Biliary Tract Carcinogenesis Model Based on Bile Metaproteomics.

Purpose: To analyze human and bacteria proteomic profiles in bile, exposed to a tumor vs. non-tumor microenvironment, in order to identify differences between these conditions, which may contribute to a better understanding of pancreatic carcinogenesis. Patients and Methods: Using liquid chromatography and mass spectrometry, human and bacterial proteomic profiles of a total of 20 bile samples (7 from gallstone (GS) patients, and 13 from pancreatic head ductal adenocarcinoma (PDAC) patients) that were collected during surgery and taken directly from the gallbladder, were compared. g:Profiler and KEGG (Kyoto Encyclopedia of Genes and Genomes) Mapper Reconstruct Pathway were used as the main comparative platform focusing on over-represented biological pathways among human proteins and interaction pathways among bacterial proteins. Results: Three bacterial infection pathways were over-represented in the human PDAC group of proteins. IL-8 is the only human protein that coincides in the three pathways and this protein is only present in the PDAC group. Quantitative and qualitative differences in bacterial proteins suggest a dysbiotic microenvironment in the PDAC group, supported by significant participation of antibiotic biosynthesis enzymes. Prokaryotes interaction signaling pathways highlight the presence of zeatin in the GS group and surfactin in the PDAC group, the former in the metabolism of terpenoids and polyketides, and the latter in both metabolisms of terpenoids, polyketides and quorum sensing. Based on our findings, we propose a bacterial-induced carcinogenesis model for the biliary tract. Conclusion: To the best of our knowledge this is the first study with the aim of comparing human and bacterial bile proteins in a tumor vs. non-tumor microenvironment. We proposed a new carcinogenesis model for the biliary tract based on bile metaproteomic findings. Our results suggest that bacteria may be key players in biliary tract carcinogenesis, in a long-lasting dysbiotic and epithelially harmful microenvironment, in which specific bacterial species' biofilm formation is of utmost importance. Our finding should be further explored in future using in vitro and in vivo investigations.

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients / Anticorpos muscarínicos e resposta da frequência cardíaca ao exercício dinâmico e a manobra de Valsalva na doença de Chagas crônica

We have studied the cardiac chronotropic responses to the Valsalva maneuver and to dynamic exercise of twenty chronic chagasic patients with normal left ventricular function and no segmental wall abnormalities by two-dimensional echocardiogram. The absolute increase in heart rate of the patients (Δ = 21.5 ± 10 bpm, M±SD) during the maneuver was significantly diminished when compared to controls (Δ = 31.30 ± 70, M±SD, p = 0.03). The minimum heart rate (58.24 ± 8.90 vs. 62.80 ± 10, p = 0.68) and the absolute decrease in heart rate at the end of the maneuver (Δ = 38.30 ± 13 vs. Δ = 31.47 ± 17, p = 0.10) were not different from controls. The initial heart rate acceleration during dynamic exercise (Δ = 12 ± 7.55 vs. Δ = 19 ± 7.27, M±SD, p = 0.01) was also diminished, but the heart rate recovery during the first ten seconds was more prominent in the sero-positive patients (Median: 14, Interquartile range: (9.75-17.50 vs. 5(0-8.75, p = 0.001). The serum levels of muscarinic cardiac auto-antibodies were significantly higher in the chagasic patients (Median: 34.58, Interquartile Range: 17-46.5, Optical Density) than in controls (Median: 0, Interquartile Range: 0-22.25, p = 0.001) and correlated significantly and directly (r = 0.68, p = 0.002) with early heart rate recovery during dynamic exercise. The results of this investigation indirectly suggest that, the cardiac muscarinic auto-antibodies may have positive agonist effects on parasympathetic heart rate control of chagasic patients.

