Ajuste de modelos não-lineares em estudos de associação entre polimorfismos genéticos e crescimento em bovino de corte.

Foram utilizados dados de peso ao nascimento, ao desmame e mensais dos 8 aos 19 meses de idade de 11 classes degenótipos, formadas pela concatenação dos polimorfismos genéticos da kappa-caseína-HinfI (CSN3): AA e AB, do hormônio docrescimento-AluI (GH): LL e LV e da ?-lactoglobulina-HaeIII (LGB): AA, AB e BB (G1=AALLAA, G2=AALLAB, G3=AALLBB,G4=AALVAB, G5=AALVBB, G6=ABLLAA, G7=ABLLAB, G8=ABLLBB, G9=ABLVAA, G10=ABLVAB e G11=ABLVBB). Asinformações foram obtidas de animais de três grupos genéticos: ½Canchim-Nelore (CN), ½Angus-Nelore (AN) e ½Simental-Nelore (SN),nascidos em 1998 e 1999 e pertencentes à Embrapa Pecuária Sudeste, São Carlos, SP. Dos cinco modelos estudados: Brody, VonBertalanffy, Richards, Gompertz e Logístico, o último apresentou melhor qualidade de ajuste. As estimativas dos parâmetros A (valorassintótico), k (taxa de maturação) e m (ponto de inflexão) obtidas do modelo Logístico, ajustado para descrever o crescimentode cada animal, foram analisadas pelo método dos quadrados mínimos, por meio de um modelo linear, que incluiu, além da médiageral, o efeito do genótipo, o ano de nascimento, o sexo e o manejo alimentar. Para os animais do grupo genético CN, os genótiposinfluenciaram significativamente as estimativas dos parâmetros A e k da curva de crescimento. O genótipo G3 apresentou valorinferior de A e superior de k em relação aos genótipos G7 e G8. Quanto aos grupos genéticos AN e SN, não foi observado efeitosignificativo do genótipo sobre nenhum dos três parâmetros. A aplicação da técnica de modelos não-lineares em estudos deassociação entre polimorfismos genéticos e crescimento animal proporcionou uma análise detalhada do desenvolvimento dosanimais de diferentes genótipos (genes: CSN3, GH e LGB)

Influência de polimorfismos genéticos sobre os parâmetros da curva de crescimento em bovinos de corte.

Registros de pesos ao nascimento, ao desmame e mensais dos 8 aos 19 meses de idade referentes à animais dos gruposgenéticos: ½Canchim-Nelore (CN), ½Angus-Nelore (AN) e ½Simental-Nelore (SN), pertencentes à Embrapa Pecuária Sudeste, SãoCarlos, SP, foram analisados pela técnica de modelos não-lineares incluindo, no modelo Logístico, os efeitos fixos de grupo decontemporâneos e das classes de genótipos dos genes da kappa-caseína-HinfI (CSN3): AA e AB, do hormônio do crescimento-AluI (GH):LL e LV e da ?-lactoglobulina-HaeIII (LGB): AA, AB e BB, com o objetivo de verificar a influência destes genes sobre a curva decrescimento destes animais. Os resultados sugerem que, os parâmetros A e k da função Logística utilizada para descrever o crescimentodos grupos genéticos CN, AN e SN, foram influenciados pelos polimorfismos dos genes CSN3, GH e LGB. As maiores diferenças entreos genótipos para os genes CSN3, GH e LGB foram observadas a partir dos 12-13 meses de idade. O genótipo AA para CSN3 apresentoumaior taxa de maturação (k) que o genótipo AB nos grupos genéticos CN, AN e SN. Quanto ao valor assintótico (A), a diferença entreAA e AB, foi pequena nos grupos genéticos CN e SN. Para o polimorfismo do GH no grupo genético AN, o genótipo LL apresentouvalores de A e k inferiores em relação ao LV, enquanto no grupo genético SN os animais do genótipo LV apresentaram menor valor deA e maior de k em relação ao LL. O mesmo ocorreu para o LGB, em que os genótipos AA e AB apresentaram estimativas do parâmetrok superiores em relação ao genótipo BB no grupo genético AN, enquanto o genótipo AB apresentou estimativa de k inferior em relaçãoao genótipo BB, no grupo genético SN

