Linfocitos TH 17: moduladores o reguladores de la infección por VIH-1.

Los linfocitos T-CD4+ llamados helper (LTh) o cooperadores, componen una población heterogénea de células constituidas por LTh naive y células efectoras: Th1, Th2, Th17, Th1/Th17 y células regulatorias LT reguladores (T-reg). Ellos desempeñan un rol central en la defensa inmune y adquieren distintas propiedades funcionales en respuesta a señales que genera el sistema inmune innato. Los Th17 cumplen un rol crítico en la interrelación entre la inmunidad innata y adaptativa, en la inflamación crónica y en el mantenimiento de la esterilidad de la mucosa gastrointestinal. La infección por el virus de la inmunodeficiencia humana (VIH-1) se caracteriza por una gradual y progresiva disfunción del sistema inmune, con su consecuencia final el Síndrome de Inmuno Deficiencia Adquirida (SIDA). La infección viral involucra la interacción de proteínas virales con la molécula de superficie celular CD4 y el receptor de quimiocinas CCR5 o CXCR4. Nuestro objetivo es evaluar cualitativamente y cuantitativamente los Th17 en relación con los subtipos de LTh en pacientes con infección por VIH-1 en distintos estadios de la infección y correlacionarlos con la clínica del paciente. Para ello se estudiarán individuos con infección por VIH-1 en distintos estadios de la infección sin tratamiento antirretroviral a los que se evaluarán cuantitativamente los niveles de LTh y las subpoblaciones Th17, Th1 y Treg. Además, se estudiarán las características funcionales de los TH17 cuantificando los niveles de IL-17, IL10 e INF-G; en suero y sobrenadante de cultivos celulares y los niveles de granulocitos. La evaluación de los Th17, en relación con el fase inmune, virológico y con la clínica del paciente nos permitirá detectar subgrupos de pacientes y nuevos marcadores de progresión de la enfermedad.

Vacinação contra influenza e pneumococo na insuficiência cardíaca: uma recomendação pouco aplicada

FUNDAMENTO: A insuficiência cardíaca (IC) cursa com frequentes descompensações e admissões ao serviço de emergência. Vacinação contra Influenza (INF) e Pneumococo (PNM) são recomendadas nas diretrizes, entretanto, as infecções respiratórias são a terceira causa de hospitalização na IC. OBJETIVO: Avaliar a frequência da vacinação contra INF e PNM em pacientes com IC na rede pública. MÉTODOS: Em estudo observacional realizado em Teresópolis, região serrana fluminense, foram utilizadas três estratégias: (I) estudo das requisições para vacina contra INF e/ou PNM na Secretaria Municipal de Saúde, entre 2004 e 2006; (II) inquérito direto a 61 pacientes com IC atendidos na atenção básica sobre sua situação vacinal contra INF e PNM; (III) inquérito direto sobre situação vacinal contra INF e PNM a 81 pacientes com IC crônica descompensada atendidos na única emergência aberta à rede pública. RESULTADOS: Na estratégia I, a vacinação contra INF e/ou PNM foi de 15,3% daqueles com indicações por doenças cardiovasculares e respiratórias. A mediana do tempo entre a indicação e a vacinação foi de 32 dias. Na estratégia II, o percentual de vacinados contra INF, com idade > 60 anos, foi de 23,1%, e de 24,6% contra PMN em todas as idades. Na estratégia III, o percentual de pacientes vacinados contra INF foi de 35,8% e contra PNM foi de 2,5%. CONCLUSÃO: A taxa de vacinação contra INF e PNM em pacientes com IC é muito baixa e ainda menor naqueles descompensados atendidos em serviço de emergência.

Ecocardiografia por Doppler tecidual no diagnóstico de rejeição após transplante cardíaco