Foram estudadas as respostas cronotrópicas cardíacas à manobra de Valsalva e ao exercício dinâmico de vinte pacientes chagásicos com função ventricular esquerda normal e sem alterações da contractilidade segmentar por ecocardiografia bidimensional. O aumento absoluto da frequência cardíaca dos pacientes (Δ = 21,5 ± 10 bpm, M ± DP) durante a manobra de Valsalva foi significativamente menor quando se comparava ao grupo controle (Δ = 31,30 ± 70, p = 0,03). A frequência cardíaca mínima (58,24 ± 8,90 vs 62,80 ± 10, p = 0,68) e a diminuição da frequência cardíaca absoluta no final da manobra (Δ = 38,30 ± 13 vs Δ = 31,47 ± 17, p = 0,10) não foram diferentes em comparação com o grupo controle. A aceleração inicial da frequência cardíaca durante o exercício dinâmico (Δ = 12 ± 7,55 vs Δ = 19 ± 7,27, p = 0,01) também foi menor, mas a recuperação da frequência cardíaca, durante os primeiros dez segundos, foi maior no grupo sero-positivos [mediana:14 (intervalo interquartil: 9,75-17,50) vs 5 (0 - 8,75), p = 0,001]. Os níveis séricos de auto-anticorpos muscarínicos cardíacos foram significativamente maiores nos pacientes chagásicos do que no grupo controle [(mediana: 34,58 densidade óptica (intervalo interquartil 17 - 46,5) vs (mediana: 0, intervalo interquartil 0 - 22,25) p = 0,001] e a correlação é significativa e direta (r = 0,68, p = 0,002) com o início da recuperação da frequência cardíaca durante o exercício dinâmico. Os resultados desta investigação sugerem que indiretamente, os auto-anticorpos muscarínicos cardíacos, podem ter ação agonista positiva sobre o controle parassimpático da frequência cardíaca dos pacientes chagásicos.

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients.

We have studied the cardiac chronotropic responses to the Valsalva maneuver and to dynamic exercise of twenty chronic chagasic patients with normal left ventricular function and no segmental wall abnormalities by two-dimensional echocardiogram. The absolute increase in heart rate of the patients (Δ = 21.5 ± 10 bpm, M±SD) during the maneuver was significantly diminished when compared to controls (Δ = 31.30 ± 70, M±SD, p = 0.03). The minimum heart rate (58.24 ± 8.90 vs. 62.80 ± 10, p = 0.68) and the absolute decrease in heart rate at the end of the maneuver (Δ = 38.30 ± 13 vs. Δ = 31.47 ± 17, p = 0.10) were not different from controls. The initial heart rate acceleration during dynamic exercise (Δ = 12 ± 7.55 vs. Δ = 19 ± 7.27, M±SD, p = 0.01) was also diminished, but the heart rate recovery during the first ten seconds was more prominent in the sero-positive patients (Median: 14, Interquartile range: (9.75-17.50 vs. 5(0-8.75, p = 0.001). The serum levels of muscarinic cardiac auto-antibodies were significantly higher in the chagasic patients (Median: 34.58, Interquartile Range: 17-46.5, Optical Density) than in controls (Median: 0, Interquartile Range: 0-22.25, p = 0.001) and correlated significantly and directly (r = 0.68, p = 0.002) with early heart rate recovery during dynamic exercise. The results of this investigation indirectly suggest that, the cardiac muscarinic auto-antibodies may have positive agonist effects on parasympathetic heart rate control of chagasic patients.

Cardiac autonomic control mechanisms in the pathogenesis of chagas' heart disease.

Primary abnormalities of the autonomic nervous system had been postulated as the pathogenic mechanisms of myocardial damage, in patients with Chagas disease. However, recent investigations indicate that these abnormalities are secondary and amenable to treatment with beta-adrenergic blockers. Moreover, muscarinic cardiac autoantibodies appear to enhance parasympathetic activity on the sinus node. Therefore, the purpose of this paper is to analyze how knowledge on Chagas' disease evolved from being initially considered as a primary cardioneuromyopathy to the current status of a congestive cardiomyopathy of parasitic origin.

[Antiadrenergic rescue therapy with amiodarone in children with severe left ventricular dysfunction secondary to scorpion envenomation]. / Terapia de resgate com amiodarona em crianças com grave disfunção ventricular esquerda causada por veneno de escorpião.

