, with hospitalization being the highest cost component in all phases. Initial and late phase net costs (2005 Canadian dollars) were $1,850 and $6,000 per patient per year, respectively. Costs among case subjects were driven by age, comorbidities, mental illness, illicit drug use and HIV coinfection. While predeath case subject and control costs were virtually the same, costs were high and case subjects died at a younger age.
HCV seropositivity is associated with increased medical costs driven by viral sequelae and medicosocial vulnerabilities (ie, mental illness, illicit drug use and HIV coinfection). Cost mitigation and health outcome improvements will require broad-based prevention programming to reduce vulnerabilities and HCV treatment to prevent disease progression, respectively.
Cost of illness; Health economics; Hepatitis C; Liver disease; Net costs; Vulnerable populations
The Multiple Sclerosis International Quality Of Life (MusiQoL) questionnaire, a 31-item, multidimensional, self-administrated questionnaire that is available in 14 languages including Spanish, has been validated using a large international sample. We investigated the validity and reliability of the Spanish version of MusiQoL in Spain.
Consecutive patients with different types and severities of multiple sclerosis (MS) were recruited from 22 centres across Spain. All patients completed the MusiQoL questionnaire, the 36-Item Short Form (SF-36) health survey, and a symptoms checklist at baseline and 21 days later. External validity, internal consistency, reliability and reproducibility were tested.
A total of 224 Spanish patients were evaluated. Dimensions of MusiQoL generally demonstrated a high internal consistency (Cronbach's alpha: 0.70-0.92 for all but two MusiQoL domain scores). External validity testing revealed that the MusiQoL index score correlated significantly with all SF-36 dimension scores (Pearson's correlation: 0.46-0.76), reproducibility was satisfactory (intraclass correlation coefficient: 0.60-0.91), acceptability was high, and the time taken to complete the 31-item questionnaire was reasonable (mean [standard deviation]: 9.8 [11.8] minutes).
The Spanish version of the MusiQoL questionnaire appears to be a valid and reliable instrument for measuring quality of life in patients with MS in Spain and constitutes a useful instrument to measure health-related quality of life in the clinical setting.
Rationale: Disparities in pediatric asthma exist in that Latino children have higher prevalence and greater morbidity from asthma than non–Latino white children. The factors behind these disparities are poorly understood, but ethnic-related variations in children's ability to accurately recognize and report their pulmonary functioning may be a contributing process.
Objectives: To determine (1) if differences exist between Latino and non–Latino white children's perceptual accuracy and (2) whether these differences are related to asthma outcomes.
Methods: Five hundred and twelve children, aged 7–16 years (290 island Puerto Ricans, 115 Rhode Island Latinos, and 107 Rhode Island non-Latino white children) participated in a 5-week home-based protocol in which twice daily they entered subjective estimates of their peak expiratory flow rate into a hand-held, programmable spirometer and then performed spirometry. Their accuracy was summarized as three perceptual accuracy scores. Demographic data, asthma severity, intelligence, emotional expression, and general symptom-reporting tendencies were assessed and covaried in analyses of the relationship of perceptual accuracy to asthma morbidity and health care use.
Measurements and Main Results: Younger age, female sex, lower intelligence, and poverty were associated with lower pulmonary function perception scores. Island Puerto Rican children had the lowest accuracy and highest magnification scores, followed by Rhode Island Latinos; both differed significantly from non–Latino white children. Perceptual accuracy scores were associated with most indices of asthma morbidity.
Conclusions: Controlling for other predictive variables, ethnicity was related to pulmonary function perception ability, as Latino children were less accurate than non–Latino white children. This difference in perceptual ability may contribute to recognized asthma disparities.
childhood asthma; symptom recognition; disparities
Trypanosoma cruzi-specific immune responses were evaluated in a total of 88 subjects living in areas endemic of Chagas disease of Argentina by IFN-γ ELISPOT assays and immunoblotting. Positive T. cruzi antigen-induced IFN-γ responses were detected in 42% of subjects evaluated (15/26 positive by conventional serology and 22/62 seronegative subjects). Using immunoblotting, T. cruzi-specific IgG reactivity was detected in all seropositive subjects and in 11% (7/61) of subjects negative by conventional serology. Measurements of T cell responses and antibodies by immunoblotting, in conjunction with conventional serology, might enhance the capability of detection of exposure to T. cruzi in endemic areas.
Trypanosoma cruzi; T cell responses; Humoral responses
Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis.
