Investigation of the Potential Targets behind the Promising and Highly Selective Antileishmanial Action of Synthetic Flavonoid Derivatives.

Leishmaniases are among the neglected tropical diseases that still cause devastating health, social, and economic consequences to more than 350 million people worldwide. Despite efforts to combat these vector-borne diseases, their incidence does not decrease. Meanwhile, current antileishmanial drugs are old and highly toxic, and safer presentations are unaffordable to the most severely affected human populations. In a previous study by our research group, we synthesized 17 flavonoid derivatives that demonstrated impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y. These cysteine proteases are highly expressed in the amastigote stage, the target form of the parasite. However, although these compounds have been already described in the literature, until now, the amastigote effect of any of these molecules has not been proven. In this work, we aimed to deeply analyze the antileishmanial action of this set of synthetic flavonoid derivatives by correlating their ability to inhibit cysteine proteases with the action against the parasite. Among all the synthesized flavonoid derivatives, 11 of them showed high activity against amastigotes of Leishmania amazonensis, also providing safety to mammalian host cells. Furthermore, the high production of nitric oxide by infected cells treated with the most active cysteine protease B (CPB) inhibitors confirms a potential immunomodulatory response of macrophages. Besides, considering flavonoids as multitarget drugs, we also investigated other potential antileishmanial mechanisms. The most active compounds were selected to investigate another potential biological pathway behind their antileishmanial action using flow cytometry analysis. The results confirmed an oxidative stress after 48 h of treatment. These data represent an important step toward the validation of CPB as an antileishmanial target, as well as aiding in new drug discovery studies based on this protease.

Angiomatosis bacilar y micobacteriosis atípica en paciente con diagnóstico reciente de infección por el virus de la inmunodeficiencia humana / Bacillary Angiomatosis and Atypical Mycobacteriosis in a patient recently diagnosed with Human Immunodeficiency Virus infection

Múltiples infecciones oportunistas pueden manifestarse simultáneamente cuando la inmunosupresión es grave en pacientes infectados por el virus de la inmunodeficiencia humana. Se presenta un caso de coinfección de VIH, Bartonella spp y Mycobacterium kansasii, siendo escasos los reportes a la fecha de dicha asociación y aun más en pacientes que desconocen su condición de VIH

Multiple opportunistic infections can manifest simultaneously when immunosuppression is severe in patients infected with the human immunodeficiency virus. A case of co-infection with HIV, Bartonella spp and Mycobacterium kansasii is presented, with few reports to date of this association and even more so in patients who are unaware of their HIV status.

Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort.

BACKGROUND: A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. METHODS: 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. RESULTS: Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. CONCLUSION: Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D.

Climate and acute/subacute paracoccidioidomycosis in a hyper-endemic area in Brazil.

BACKGROUND: Paracoccidioidomycosis (PCM) is Latin America's most prevalent systemic mycosis, carrying an important social burden. Its agent, Paracoccidioides brasiliensis, has rarely been identified in nature. Studies characterizing acute/subacute PCM incidence and their relationship with climate variables are not available. This work analysed a series of acute/subacute cases that occurred in the Botucatu area, São Paulo State, Brazil, from 1969 to 1999, as an outcome of weather variability. METHODS: Stepwise regression of annual data was applied to model incidence, calculated based on 91 cases, from lagged variables: antecedent precipitation, air temperature, soil water storage, absolute and relative air humidity, and Southern Oscillation Index (SOI). RESULTS: Multiple regression analyses resulted in a model, which explains 49% of the incidence variance, taking into account the absolute air humidity in the year of exposure, soil water storage and SOI of the previous 2 years. CONCLUSIONS: The correlations may reflect enhanced fungal growth after increase in soil water storage in the longer term and greater spore release with increase in absolute air humidity in the short term.