BACKGROUND: Children with scorpion envenomation have massive sympathetic activation and variable degrees of left ventricular systolic dysfunction. OBJECTIVE: To evaluate a rescue protocol for children with severe left ventricular dysfunction secondary to scorpion envenomation. METHODS: Four children, after scorpion envenomation, were subjected to a rescue protocol for acute left ventricular dysfunction: Endotracheal intubation and respiratory assistance, electrocardiograms, chest x-Ray, echocardiograms and blood samples for norepinephrine and troponin I serum levels. Samples and echocardiograms were repeated at 12, 24 and 48 hours. Intravenous medications: Dobutamine: 4-6 microg/kg/min. Amiodarone: 3 mg/kg during a 2 hour period. Maintenance: 5 mg/kg/day. Furosemide: 0.5 mg/kg/dose. Diuretics were given when the systemic blood pressure was above percentile fifty. Amiodarone, Dobutamine and Furosemide were administered during the first 48 hours. Beta-adrenergic blockers and angiotensin converting enzyme were given, at 48 hours after admission, once the left ventricular Ejection fraction > 0.35 and the clinical status had improved. RESULTS: On admission, norepinephrine was 1,727.50 +/-794.96 pg/ml, troponin I 24.53 +/- 14.09 ng/ml and left ventricular ejection fraction 0.20 +/- 0.056. At twelve hours, norepinephrine and troponin I serum levels were down to half of the initial values and the ejection fraction increased to 0.32 +/- 0.059. During the next 24 and 48 hours, the ejection fraction rose to 0.46 +/- 0.045, (p<0.01) and norepinephrine and troponin diminished to 526.75 +/- 273.73 (p < 0.02) and 2.20 +/- 2.36 (p<0.02) respectively. CONCLUSION: Amiodarone, by acting as a neuromodulator, is very likely responsible for the early and progressive decrease of serum norepinephrine.

Terapia de resgate com amiodarona em crianças com grave disfunção ventricular esquerda causada por veneno de escorpião / Antiadrenergic rescue therapy with amiodarone in children with severe left ventricular dysfunction secondary to scorpion envenomation / Terapia de rescate con amiodarona en niños con severa disfunción ventricular izquierda ocasionada por veneno de escorpión

Fundamentos: As crianças picadas por escorpião, pressintam ativação maciça do sistema nervoso simpática com vários graus de disfunção sistólica ventricular esquerda. Oobjetivo: Testar um protocolo de resgate em crianças com grave disfunção ventricular esquerda causada por picada de escorpião. Métodos: Quatro crianças após serem picadas por escorpião foram submetidas a: Encubação endotraqueal e suporte respiratório, eletrocardiograma, radiografia de tórax, ecocardiograma e determinação sérica da norepinefrina e troponina I. As análises foram repetidas após 12, 24 e 48 horas. As seguintes medicações intravenosas foram administradas: dobutamina 4-6 μg/kg/min; amiodarona 3 mg/kg durante duas horas, com dose de manutenção de 5 mg/kg/dia; e furosemida 0,5 mg/kg. Amiodarona, dobutamina e furosemida foram administradas durante as primeiras 48 horas. Bloqueadores beta-adrenérgicos e inibidores da enzima conversora da angiotensina foram administrados até 48 após a internação, uma vez que o estado clínico havia melhorado e a fração de ejeção ventricular esquerda encontrava-se acima de 0,35 por cento. Resultados: Na admissão, a dosagem da norepinefrina foi 1.727,50± 794,96 pg/ml, a de troponina I 24,53 ± 14,09 ng/ml e a fração de ejeção do ventrículo esquerdo foi 0,20 ± 0,056. Após 12 horas, os níveis séricos de norepinefrina e de troponina I diminuíram para a metade dos valores iniciais e a fração de ejeção aumentou para 0,32 ± 0,059. Durante as 24 e 48 horas subseqüentes, a fração de ejeção elevou-se para 0,46 ± 0,045 (p<0,01) e a norepinefrina e de troponina I diminuíram para 526,75 ± 273,73 (p< 0,02) e 2,20 ± 2,36 (p<0,02) respectivamente. Conclusão: É bem provável que a amiodarona, ao agir como neuromodulador, seja responsável pela redução rápida e progressiva dos níveis séricos de norepinefrina.