FUNDAMENTO: A biópsia endomiocárdica (BEM) é o método padrão-ouro para o diagnóstico de rejeição celular (RC) após transplante cardíaco (TC). OBJETIVO: Testar a hipótese de que o exame de imagem por Doppler tecidual (IDT) pode detectar RC > 3A e agregar informação diagnóstica, comparado ao Doppler convencional. MÉTODOS: Cinquenta e quatro pacientes com TC foram submetidos à BEM e estudo ecocardiográfico através de IDT em até 24 horas. Comparamos os pacientes com TC e RC > 3A com pacientes com TC e RC < 3A, com um grupo controle normal (13 pacientes). Foram medidas através da IDT, as velocidades sistólica (S), diastólica precoce (e'), diastólica tardia (a') relação das velocidades e'/a' no anel ventricular esquerdo, nos segmentos basal e médio das paredes septal (SEP), lateral (LAT), inferior (INF) e no anel ventricular direito. RESULTADOS: Os pacientes com TC mostraram RC > 3A em 39/129 (30,2%) das BEM. O melhor preditor isolado para o diagnóstico de RC foi a a'LAT, com sensibilidade de 76,3%, especificidade de 73,8% (p = 0,001). Na análise multivariada, a a'LAT (p = 0,001), a'SEP (p = 0,002), relação e'/a' LAT (p = 0,006), relação e'Mitral/ e'LAT (p = 0,014), SINF (p = 0,009) foram preditores de RC > 3A. Obtivemos um escore com sensibilidade de 88,2%, acurácia de 79,6%, e valor preditivo negativo de 92,9% para diagnosticar RC > 3A. O Doppler convencional (fluxo mitral e pulmonar venoso) não foi relevante para predizer a RC > 3A. CONCLUSÃO: O estudo de IDT agregou informação diagnóstica para predizer RC > 3A quando comparado ao Doppler convencional. O modelo baseado em IDT pode ser tornar um método em potencial para detectar RC > 3A após TC.

Excesso de Peso, Variáveis Antropométricas e Pressão Arterial em Escolares de 10 a 18 Anos

Fundamento: Estima-se que a prevalência de hipertensão em crianças e adolescentes varie entre 1-13%. O excesso de peso e a obesidade central estão relacionados aos níveis pressóricos em adultos e podem ser importantes na patogênese precoce da HAS quando presentes na infância. Objetivos: Identificar a associação entre variáveis antropométricas e níveis pressóricos em escolares de 5.ª a 8.ª séries e avaliar qual medida obteve maior correlação com a medida dos níveis pressóricos. Métodos: Estudo transversal contemporâneo com amostra de base populacional probabilística por conglomerados em escolas públicas do ensino fundamental de Porto Alegre, de alunos matriculados entre a 5.ª e a 8.ª série. Foram coletados dados sobre fatores de risco familiares e antropometria. A análise estatística incluiu correlações e ajuste dos intervalos de confiança para conglomerados. Resultados: A média de idade dos participantes foi de 12,57 (± 1,64) anos, dos quais 55,2% eram do sexo feminino. Encontraram-se 11,3% da amostra com níveis pressóricos alterados e 16,2% com valores limítrofes. Das variáveis antropométricas analisadas, a que demonstrou maior correlação com valores pressóricos aumentados foi o diâmetro do quadril (r = 0,462, p < 0,001) seguido de circunferência abdominal menor (r = 0,404, p < 0,001) e prega cutânea abdominal (r = 0,291, p < 0,001). Conclusão: Foi observada associação entre as circunferências da cintura e dobras cutâneas e níveis pressóricos aumentados nos escolares da amostra. Portanto, é de fundamental importância que a aferição da pressão arterial e as medidas de cintura e quadril sejam rotina nos serviços de saúde de forma precoce a fim de prevenir essa condição patológica.

Neural Mechanisms and Delayed Gastric Emptying of Liquid Induced Through Acute Myocardial Infarction in Rats

Background: In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats. Objective: Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABAB receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats. Methods: Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABAB receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1mA/10s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal. Results: No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABAB receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. Conclusion: Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN.

search for a novel diagnostic marker or therapeutic target for gastrointestinal cancer

Gastrointestinal cancers, HCC, ectopeptidases, differential display, gasdermin-like