Drug Susceptibility in Leishmania Isolates Following Miltefosine Treatment in Cases of Visceral Leishmaniasis and Post Kala-Azar Dermal Leishmaniasis

Resistance to antimonials has emerged as a major hurdle to the treatment and control of VL and led to the introduction of Miltefosine as first line treatment in the Indian subcontinent. MIL is an oral drug with a long half-life, and it is feared that resistance may emerge rapidly, threatening control efforts under the VL elimination program. There is an urgent need for monitoring treatment efficacy and emergence of drug resistance in the field. In a set of VL/PKDL cases recruited for MIL treatment, we observed comparable drug susceptibility in pre- and post-treatment isolates from cured VL patients while MIL susceptibility was significantly reduced in isolates from VL relapse and PKDL cases. The PKDL isolates showed higher tolerance to MIL as compared to VL isolates. Both VL and PKDL isolates were uniformly susceptible to PMM. MIL transporter genes LdMT/LdRos3 were previously reported as potential resistance markers in strains in which MIL resistance was experimentally induced. The point mutations and the down-regulated expression of these transporters observed in vitro could, however, not be verified in natural populations of parasites. LdMT/LdRos3 genes therefore, do not appear to be suitable markers so far for monitoring drug susceptibility in clinical leishmanial isolates

A genome scan for milk production traits in dairy goats reveals two new mutations in <i>Dgat1</i> reducing milk fat content

The quantity of milk and milk fat and proteins are particularly important traits in dairy livestock. However, little is known about the regions of the genome that influence these traits in goats. We conducted a genome wide association study in French goats and identified 109 regions associated with dairy traits. For a major region on chromosome 14 closely associated with fat content, the Diacylglycerol O-Acyltransferase 1 (DGAT1) gene turned out to be a functional and positional candidate gene. The caprine reference sequence of this gene was completed and 29 polymorphisms were found in the gene sequence, including two novel exonic mutations: R251L and R396W, leading to substitutions in the protein sequence. The R251L mutation was found in the Saanen breed at a frequency of 3.5% and the R396W mutation both in the Saanen and Alpine breeds at a frequencies of 13% and 7% respectively. The R396W mutation explained 46% of the genetic variance of the trait, and the R251L mutation 6%. Both mutations were associated with a notable decrease in milk fat content. Their causality was then demonstrated by a functional test. These results provide new knowledge on the genetic basis of milk synthesis and will help improve the management of the French dairy goat breeding program

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization. The migration of population from endemic to nonendemic areas, and tourist activities in endemic regions are spreading the disease to new areas. Unfortunately, treatment of leishmaniasis is far from satisfactory, with only a few drugs available that show significant side-effects. Here, we show in vitro and in vivo evidence for the antileishmanial activity of the ether phospholipid edelfosine, being effective against a wide number of Leishmania spp. causing cutaneous, mucocutaneous and visceral leishmaniasis. Our experimental mouse and hamster models demonstrated not only a significant antileishmanial activity of edelfosine oral administration against different wild-type Leishmania spp., but also against parasites resistant to pentavalent antimonials, which constitute the first line of treatment worldwide. In addition, edelfosine exerted a higher antileishmanial activity and a lower proneness to generate drug resistance than miltefosine, the first drug against leishmaniasis that can be administered orally. These data, together with our previous findings, showing an anti-inflammatory action and a very low toxicity profile, suggest that edelfosine is a promising orally administered drug for leishmaniasis, thus warranting clinical evaluation

Treatment of American tegumentary leishmaniasis in special populations : a summary of evidence