Background: Children with scorpion envenomation have massive sympathetic activation and variable degrees of left ventricular systolic dysfunction. Objective: To evaluate a rescue protocol for children with severe left ventricular dysfunction secondary to scorpion envenomation. Methods: Four children, after scorpion envenomation, were subjected to a rescue protocol for acute left ventricular dysfunction: Endotracheal intubation and respiratory assistance, electrocardiograms, chest x-Ray, echocardiograms and blood samples for norepinephrine and troponin I serum levels. Samples and echocardiograms were repeated at 12, 24 and 48 hours. Intravenous medications: Dobutamine: 4-6 μg/kg/min. Amiodarone: 3 mg/kg during a 2 hour period. Maintenance: 5 mg/kg/day. Furosemide: 0.5 mg/kg/dose. Diuretics were given when the systemic blood pressure was above percentile fifty. Amiodarone, Dobutamine and Furosemide were administered during the first 48 hours. Beta-adrenergic blockers and angiotensin converting enzyme were given, at 48 hours after admission, once the left ventricular Ejection fraction > 0.35 and the clinical status had improved. Results: On admission, norepinephrine was 1,727.50 ±794.96 pg/ml, troponin I 24.53 ± 14.09 ng/ml and left ventricular ejection fraction 0.20 ± 0.056. At twelve hours, norepinephrine and troponin I serum levels were down to half of the initial values and the ejection fraction increased to 0.32 ± 0.059. During the next 24 and 48 hours, the ejection fraction rose to 0.46 ± 0.045, (p<0.01) and norepinephrine and troponin diminished to 526.75 ± 273.73 (p < 0.02) and 2.20 ± 2.36 (p<0.02) respectively. Conclusion: Amiodarone, by acting as a neuromodulator, is very likely responsible for the early and progressive decrease of serum norepinephrine.

Fundamento: Los niños con picaduras de escorpión sufren activación masiva del sistema nervioso simpático con varios grados de disfunción sistólica ventricular izquierda. Objetivo: Probar un protocolo de rescate en niños con disfunción ventricular severa izquierda ocasionada por picadura de escorpión. Métodos: Cuatro niños tras un escorpión picarlas se sometieron a: incubación endotraqueal y soporte respiratorio, electrocardiograma, radiografía de tórax, ecocardiograma y determinación sérica de la norepinefrina y troponina I. Los análisis se repitieron tras 12, 24 y 48 horas. Las siguientes medicaciones intravenosas se administraron: dobutamina 4-6 mcg/kg/min; amiodarona 3 mg/kg durante dos horas, con dosis de mantenimiento de 5 mg/kg/día; y furosemida 0.5 mg/kg. Amiodarona, dobutamina y furosemida se administraron durante las primeras 48 horas. Bloqueante betaadrenergicos e inhibidores de la enzima convertidora de la angiotensina se administraron hasta 48 tras la internación, una vez que el estado clínico había mejorado y la fracción de eyección ventricular izquierda se hallaba superior a un 0,35 por ciento. Resultados: Al ingreso, la dosificación de la norepinefrina fue 1727,50± 794,96 pg/ml, la de troponina I 24,53 ± 14,09 ng/ml y la fracción de eyección del ventrículo izquierdo fue 0,20 ± 0,056. Tras 12 horas, los niveles séricos de norepinefrina y de troponina I disminuyeron para la mitad de los valores iniciales y la fracción de eyección aumentó para 0,32 ± 0,059. Durante las 24 y 48 horas subsiguientes, la fracción de eyección se elevó para 0,46 ± 0,045 (p<0,01) y la norepinefrina y de troponina I se redujeron para 526,75 ± 273,73 (p< 0,02) y 2,20 ± 2,36 (p<0,02) respectivamente. Conclusión: Es bien probable que la amiodarona, al actuar como neuromodulador, sea responsable de la reducción rápida y progresiva de los niveles séricos de norepinefrina.

