Aqueous biphasic system based on cholinium ionic liquids: extraction of biologically active phenolic acids

Phenolic acids are aromatic secondary plant metabolites, widely spread throughout the plant kingdom. Due to their biological and pharmacological properties, they have been playing an important role in phytotherapy and consequently techniques for their separation and purification are in need. This thesis aims at exploring new sustainable separation processes based on ionic liquids (ILs) in the extraction of biologically active phenolic acids. For that purpose, three phenolic acids with similar chemical structures were selected: cinnamic acid, p-coumaric acid and caffeic acid. In the last years, it has been shown that ionic liquids-based aqueous biphasic systems (ABSs) are valid alternatives for the extraction, recovery and purification of biomolecules when compared to conventional ABS or extractions carried out with organic solvents. In particular, cholinium-based ILs represent a clear step towards a greener chemistry, while providing means for the implementation of efficient techniques for the separation and purification of biomolecules. In this work, ABSs were implemented using cholinium carboxylate ILs using either high charge density inorganic salt (K3PO4) or polyethylene glycol (PEG) to promote the phase separation of aqueous solutions containing three different phenolic acids. These systems allow for the evaluation of effect of chemical structure of the anion on the extraction efficiency. Only one imidazolium-based IL was used in order to establish the effect of the cation chemical structure. The selective extraction of one single acid was also researched. Overall, it was observed that phenolic acids display very complex behaviours in aqueous solutions, from dimerization to polymerization and also hetero-association are quite frequent phenomena, depending on the pH conditions. These phenomena greatly hinder the correct quantification of these acids in solution.

Development of novel active pharmaceutical ionic liquids and salts based on antibiotics and anti-fungal drugs

Ionic Liquids (ILs) are class of compounds, which have become popular since the mid-1990s. Despite the fact that ILs are defined by one physical property (melting point), many of the potential applications are now related to their biological properties. The use of a drug as a liquid can avoid some problems related to polymorphism which can influence a drug´s solubility and thus its dosages. Also, the arrangement of the anion or cation with a specific drug might be relevant in order to: a) change the correspondent biopharmaceutical drug classification system; b) for the drug formulation process and c) the change the Active Pharmaceutical Ingredients’ (APIs). The main goal of this Thesis is the synthesis and study of physicochemical and biological properties of ILs as APIs from beta-lactam antibiotics (ampicillin, penicillin G and amoxicillin) and from the anti-fungal Amphotericin B. All the APIs used here were neutralized in a buffer appropriate hydroxide cations. The cation hydroxide was obtained on Amberlite resin (in the OH form) in order to exchange halides. The biological studies of these new compounds were made using techniques like the micro dilution and colorimetric methods. Overall a total of 19 new ILs were synthesised (6 ILs based on ampicillin, 4 ILs, based on amoxicillin, 6 ILs based on penicillin G and 4 ILs based on amphotericin B) and characterized by spectroscopic and analytical methods in order to confirm their structure and purity. The study of the biological properties of the synthesised ILs showed that some have antimicrobial activity against bacteria and yeast cells, even in resistant bacteria. Also this work allowed to show that ILs based on ampicillin could be used as anti-tumour agents. This proves that with a careful selection of the organic cation, it is possible to provoke important physico-chemical and biological alteration in the properties of ILs-APIs with great impact, having in mind their applications.

Indexing and active fund management: International evidence

Author's pre-print

Nutritional assessment and lipid profile in HIV-infected children and adolescents treated with highly active antiretroviral therapy

INTRODUCTION: HIV-infected children and adolescents treated with highly active antiretroviral therapy (HAART) regimens that include a protease inhibitor (PI) can show significant improvements in clinical outcomes, nutritional status and quality of life. The study aimed to report nutritional and metabolic alterations for pediatric patients continuously exposed to HAART and for healthy controls for up to 1 year. METHODS: Clinical, anthropometric, lipid profile and food intake data were collected prospectively over approximately 12-months for each patient. RESULTS: Fifty-one individuals were studied, of these, 16 were healthy. After 12 months follow-up, HIV-positive individuals remained below the healthy control group parameters. No change was observed concerning food intake. Triglyceride serum levels were higher in patients using protease inhibitor at the onset of the study [PI groups: 114 (43 - 336), and 136 (63 - 271) versus control group: 54.5 (20 - 162); p = 0.003], but after twelve months follow-up, only the group using protease inhibitor for up to two months presented higher values [140 (73 - 273) versus 67.5 (33 - 117); p = 0.004]. HDL-cholesterol was lower in HIV-positive individuals [HIV-positive groups: 36 (27 - 58) and 36 (23 - 43); control 49.5 (34 - 69); p = 0.004]. CONCLUSIONS: HIV-infected children and adolescents treated with highly active antiretroviral therapy showed compromised nutritional parameters compared to a paired healthy control group. Individuals using protease inhibitor presented worse triglyceride serum levels compared to their healthy counterparts.