Análise da variação qualitativa em amostras pequenas

Na aplicação do X2-teste devemos distinguir dois casos : Á) Quando as classes de variáveis são caracterizadas por freqüências esperadas entre p = 0,1 e p = 0,9, podemos aplicar o X2-teste praticamente sem restrição. É talvez aconselhável, mas não absolutamente necessário limitar o teste aos casos nos quais a freqüência esperada é pelo menos igual a 5. e porisso incluimos na Táboa II os limites da variação de dois binômios ( 1/2 + 1/2)n ( 1/4 + 3/4)n para valo r es pequenos de N e nos três limites convencionais de precisão : ,5%, 1% e 0,1%. Neste caso, os valores dos X2 Índividuais têm apenas valor limitado e devemos sempre tomar em consideração principalmente o X2 total. O valor para cada X2 individual pode ser calculado porqualquer das expressôe seguintes: x2 = (f obs - f esp)²> f. esp = ( f obs - pn)2 pn = ( f obs% - p)2.N p% (100 - p%) O delta-teste dá o mesmo resultado estatístico como o X2-teste com duas classes, sendo o valor do X2-total algébricamente igual ao quadrado do valor de delta. Assim pode ser mais fácil às vezes calcular o X2 total como quadrado do desvio relativo da. variação alternativa : x² = ( f obs -pn)² p. (1-p)N = ( f obs - p %)2.N p% (100 - p%) B) Quando há classes com freqüência esperada menor do que p = 0,1, podemos analisar os seus valores individuais de X2, e desprezar o valor X2 para as classes com p maior do que 0,9. O X2-teste, todavia, pode agora ser aplicado apenas, quando a freqüência esperada for pelo menos igual ou maior do que 5 ou melhor ainda, igual ou maior do que 10. Quando a freqüência esperada for menor do que 5, a variação das freqüências observadas segue uma distribuição de Poisson, não sendo possível a sua substituição pela aproximação Gausseana. A táboa I dá os limites da variação da série de Poisson para freqüências esperadas (em números) desde 0,001 até 15. A vantagem do emprego da nova táboa I para a comparação, classe por classe, entre distribuições esperadas e observadas é explicada num exemplo concreto. Por meio desta táboa obtemos informações muito mais detablhadas do que pelo X2-teste devido ao fato que neste último temos que reunir as classes nas extremidades das distribuições até que a freqüência esperada atinja pelo menos o valor 5. Incluimos como complemento uma táboa dos limites X2, pára 1 até 30 graus de liberdade, tirada de um outro trabalho recente (BRIEGER, 1946). Para valores maiores de graus da liberdade, podemos calcular os limites por dois processos: Podemos usar uma solução dada por Fischer: √ 2 X² -√ 2 nf = delta Devem ser aplicados os limites unilaterais da distribuição de Gauss : 5%:1, 64; 1%:2,32; 0,1%:3,09: Uma outra solução podemos obter segundo BRIEGER (1946) calculando o valor: √ x² / nf = teta X nf = teta e procurando os limites nas táboas para limites unilaterais de distribuições de Fischer, com nl = nf(X2); n2 = inf; (BRIEGER, 1946).

Visual analysis, clustering, and classification of contrast-enhanced tumor perfusion MRI data

Magdeburg, Univ., Fak. für Inf., Diss., 2014

Impact of genetic SLC28 transporter and ITPA variants on ribavirin 21 serum level, hemoglobin drop and therapeutic response in patients with HCV infection

Background: T reatment o f chronic hepatitis C i s evolving, a nd direct acting antivirals ( DAAs) are now a dded to p egylated interferon-α ( Peg- INF-α) and ribavirin (RBV) for the treatment o f hepatitis C v irus ( HCV) genotype 1 infection. DAAs c ause d ifferent side effects and can even worsen RBV induced hemolytic anemia. T herefore, identifying host genetic d eterminants of R BV bioavailability and therapeutic e fficacy will remain crucial for individualized treatment. Recent d ata showed associations between R BV induced h emolytic anemia and genetic polymorphisms o f concentrative nucleoside transporters s uch as C NT3 (SLC28A3) and i nosine t riphosphatase (ITPA). T o analyze t he association of genetic variants of SLC28 transporters and ITPA with RBV induced hemolytic anemia and treatment o utcome. Methods: I n our study, 173 patients f rom t he S wiss Hepatitis C C ohort Study and 2 2 patients from Swiss Association for the Study of the Liver study 24 (61% HCV g enotype 1, 3 9% genotypes 2 o r 3) were analyzed for SLC28A2 single nucleotide p olymorphism (SNP) rs11854484, SLC28A3 rs56350726 and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101. RBV serum levels during treatment were measured in 49 patients. Results: SLC28A2 r s11854484 genotype TT was associated with significantly higher dosage- and body weight-adjusted RBV levels as compared to genotypes TC and CC (p=0.04 and p=0.02 at weeks 4 and 8, respectively). ITPA SNPs rs1127354 and rs7270101 were associated with h emolytic a nemia both in genotype as w ell as i n allelic a nalyses. SLC28A3 rs56350726 genotype TT (vs. AT/AA, RR=2.1; 95% CI 1.1-4.1) as well as the T allele (vs. A; RR=1.8, 95% CI 1.1-3.2) were associated with increased SVR rates. The combined analysis of overall ITPA activity and SLC28 v ariants together revealed n o significant a dditive effects on either treatment-related anemia or SVR. Conclusions: T he newly identified association between RBV serum levels a nd SLC28A2 rs11854484 genotype as well as the replicated association of ITPA and SLC28A3 g enetic p olymorphisms w ith RBV induced hemolytic anemia and treatment r esponse underpin the need for further studies on host genetic d eterminants of R BV bioavailability and therapeutic e fficacy f or individualized treatment of chronic hepatitis C.