Efectividad de la técnica de relajación de schultz modificada en la parte final de la clase de educación física / Effectiveness of the modified Schultz relaxation technique in the final part of the physical education class

Se realizó un estudio experimental prospectivo con el objetivo de evaluar la eficacia de la Técnica de Relajación de Schultz modificada, para la recuperación de los estudiantes en la parte final de la clase de Educación Física. Se seleccionaron de forma aleatoria dos grupos de 32 estudiantes del sexo femenino de la carrera de Medicina; un grupo recibió la técnica de relajación de Schultz modificada y el otro recibió la técnica de relajación tradicional. El estudio se llevó a cabo en el segundo semestre del curso 2003–2004, se tomó el pulso y la frecuencia respiratoria en la parte final de las tres partes en que se divide la clase. Los resultados obtenidos en la misma demostraron que la recuperación con la técnica de relajación de Schultz modificada en los estudiantes del grupo experimental fue superior a los estudiantes del grupo de control en un 28 por ciento

Nasopharyngeal colonization by Haemophilus influenzae in children attending day-care centers, in Ribeirão Preto, State of São Paulo, Brazil

A colonização da nasofaringe por Haemophilus influenzae (Hi) foi estudada em 114 crianças saudáveis com menos de 3 anos de idade e que freqüentam creches (day-care centers DCC) em Ribeirão Preto, estado de São Paulo, Brasil. Para cada uma das cepas isoladas foram determinados o biótipo, o sorotipo (por antisoro especifico e PCR) e a sensibilidade a 14 antibióticos. A freqüência de colonização por Hi foi de 72,0 por cento. As cepas isoladas foram identificadas como pertencentes aos biótipos II (36,5 po cento), I (21,5 por cento), V (18,2 por cento) e III (16,1 por cento). A freqüência encontrada de cepas encapsuladas foi de 3,2 por cento para o tipo f, 1,0 por cento para o tipo b, 1,0 por cento para o tipo d e 1,0 por cento para o tipo e. A resistência para trimetoprim-sulfametoxazole e ampicilina foi de 46,2 por cento e 10,7 por cento respectivamente. Resistência múltipla foi encontrada em 14 (15,0 por cento) das cepas analisadas. 13,9 por cento das cepas analisadas eram produtoras de b-lactamase, e não foi recuperada nenhuma cepa b-lactamase negativa e ampicilina resistente. DCCs são considerados locais de risco, com um alto potencial de disseminação de microrganismos e por isto devem ser continuadamente monitorados com a finalidade de detectar a eliminação da colonização da nasofaringe por cepas H. influenzae tipo b das crianças que freqüentam DCC, ou detectar a sua substituição por outro tipo de cepa.

Comparison of two slide agglutination serotyping methods and PCR-based capsule typing for the characterization of Haemophilus influenzae serotypes

Noventa e três isolados nasofaringeanos de H. influenzae foram sorotipados através de 2 métodos de aglutinação em lamina (SAST 1 e SAST 2) e os resultados foram comparados com a sorotipagem por PCR. SAST 1 apresentou uma baixa correlação com os resultados obtidos por PCR (75,2 por cento) enquanto que SAST 2 mostrou uma melhor concordância com os resultados da técnica molecular (93,5 por cento). Estes resultados indicam que SAST 2 pode ser um método alternativo para a correta detecção de H. influenzae tipo b.

Transmission dynamics of Taenia solium and potential for pig-to-pig transmission.

Taenia solium taeniasis/cysticercosis is one of few potentially eradicable infectious diseases and is the target of control programs in several countries. The larval stage of this zoonotic cestode invades the human brain and is responsible for most cases of adult-onset epilepsy in the world. Our current understanding of the life cycle implicates humans as the only definitive host and tapeworm carrier, and thus the sole source of infective eggs that are responsible for cysticercosis in both human and pigs through oral-faecal transmission. Here we review transmission dynamics of porcine cysticercosis including an alternative pig-to-pig route of transmission, previously not suspected to exist. Second-hand transmission of T. solium eggs could explain the overdispersed pattern of porcine cysticercosis, with few pigs harbouring heavy parasite burdens and many more harbouring small numbers of parasites.