Anti-HBs levels among children and adolescents with complete immunization schedule against hepatitis B virus. A cross-sectional study in Blumenau, State of Santa Catarina, Brazil, 2007-2008

INTRODUCTION: Vaccination is the main tool for preventing hepatitis B virus (HBV) infection; however, following the completion of the vaccination series, the concentrations of anti-HBs can decline over the years and reach levels less than 10mIU/mL. The persistence of protection in these individuals is still unknown. The present study aimed to determine the anti-HBs antibody levels among children and adolescents who had received a complete vaccination course for hepatitis B. METHODS: Antibodies against HBV surface antigen (anti-HBs) were tested in 371 individuals aged 10 to 15 years-old. RESULTS: Volunteers who showed undetectable quantities of anti-HBs accounted for 10.2% of the population studied and 39.9% presented antibody titers of less than 10mIU/mL. Anti-HBs > 10mIU/mL were verified in 49.9%. CONCLUSIONS: These results corroborate other studies indicating levels of anti-HBs below 10mIU/mL in vaccinated individuals. Additional studies are required to assess whether this indicates susceptibility to HBV infection and the need and age for booster doses.

Enteric parasites in HIV-1/AIDS-infected patients from a Northwestern São Paulo reference unit in the highly active antiretroviral therapy era

INTRODUCTION: We describe the epidemiology of intestinal parasites in patients from an AIDS reference service in Northeastern São Paulo, Brazil. METHODS: Retrospective evaluation was done for all HIV-1/AIDS-positive patients whose Hospital de Base/São José do Rio Preto laboratorial analysis was positive for enteroparasites after diagnosis of HIV-1 infection, from January 1998 to December 2008. Statistical analysis was performed using the R statistical software version 2.4.1. The level of significance adopted was 5%. RESULTS: The most frequent protozoan was Isospora belli (4.2%), followed by Giardia lamblia (3.5%), Entamoeba coli (2.8%), and Cryptosporidium parvum (0.3%). Ancylostoma duodenale (1.4%) was the most frequently detected helminth, while Taenia saginata and Strongiloides stercoralis were found in 0.7% of the samples. The results showed that diarrhea was significantly associated with giardiasis and isosporiasis. However, no association was observed between CD4+ cell counts, viral load, and the characteristics of any particular parasite. CONCLUSIONS: Our data may be useful for further comparisons with other Brazilian regions and other developing countries. The data may also provide important clues toward improving the understanding, prevention, and control of enteric parasites around the world.

Active surveillance of American tegumentary leishmaniasis in endemic areas in rural Bolivia

INTRODUCTION: American tegumentary leishmaniasis (ATL), including mucocutaneous leishmaniasis (MCL) and localized cutaneous leishmaniasis (LCL), is endemic in Bolivia. We describe the results of active surveillance of ATL from 2001 to 2006 and assess demographic data related to ATL epidemiology in the Yungas valleys. METHODS: Community-based active ATL surveillance was performed by the institutions SERVIR, CÁRITAS, and the Health Services Department of La Paz, whose files were reviewed retrospectively. A cross-sectional survey was carried out to assess demographic data in two communities. RESULTS: Two thousand nine hundred nine cases of ATL were detected from 2001 to 2006: 2,488 (85.5%) corresponded to LCL and 421 (14.5%) to MCL. A reduction in the proportion of mucosal cases was observed between 2001 and 2006. The proportion of MCL cases increased with age and was higher among males (15.5% versus 12.1%, p=0.018). The rate of positivity via direct observation of the parasite in dermal scrapings and in parasite cultivation was significantly higher for LCL than for MCL (p<0.001 and p=0.009, respectively). The rate of reactivity in the leishmanin skin test was higher in the group with mucosal lesions (p=0.012). The cross-sectional survey showed that 40% of the families had emigrated from the Altiplano. CONCLUSIONS: It is necessary to undertake continuous case detection of ATL in the area, where the disease presents a high rate of mucosal cases. Increasing incidence seems to be associated with immigration and continuous deforestation to expand the crop-growing areas.