As HIV and hepatitis C (HCV) share some modes of transmission co-infection is not uncommon. This study used a population-based sample of HIV and HCV tested individuals to determine the prevalence of HIV/HCV co-infection, the sequence of virus diagnoses, and demographic and associated risk factors.
Positive cases of HIV were linked to the combined laboratory database (of negative and positive HCV antibody results) and HCV reported cases in British Columbia (BC).
Of 4,598 HIV cases with personal identifiers, 3,219 (70%) were linked to the combined HCV database, 1,700 (53%) of these were anti-HCV positive. HCV was diagnosed first in 52% of co-infected cases (median time to HIV identification 3 1/2 years). HIV and HCV was diagnosed within a two week window in 26% of cases. Among individuals who were diagnosed with HIV infection at baseline, subsequent diagnoses of HCV infection was independently associated with: i) intravenous drug use (IDU) in males and females, Hazard Ratio (HR) = 6.64 (95% CI: 4.86-9.07) and 9.76 (95% CI: 5.76-16.54) respectively; ii) reported Aboriginal ethnicity in females HR = 2.09 (95% CI: 1.34-3.27) and iii) males not identified as men-who-have-sex-with-men (MSM), HR = 2.99 (95% CI: 2.09-4.27).
Identification of HCV first compared to HIV first was independently associated with IDU in males and females OR = 2.83 (95% CI: 1.84-4.37) and 2.25 (95% CI: 1.15-4.39) respectively, but not Aboriginal ethnicity or MSM. HIV was identified first in 22%, with median time to HCV identification of 15 months;
The ability to link BC public health and laboratory HIV and HCV information provided a unique opportunity to explore demographic and risk factors associated with HIV/HCV co-infection. Over half of persons with HIV infection who were tested for HCV were anti-HCV positive; half of these had HCV diagnosed first with HIV identification a median 3.5 years later. This highlights the importance of public health follow-up and harm reduction measures for people identified with HCV to prevent subsequent HIV infection.
Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites’ resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
An estimated 250,000 Canadians are infected with the hepatitis C virus (HCV). The present study describes a cohort of individuals with HCV referred to community-based, integrated prevention and care projects developed in British Columbia. Treatment outcomes are reported for a subset of individuals undergoing antiviral therapy at four project sites.
Four demonstration projects based on a public health nurse and physician partnership were established in rural and small urban centres in British Columbia. Comprehensive medical assessments determined whether individuals received treatment, or counselling and education. Outcomes of the treatment group were compared with published randomized controlled trials. Client demographics were mapped using geographical information systems applications.
A total of 1795 individuals were referred to the clinics for medical assessment between Septmber 2001 and December 2005. After assessment, 26% were eligible for therapy, while 74% received counselling and education. Wait times decreased annually, with one-half of all referrals assessed within 30 days. Combination antiviral therapy was initiated in 363 clients with interferon plus ribavirin (n=36) or pegylated interferon plus ribavirin (n=327). Treatment outcomes were available for 205 individuals. The overall rate of sustained virological response was 61% (126 of 205 individuals). The number of individuals assessed at each site represented, on average, 20% of the total cumulative reported HCV cases in the catchment areas.
The study findings illustrate how a public health nurse and physician partnership can service a population with complex medical needs while simultaneously increasing local capacity. Treatment outcomes were comparable with published clinical trials.
Capacity enhancement; HCV treatment; Hepatitis C virus
Background: There are indications that mortality in breast cancer is related with dietary factors, but no study has been large enough to characterise reliably how, this risk is influenced. To establish a logistic regression equation that would predict breast cancer from factors in the endocrinological and metabolic profile, we studied endocrinological and metabolic risk factors that are modified by the diet, in a population of women with breast cancer in southern Spain.
Patients and Methods: We carried out a simple a case-control study comparing 204 women with breast cancer (96 premenopausal and 108 postmenopausal women) and 250 healthy control subjects. The predictive variables were basal glycaemia, insulin, glycosylated haemoglobin (HbA1c), C-peptide, insulin-like growth factor-I (IGF-I), total cholesterol, triglycerides, high density lipoprotein-c (HDL-C), low density lipoprotein-c (LDL-C), selenium and Quetelet index (BMI).
Results: The metabolic profile differed between pre- and postmenopausal patients, and metabolic alterations were greater in postmenopausal than in premenopausal women. The differences between healthy subjects and breast cancer patients were clearly significant.
Conclusions: Our findings have several potential practical applications in the early detection of breast cancer, especially in premenopausal women; in primary prevention; and in the development of a mathematical model of breast carcinogenesis.