We aimed to assess and synthesize the information available in the literature regarding the treatment of American tegumentary leishmaniasis in special populations. We searched MEDLINE (via PubMed), EMBASE, LILACS, SciELO, Scopus, Cochrane Library and mRCT databases to identify clinical trials and observational studies that assessed the pharmacological treatment of the following groups of patients: pregnant women, nursing mothers, children, the elderly, individuals with chronic diseases and individuals with suppressed immune systems. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The available evidence suggests that the treatments of choice for each population or disease entity are as follows: nursing mothers and children (meglumine antimoniate or pentamidine), patients with renal disease (amphotericin B or miltefosine), patients with heart disease (amphotericin B, miltefosine or pentamidine), immunosuppressed patients (liposomal amphotericin), the elderly (meglumine antimoniate), pregnant women (amphotericin B) and patients with liver disease (no evidence available). The quality of evidence is low or very low for all groups. Accurate controlled studies are required to fill in the gaps in evidence for treatment in special populations. Post-marketing surveillance programs could also collect relevant information to guide treatment decision-making

Thalidomide in the treatment of erythema nodosum leprosum (ENL): systematic review of clinical trials and prospects of new investigations

FUNDAMENTOS: A hanseníase persiste como problema de saúde pública, e episódios de ENH são eventos agudos que ocorrem antes, durante e após PQT. Na última década, o uso da talidomida como agente imunomodulador foi expandido a outras doenças. OBJETIVOS: realizar revisão sistemática dos ensaios clínicos publicados sobre a eficácia e efeitos colaterais da talidomida no ENH. Descrever metodologia e resultados da triagem para recrutamento de ensaio clínico visando avaliar dose-resposta da talidomida seguida de desmame no ENH moderado e grave, realizado no Brasil. MÉTODOS: Analisaram-se ensaios publicados sobre talidomida no ENH. Foi delineado um ensaio clínico duplo-cego randomizado para avaliar dose de 100 thalid 300mg/dia de talidomida durante fase aguda de ENH, seguida de desmame da talidomida, thalid placebo. Para este ensaio clínico descreve-se metodologia e dados de recrutamento de pacientes, com ênfase na gravidade dos episódios de ENH. RESULTADOS: Os seis ensaios clínicos publicados nas décadas de 1960 e 1970 apontam para o benefício da talidomida no ENH, embora diferenças metodológicas dificultem a comparação. Na fase de recrutamento do ensaio brasileiro, dos 143 pacientes de ENH triados, 65% eram potencialmente elegíveis. A associação com neurite em 56,4% dos ENH moderados e graves exigiu co-intervenção com corticosteróide. CONCLUSÃO: O padrão de recrutamento dos pacientes evidenciou alta freqüência de neurite nos episódios de ENH. O esquema de talidomida isolada no ENH foi avaliado como infreqüente na prática clínica brasileira. O desafio atual é acumular evidências sobre a eficácia e efeitos colaterais da talidomida em associação com corticosteróides.BACKGROUND: Leprosy remains a public health problem. Episodes of erythema nodosum leprosum (ENL) are acute events that occur before, during and after polychemotherapy. In the last decade, the use of thalidomide as an immunomodulating agent was expanded to other diseases. OBJECTIVES: To perform a systematic review of published clinical trials on efficacy and side effects of thalidomide in ENL. To describe the methodology and screening results of recruiting for a clinical trial performed in Brazil, which aimed to assess the dose-response of thalidomide followed by tapering regimen in severe and moderate cases of ENL. METHODS: Published clinical trials on the use of thalidomide in ENL were analyzed. A randomized, double-blind clinical trial was designed to evaluate the doses of 100mg versus 300mg/day thalidomide during the acute stage of ENL, followed by thalidomide tapering regimen versus placebo. For this clinical trial, the methodology and data for enrollment of patients were described, with an emphasis on severity of ENL episodes. RESULTS: Six clinical trials published in the 1960's and 1970's indicated the benefits of thalidomide in ENL, although methodological differences made comparison difficult. In the enrollment stage of the Brazilian trial, 65% of patients were potentially eligible out of 143 ENL patients screened. The association with neuritis in 56.4% of moderate and severe cases of ENL required the co-intervention with steroids. CONCLUSION: The patients' enrollment pattern demonstrated high frequency of neuritis in ENL episodes. The treatment regimen with thalidomide in monotherapy for ENL was considered infrequent in the clinical practice in Brazil. The current challenge is to accumulate evidence about efficacy and side effects of thalidomide in combination with steroids