What Does It Take to Synergistically Combine Sub-Potent Natural Products into Drug-Level Potent Combinations?

10.1371/journal.pone.0049969PLoS ONE711

Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasisThe study was supported in Spain by grants from Ministerio de Ciencia e Innovación FIS PI11/00095 and FISPI14/00366 from the Instituto de Salud Carlos III within the Network of TropicalDiseases Research (VI P I+D+I 2008-2011, ISCIII -Subdirección General de Redes y Centros de Investigación Cooperativa (RD12/0018/0009)). This work was also supported in Brazil by a grant from CNPq (Ciencia sem Fronteiras-PVE 300174/2014-4). A CBMSO institutional grant from Fundación Ramón Areces is also acknowledged. EAFC is a grant recipient of CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

A mechanical comparison between conventional and modified angular plates for proximal humeral fractures

The objective of this study is to present a modified angular blade plate for fixing 2-part and even 3-part fractures of the proximal humerus, as well as the results of the comparative mechanical test between the conventional angular blade plate and this new modified plate. The plates were tested in flexion and rotational trials in a wooden model that simulated a 2-part humeral fracture of the proximal extremity. The results (mean +/- SD) of bending strength and stiffness obtained after testing showed findings of 601 +/- 349 N and 0.5 +/- 0.2 N/mm, respectively, for the conventional plate and 4005 +/- 164 N and 3.9 +/- 0.7 N/mm, respectively, for the modified plate. The torsional stiffness test showed findings of 1.26 +/- 0.09 KN.mm degrees for the conventional plate and 1.74 +/- 0.21 KN.mm degrees for the modified plate. The test of torsional moment showed findings of 57.0 +/- 7.6 KN.mm for the conventional plate and 115.2 +/- 9.3 KN.mm for the modified plate. The test of angular displacement of the torsional moment showed findings of 50.8 degrees +/- 7.2 degrees for the conventional plate and 70.2 degrees +/- 2.6 degrees for the modified plate. The results of the mechanical trials of flexion and rotation were superior for the modified angular blade plate compared with the conventional angular blade plate.17463163

Apresentação clínica da doença de Chagas crônica em indivíduos idosos Clinical presentation of chronic Chagas disease in elderly individuals

Com o objetivo de avaliar a apresentação clínica da doença de Chagas em idosos foi realizado estudo retrospectivo utilizando-se os prontuários de doentes atendidos em ambulatório de referência. A casuística foi dividida em idosos (> 60 anos) e não idosos. Avaliou-se: sexo, co-morbidades, forma clínica, eletrocardiograma e títulos das sorologias. Idosos (61 casos): média de idade de 66,0 &plusmn; 5 anos, 67,2% do sexo feminino; comorbidades em 59%, mais freqüente a hipertensão arterial sistêmica (HAS)= 39,3%; forma indeterminada= 1,6%, forma cardíaca= 88,5%, forma digestiva= 36,1%; alterações freqüentes no eletrocardiograma: bloqueio divisional ântero-superior esquerdo (BDASE)= 41%, bloqueio completo de ramo direito (BCRD)= 32,8%, extra-sístole ventricular (EV)=22,9%. Não idosos (61 casos): média de idade: 39,30&plusmn;8,36 anos, 54,1% do sexo feminino; comorbidades em 50,8%, mais freqüente a HAS (26,2%); forma indeterminada= 18% (p<0,05), forma cardíaca= 78,7%, forma digestiva= 32,8%; alterações freqüentes no eletrocardiograma: BDASE= 24,6%, BCRD= 21,3%, EV =18%. Concluindo, não houve diferenças clínicas entre indivíduos idosos e não idosos e a forma indeterminada predominou nos indivíduos abaixo dos 60 anos.<br>This study had the aim of evaluating the clinical presentation of chronic Chagas disease among the elderly. It was a retrospective analysis of clinical records at an outpatient referral service. The sample was divided into two groups: elderly (> 60 years old) and non-elderly. Sex, comorbidities, clinical form, electrocardiogram and serological titers were evaluated. In the elderly group (61 cases), the mean age was 66.03 &plusmn; 5 years; 67.2% were female; 59% presented comorbidities (most frequently systemic arterial hypertension, in 39.3%); 1.6% had the indeterminate clinical form, 88.5% the cardiac form and 36% the digestive form; and abnormalities were frequently found on electrocardiograms: 41% presented anterosuperior left bundle branch block (AS-LBBB), 32.8% presented right bundle branch block (RBBB) and 22.9% presented ventricular ectopic beats (VEB). In the non-elderly group (61 cases), the mean age was 39.30 &plusmn; 8.36 years; 54.1% were female; 50.8% presented comorbidities (most frequently systemic arterial hypertension, in 26.2%); 18% had the indeterminate clinical form (p<0.05), 78.7% the cardiac form and 32.8% the digestive form; and abnormalities were frequently found on electrocardiogram: 24.6% presented AS-LBBB, 21.3% RBBB and 18% VEB. It was concluded that there were no clinical differences between elderly and non-elderly Chagas patients. The indeterminate clinical form predominated in patients less than 60 years old