Short report: secondary transmission in porcine cysticercosis: description and their potential implications for control sustainability.

Taenia solium taeniasis/cysticercosis is one of few potentially eradicable infectious diseases and is the target of control programs in several countries. The larval stage of this zoonotic cestode invades the human brain and is responsible for most cases of adult-onset epilepsy in the world. The pig is the natural intermediate host, harboring the larvae or cysticerci. Our current understanding of the life cycle implicates humans as the only definitive host and tapeworm carrier (developing taeniasis) and thus the sole source of infective eggs that are responsible for cysticercosis in both human and pigs through oral-fecal transmission. Here we show evidence of an alternative pig-to-pig route of transmission, previously not suspected to exist. In a series of four experiments, naive sentinel pigs were exposed to pigs that had been infected orally with tapeworm segments (containing infective eggs) and moved to a clean environment. Consistently in all four experiments, at least one of the sentinel pigs became seropositive or infected with parasite cysts with much lower cyst burdens than did primarily infected animals. Second-hand transmission of Taenia solium eggs could explain the overdispersed pattern of porcine cysticercosis, with few pigs harboring heavy parasite burdens and many more harboring small numbers of parasites. This route of transmission opens new avenues for consideration with respect to control strategies.

Resistência à insulina: métodos diagnóstico e fatores que influenciam a açäo da insulina / Insulin resistance: diagnostic methods and factors that influence the insulin action

Os autores apresentam uma definição de resistência à insulina e discutem os métodos diagnósticos desde o padrão-ouro - o "clamp" euglicêmico hiperinsulinêmico, passando pela prova de supressão da insulina, a infusão contínua de glicose, a prova de tolerância à glicose endovenosa com um modelo matemático mínimo, até o teste de tolerância à insulina. Analisam também a glicemia e insulina basais e após sobrecarga oral de glicose. Finalmente mostram fatores que influenciam a ação da insulina, como: peso corporal, condicionamento físico, pêso ao nascimento, tipo de fibra muscular predominante, hormônios, densidade capilar e fluxo no músculo esquelético, dieta, idade e hereditariedade.

Diagnóstico topográfico em adultos com apnéia obstrutiva do sono / Obstructive sleep apnea in adults: topographic diagnosis

Foram examinados dezesseis adultos, entre 20 e 66 anos de idade. Destes, 14 eram brancos, um preto e um amarelo. Dez homens e seis mulheres, com peso que variou de 58 a 97 Kg. Todos tinham diagnóstico de apnéia obstrutiva do sono confirmado pela polissonografia. O diagnóstico topográfico foi feito pelo exame ORL, endoscopia nasofaríngica e avaliação radiológica. Encontramos anomalias na esfera ORL em 100 por cento dos casos, sendo 87 por cento no segmento velofaríngico e 50 por cento no segmento nasal. As anomalias do segmento velofaríngico mais freqüentemente encontrados foram: hipertrofia de úvula, palato e pilares (87 por cento), hipertrofia das amígdalas palatinas (81 por cento). As anomalias do segmento nasal mais encontradas por nós foram: desvio do septo nasal (38 por cento), hipertrofia da conchas inferiores (38 por cento). Nesta nossa série predominaram as anomalias isoladas (63 por cento) sobre as associadas (37 por cento)

Lesäo linfoepitelial benigna: "doença de Mikulicz"; relato de um caso / Benigne lynphoepithelial lesion: \"Mikulicz's disease\"; report of case

A lesäo linfoepitelial benigna ocorre como um aumento uni ou bilateal das glândulas salivares. A parótida é a glândula mais frequentemente acometidas, mas eventualmente acontece o comprometimento das glândulas submandibulares. Apresentamos o relato de um caso acompanhado em nosso ambulatório, cujo diagnóstico clínico e histológico foi compatível com lesäo linfoepitelial benigna ou "DOENCA DE MIKULICZ"