Leprosy in Buriticupu, state of Maranhão: active search in the general population

INTRODUCTION: This study was developed to evaluate the situation of leprosy in the general population of the municipality of Buriticupu, State of Maranhão, Brazil. METHODS: We used the method of active search to identify new cases from 2008 to 2010. Bacilloscopy of intradermal scrapings was performed in all patients with skin lesions compatible with leprosy, and histopathological examination in those who had doubts on the definition of the clinical form. RESULTS: The study included 19,104 individuals, with 42 patients diagnosed with leprosy after clinical examination, representing a detection rate of 219.84 per 100,000 inhabitants. The predominant clinical presentation was tuberculoid with 24 (57.1%) cases, followed by borderline with 11, indeterminate with four, and lepromatous with three cases. The study also allowed the identification of 81 patients with a history of leprosy and other skin diseases, such as pityriasis versicolor, dermatophytosis, scabies, vitiligo, and skin carcinoma. The binomial test showed that the proportion of cases in the headquarters was significantly higher than that in the villages (p = 0.04), and the generalized exact test showed that there was no association between age and clinical form (p = 0.438) and between age and gender (p = 0.083). CONCLUSIONS: The elevated detection rate defines the city as hyperendemic for leprosy; the active search for cases, as well as the organization of health services, is an important method for disease control.

Perceptions of the usefulness of external support to immunization coverage in Guinea-Bissau: a Delphi analysis of the GAVI-Alliance cash-based support

INTRODUCTION: Although many countries have improved vaccination coverage in recent years, some, including Guinea-Bissau, failed to meet expected targets. This paper tries to understand the main barriers to better vaccination coverage in the context of the GAVI-Alliance (The Global Alliance for Vaccines and Immunisation) cash-based support provided to Guinea-Bissau. METHODS: The analysis is based on a document analysis and a three round Delphi study with a final consensus meeting. RESULTS: Consensus attributed about 25% of the failure to perform better to implementation problems; and about 10% to governance and also 10% to scarce resources. The qualitative analysis validates the importance of implementation issues and upgraded the relevance of the human resources crisis as an important drawback. The recommendations were balanced in their upstream-downstream focus but were blind to health information issues and logistical difficulties. CONCLUSIONS: It is commendable that such a fragile state, with all sorts of barriers, manages to sustain a slow steady growth of its vaccination coverage. Not reaching the targets set reflects the inappropriateness of those targets rather than a lack of commitment of the health workforce. In the unstable context of countries such as Guinea-Bissau, the predictability of the funds from global health initiatives like the GAVI-Alliance seem to make all the difference in achieving small consistent health gains even in the presence of other major bottlenecks.

Momentum risk: An approach following the correlations between active stocks

The momentum anomaly has been widely documented in the literature. However, there are still many issues where there is no consensus and puzzles left unexplained. One is that strategies based on momentum present a level of risk that is inconsistent with the diversification that it offers. Moreover, recent studies indicate that this risk is variable over time and mostly strategy-specific. This work project hypothesises and proves that this evidence is explained by the portfolio constitution of the momentum strategy over time, namely the covariance and correlation between companies in the top and down deciles and across them.

Spontaneous reporting of adverse events following pandemic influenza A (H1N1) immunization in a reference center in the State of Sao Paulo, Brazil

Introduction This paper describes adverse events (AEs) temporally associated to the pandemic influenza A (H1N1) vaccine observed in a reference center in São Paulo, Brazil, during a 2010 mass vaccination campaign. Methods A retrospective study involving persons who sought medical care for AEs following influenza vaccination. Data were retrieved from medical records, vaccine AE notification forms, and a computerized system for immunobiological registration. Results Sixty-six vaccinees sought medical care for AEs after immunization. The most frequent AEs were fever, headache, myalgia, and pain at the injection site. No serious AEs were reported. Conclusions Few vaccinees spontaneously reported AEs to influenza A (H1N1) vaccine at this center.