Acute Eosinophilic and Neutrophilic Pneumonia following Transarterial Chemoembolization with Drug-Eluting Beads Loaded with Doxorubicin for Hepatocellular Carcinoma: A Case Report.

At an intermediate or advanced stage, i.e. stage B or C, based on the Barcelona Clinic Liver Cancer classification of hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) may be offered as a treatment of palliative intent. We report the case of a patient suffering from acute respiratory distress syndrome after TACE with drug-eluting beads loaded with doxorubicin for HCC. To our knowledge, this is the first case described where a bronchoalveolar lavage was performed, and where significant levels of alveolar eosinophilia and neutrophilia were evident, attributed to a pulmonary toxicity of doxorubicin following liver chemoembolization. © 2014 S. Karger AG, Basel.

Reduced quality of life associated adverse events in intermediate hepatocellular carcinoma patients treated with PRECISION TACE with drug eluting beads: Results from the PRECISION V randomized trial : B-241

Purpose: To evaluate the extent of quality of life (QoL) associated adverse events (AEs) following PRECISION TACE with DC Bead compared with conventional transarterial chemoembolisation (cTACE). Methods and Materials: 201 intermediate HCC patients were treated with DC Bead (PRECISION TACE) or conventional TACE (cTACE) with doxorubicin in the PRECISION V clinical study. 93 patients were treated with DC Bead and 108 Patients with cTACE every 2 months and followed up for 6 months. AEs were classified according to the South West Oncology Group criteria. QoL associated AEs were defined as alopecia, constipation, nausea, vomiting, pyrexia, chills, asthenia, fatigue, and headache. Results: The biggest difference in QoL associated AEs was for alopecia: 2 patients (2.2%) for DC-Bead versus 21 patients (19.4%) for cTACE. For other clinical symptoms, constipation (n=10; 10.8% vs. n=13; 12%), vomiting (n=10; 10.8% vs. n=14; 13.0%), pyrexia (n=16; 17.2% vs. n=26; 24.1%), chills (n=1; 1.1% vs. n=5; 4.6%), and headache (n=2; 2.2% vs. n=8; 7.4%) showed lower incidence in the DC Bead group versus cTACE. Nausea, n= 15; 13.9% (n=15; 16.1%) and fatigue, n=6; 5.6% (n=13; 14.0%) were lower for cTACE. Total dose of doxorubicin was on average 35% higher in the DC Bead group. Conclusion: Although patients in the DC Bead group received a higher doxorubicin dose, less QoL associated AEs were reported for this group. Alopecia, the most obvious outward sign of toxicity, was only reported in a tenth of DC Bead patients. Thus, PRECISION TACE with DC Bead improves quality of life associated adverse events.

Cell mediated immunity in Chagas' disease: Trypanosoma cruzi antigens induce suppression of the in vitro proliferative response of mononuclear cells

The partial suppression of the cell-mediated immune response by Trypanosoma cruzi antigens in patients with Chagas' disease is demonstrated in a costimulation assay with T. cruzi antigens and Mycobacterium tuberculosis purified protein derivative (PPD) or Tetanus toxoid (TT). ononuclear cells from 13 patients with chagasic infection without evidence of heart disease, 10 patients with chagasic cardiomyopathy and 7 healthy blood donors were stimulated with antigen A (autoclaved epimastigotes), PPD, TT, PPD + A, PPD + TT and TT + A. The average percentage of suppression induced by costimulation of mononuclear cells with PPD and antigen A was 47.1% in patients with chagasic infection without heart disease (INF), 38.8% in patients with chagasic cardiomyopathy (CDM) and 23.3% in healthy controls. Similar values were observed when living trypomastigotes were used. A costimulatory study with PPD and TT, PPD and A and TT and A was carried out in 8 patients with chagasic infection, in order to evaluate the possibility that this difference could be due to a nonspecific inhibitory effect. The mean suppression induced by TT + PPD was -8.9, with TT + A was 52.7 and with PPD + A was 50.1. The data reported show that T. cruzi antigens induce a specific suppression of the proliferative responseof mononuclear cells, that might be relevant to the persistence of the parasite in the host.

Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06).

BACKGROUND: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS: Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION: Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.