Acutely decompensated systolic heart failure: effects of frequent doses of furosemide vs a single dose plus carvedilol on clinical status, neurohormonal activation and ventricular arrhythmias.

Beta blockers are contraindicated in patients with acutely decompensated heart failure. Current therapeutic strategies increase morbidity and mortality. We have compared the effects of frequent doses of diuretics vs a single dose of diuretics and cautious uptitration of carvedilol. Our results indicate that, although clinical compensation is achieved with both strategies; the effects on neurohormonal activation and ventricular arrhythmias are opposite.

Adaptación morfológica del corazón a la hipertensión arterial esencial: fisiopatología e implicaciones terapéuticas / Morphologic adaptation of the heart to high blood pressure: pathophysiology and therapeutic implications

El diseño experimental de los estudios prospectivos sobre el tratamiento de la hipertensión arterial esencial, ha ignorado un aspecto fundamental de la fisiopatología del paciente hipertenso: Los pacientes hipertensos no son homogéneos, en lo que respecta a los mecanismos responsables del aumento de la presión arterial. La adptación cardiovascular a la hipertensión arterial es anatómica y funcionalmente heterogénea. Investigaciones clínicas recientes indican que, esta heterogeneidad, puede ser minimizada con el uso de la eco-cardiografía. El análisis de los perfiles hemodinámicos y neurohormonales de los pacientes hipertensos permite distinguir la presencia de denominadores comunes: La hipertrofia ventricular concéntrica y la hipertrofia ventricular excéntrica representan los extremos opuestos de adaptación del corazón a la hipertensión arterial. El primero se caracteriza por tener una forma geométrica elíptica, con un perfil hemodinámico de gasto cardíaco normal y resistencias vasculares periféricas elevadas. Los niveles plasmáticos de renina y de los péptidos natriuréticos están elevados.

The experimental design of clinical studies, on the pharmacological treatment of essencial hypertension, has ignored a fundamental issue: Hypertensive patiens are not a homogenous population. The adaptation of the cardiovascular system to hypertension is structurally and funtionally heterogeneous. Recent clinical investigations suggest that this heterogeneity can be minimized by echocardiography. Thus, when the hemodynamic and neurohormonal profiles of untreated hypertensive patients are considered, in the particular context of the cardiac morphologic adaptation to high blood pressure, distinct common denominator emerge. Concentric Hypertrophy is characterized by an elliptic left ventricle, normal stroke volume and high peripheral vascular resistance. Its predominant neurohormonal profile includes elevated plasma renin and natriuretic peptide levels. Conversely, most patients with eccentric hypertrophy have a spheric left ventricle, increased stroke volume and low peripheral vascular resistance. Its corresponding neurohormonal profile shows low serum renin and anhanced sympathetic nervous activity. The therapeutic response, to angiotensin II antagonists and to beta-adrenergic blockers, of these two geometric patterns is also different. Concentric hypertrophy is substantially reversed by angiotensin II blockers, where as, eccentric hypertrophy is refractory to both, angiotensin II blockerds and atenol. These facts raise a relevant question: Should ventricular geometry be considered when deciding which antihypertensive drug is to be prescribed?.

Patterns of left ventricular hypertrophy in essential hypertension: should echocardiography guide the pharmacological treatment?

The experimental design of clinical studies, on the pharmacological treatment of essential hypertension, has ignored a fundamental issue: Hypertensive patients are not a homogenous population. The adaptation of the cardiovascular system to hypertension is structurally and functionally heterogeneous. Recent clinical investigations suggest that this heterogeneity can be minimized by echocardiography. Thus, when the hemodynamic and neurohormonal profiles of untreated hypertensive patients are considered, in the particular context of the cardiac morphologic adaptation to high blood pressure, distinct common denominators emerge. Concentric and eccentric hypertrophy, the two most common patterns of ventricular hypertrophy, are at the extremes of the geometric spectrum. Concentric hypertrophy is characterized by an elliptic left ventricle, normal stroke volume and high peripheral vascular resistance. Its predominant neurohormonal profile includes elevated plasma renin and natriuretic peptide levels. Conversely, most patients with eccentric hypertrophy have a spheric left ventricle, increased stroke volume and low peripheral vascular resistance. Its corresponding neurohormonal profile shows low serum renin and enhanced sympathetic nervous activity. The therapeutic response, to angiotensin II antagonists and to beta-adrenergic blockers, of these two geometric patterns is also different. Concentric hypertrophy is substantially reversed by losartan, whereas, eccentric hypertrophy is refractory to both, losartan and atenolol. These facts raise a relevant question: Should ventricular geometry be considered when deciding which antihypertensive drug is to be prescribed?