New focus of active transmission of Chagas disease in indigenous populations in the Peruvian Amazon basin

Introduction Several cases of acute Chagas disease (ACD) have been reported in the Peruvian Amazon basin. Methods The objective was to describe and investigate 6 ACD cases in children from indigenous Amazon communities in the province of Datem del Marañón in Loreto department (2006-2010). Results The mean age was 3.6 years. All patients had fever, 4/6 hepatomegaly, 2/6 splenomegaly, and 5/6 had trypomastigotes of Trypanosoma cruzi on thick smears. The fatality rate was 33.3%. Rhodnius pictipes and Rhodnius robustus adults were found inside the homes and in the peri-domiciles. Conclusions All cases reported were isolated cases. We report a new focus of ACD in indigenous populations.

Active and latent tuberculosis in prisoners in the Central-West Region of Brazil

Introduction Jailed populations exhibit high rates of tuberculosis (TB) infection and active disease. Methods A cross-sectional study was performed to estimate the prevalence of latent and active TB and to identify factors associated with latent infection in inmates. Results The prevalence of latent TB was 49%, and the prevalence of active TB was 0.4%. The presence of a Bacille Calmette-Guérin (BCG) scar (prevalence ratio (PR)=1.65; 95% confidence interval (CI): 1.09-2.50; p=0.0162) and the World Health Organization (WHO) score for active TB in prisons (PR=1.07; 95% CI: 1.01-1.14; p=0.0181) were correlated with infection. Conclusions The identification of associated factors and the prevalence of latent and active TB allows the development of plans to control this disease in jails.

Active surveillance to determine the impact of methicillin resistance on mortality in patients with bacteremia and influences of the use of antibiotics on the development of MRSA infection

Introduction Methicillin-resistant Staphylococcus aureus (MRSA) is among the most important pathogens of nosocomial infections, mainly in intensive care units (ICUs), and accounts for 40-60% of all healthcare-associated S. aureus infections. We evaluated the incidence of nosocomial infection by S. aureus, identified the risk factors for MRSA infection, and evaluated the effect of resistance to methicillin on mortality in patients. Methods We conducted MRSA surveillance at a university hospital in Brazil from January 1, 2010, to December 31, 2010, and performed a retrospective case-control matched study to evaluate the frequency of subsequent MRSA bacteremia and death among patients. We evaluated and compared the risk factors between patients with MRSA and methicillin-sensitive Staphylococcus aureus (MSSA) infection. Results Sepsis was the most common cause of infection (17.7/1,000 patient-days), followed by surgical site (11.4/1,000 patient-days), pneumonia (4.1/1,000 patient-days), and urinary tract infection (2.4/1,000 patient-days). The significant risk factors were time of hospitalization, use of central vascular catheter (CVC), urinary catheter, nasogastric tube, parenteral nutrition, tracheostomy, mechanical ventilation, and previous antibiotic administration, the latter of which was the only independent risk factor for MRSA infection. Mortality was significantly higher in patients with MRSA. The number of antibiotics tested was not related to increases in the frequency of MRSA/1,000 patient-days. The incidence of mortality attributable to MRSA (bloodstream infection) BSI was 50%. Conclusions Surveillance results showed that the use of high levels of antibiotics was directly related to the development of MRSA infection, and the mortality attributable to MRSA in patients with bacteremia was significant.

Non-gyrator type active inductors

Modern CMOS radio frequency (RF) Receivers have enabled efficient and increasing applications. The main requirement is to have system in a single chip, in order to minimize area and cost. For the purpose it is required the development of inductorless circuits for the key blocks of an RF receiver. Examples of this key blocks are RC oscillators, RF band pass filters, and Low Noise Amplifiers. The present dissertation presents an inductorless wideband MOSFET-only RF Non-Gyrator Type of Active Inductors with low area, low cost, and very low power, capable of covering the whole WMTS, and ISM, band and intended for biomedical applications. The proposed circuit is based on a floating capacitor connected between two controlled current sources. The first current source, which is controlled by the circuit input voltage, has two objectives: supply current to the capacitor (