Case-control study; breast cancer; carcinogenesis; metabolic profile.
To ensure the highest efficiency, health services should be provided with the least possible complexity. The aim of this study is to quantify the degree of appropriateness in preoperatory hospital stays and to analyse those factors associated with a greater inappropriate use.
Historical cohort study. The histories of 440 hospitalised patients who underwent at least one surgical procedure were analysed. Data collection was carried out by doctors not involved in the services studied, following the Appropriateness Evaluation Protocol. A bivariate and multivariate analysis of the factors associated with the appropriateness of preoperatory stays was carried out.
The mean number of days of preoperatory stay was 5.5 (SD 5.11), of which a mean number of 2.5 days were considered to be inappropriate (SD 4.11). The overall rate of inappropriateness was 45.2% (CI 95% 43.3–47.1). The multivariate analysis showed a positive association of the inappropriateness of the preoperatory stay with weekend days, programmed admission, hospital stays longer than 7 days, medical records incorrectly or incompletely documented and the age groups of 45–65 and the >65 with respect to the <45 age group. Sex and an incorrect or incomplete nursing register did not show such an association.
The inappropriate use of hospital stay during preoperatory care affects almost half the period and there are some risk determinants that could act as indicators at admission. In addition, the efficiency of care provision was found to vary greatly from the point of view of its appropriateness.
This is the first study to characterize the environmental conditions which contribute to the presence and proliferation of environmental mycobacteria in a major freshwater river. Over 20 different species of environmental mycobacteria were isolated, including the pathogenic M. avium and M. kansasii. Species of the rapidly growing M. fortuitum complex were the most commonly isolated mycobacteria, and one-third of all isolates were not identified at the species level, even by 16S sequencing. PCR restriction analysis of the hsp65 gene was more accurate and rapid than biochemical tests and as accurate as yet less expensive than 16S sequencing, showing great promise as a new tool for species identification of environmentally isolated mycobacteria. Total environmental mycobacteria counts positively correlated with coliform and Escherichia coli counts and negatively correlated with chemical toxicity and water temperature. Environmental mycobacteria can survive in the alkaline conditions of the river despite previous reports that especially acidic conditions favor their presence. A representative river isolate (M. fortuitum) survived better than E. coli O157:H7 at pHs below 7 and above 8 in nutrient broth. The river strain also retained viability at 8 ppm of free chlorine, while E. coli was eliminated at 2 ppm and above. Thus, in vitro studies support environmental observations that a variety of extreme conditions favor the hardy environmental mycobacteria.
The Rio Grande River is the natural boundary between U.S. and Mexico from El Paso, TX to Brownsville, TX. and is one of the major water resources of the area. Agriculture, farming, maquiladora industry, domestic activities, as well as differences in disposal regulations and enforcement increase the contamination potential of water supplies along the border region. Therefore, continuous and accurate assessment of the quality of water supplies is of paramount importance. The objectives of this study were to monitor water quality of the Rio Grande and to determine if any correlations exist between fecal coliforms, E. coli, chemical toxicity as determined by Botsford's assay, H. pylori presence, and environmental parameters. Seven sites along a 112-Km segment of the Rio Grande from Sunland Park, NM to Fort Hancock, TX were sampled on a monthly basis between January 2000 and December 2002.
The results showed great variability in the number of fecal coliforms, and E. coli on a month-to-month basis. Fecal coliforms ranged between 0–106 CFU/100 ml while E. coli ranged between 6 to > 2419 MPN. H. pylori showed positive detection for all the sites at different times. Toxicity ranged between 0 to 94% of inhibition capacity (IC). Since values above 50% are considered to be toxic, most of the sites displayed significant chemical toxicity at different times of the year. No significant correlations were observed between microbial indicators and chemical toxicity.
The results of the present study indicate that the 112-Km segment of the Rio Grande river from Sunland Park, NM to Fort Hancock, TX exceeds the standards for contact recreation water on a continuous basis. In addition, the presence of chemical toxicity in most sites along the 112-Km segment indicates that water quality is an area of concern for the bi-national region. The presence of H. pylori adds to the potential health hazards of the Rio Grande. Since no significant correlation was observed between the presence of H. pylori antigens and the two indicators of fecal contamination, we can conclude that fecal indicators cannot be used to detect the presence of H. pylori reliably in surface water.
Chlorine concentrations below 0.8 mg/liter inactivated poliovirus without causing separation of the viral components. These results indicate that the release of RNA from the capsids is the result, not the cause, of virus inactivation by chlorine.