Mechanisms of neurohormonal activation in chronic congestive heart failure: pathophysiology and therapeutic implications.

Patients with chronic congestive heart failure have a sequential and incessant activation of those neurohormonal systems, which control body fluids, cardiac output and systemic blood pressure. Neurohormonal activation is initially selective and regional. Generalized activation is a late event in the natural history of congestive heart failure. Although the ultimate stimulus responsible for the activation of these neurohormonal systems is unknown, a decreased cardiac output and diminished effective blood volume have been proposed as the responsible mechanisms. However, extensive clinical and experimental research suggest that cardiac remodeling and loading of low-pressure cardiac receptors with sympathetic afferents could be the triggering events followed by unloading of high-pressure carotid receptors by decreased cardiac output and diminished effective blood volume.

Vagal dysfunction and the pathogenesis of chronic Chagas disease.

Vagal dysfunction is thought to be an early, primary and specific abnormality of chronic Chagas disease. However, chagasic patients with unequivocal evidence of heart disease, can have normal or abnormal vagal control of heart rate. A common explanation for these apparently discordant and contradictory results is proposed.

A modified and unifying neurogenic hypothesis can explain the natural history of chronic Chagas heart disease.

The pathogenesis of chronic Chagas disease still is an unresolved and controversial issue. Parasite persistence and autoimmune responses cannot explain the spectrum of chronic Chagas disease. However, a modified neurogenic hypothesis, concerning the timing and mechanisms responsible for the cardiac parasympathetic damage and for the activation of the sympathetic nervous system and of other neurohormonal systems, unifies cardiac remodelling and neurohormonal activation to explain most of the events of the natural history of Chagas disease.

Valsalva maneuver in chagasic patients with documented past medical history of acute chagasic myocarditis.

BACKGROUND: We studied the heart rate responses to the Valsalva maneuver in eight patients with documented past medical history of acute Chagas' disease. METHODS: Four patients were studied 8-21 months after the acute episode and four, 58-68 months thereafter (age 25+/-8.65 years M+/-S.D.). Seventeen healthy subjects of similar age were included as controls (age 27+/-7.5 years, P=NS). RESULTS: Baseline heart rate was higher in chagasic patients (88+/-15 beats/min) compared to controls (69.8+/-9.8, P=0.001). Maximum heart rate at phase II of the maneuver was also higher (114+/-16.3 vs. 101.5+/-9.9, P=0.02). Minimum heart rate at phase IV was, however, not different (57.4+/-10.4 vs. 63.3+/-7.3 P=NS). The magnitude of the absolute negative change at phase IV was larger in the chagasic patients, although, not different (-50.8+/-13.8 vs. -44+/-13.8, P=NS). The Valsalva index was 1.81+/-0.26 in the chagasic patients and 1.82+/-0.42 in the controls (P=NS). Minimum heart rate at phase IV correlated neither with the baseline heart rate (r=-0.28, P=NS) nor with the Valsalva index (r=-0.40, P=NS). The magnitude of the absolute negative change during phase IV correlated with, both, the baseline heart rate (r=-0.80, P<0.01) and the Valsalva index (r=-0.95, P<0.0001). The higher baseline high rate influenced the magnitude of the negative heart rate change, but not the minimum heart rate reached at phase IV. CONCLUSIONS: Chagasic patients with proven past medical history of acute Chagas' disease had unimpaired heart responses to the Valsalva maneuver.