Síndrome de ativação macrofágica em paciente com lúpus eritematoso sistêmico juvenil

A hemofagocitose reativa ou síndrome de ativação macrofágica (SAM) é uma complicação das doenças inflamatórias sistêmicas, causada por expansão de células T e macrófagos, com produção maciça de citocinas pró-inflamatórias, ocorrendo mais freqüentemente na artrite idiopática juvenil sistêmica e raramente no lúpus eritematoso sistêmico juvenil (LESJ). OBJETIVO: Relatar um caso de LESJ que evoluiu com SAM precipitada por infecção e infarto esplênico, com desfecho fatal. RELATO DE CASO: Uma menina de 7 anos, com diagnóstico de LESJ desde os 5 anos, evoluiu com artrite em atividade, alopecia intensa, citopenias, cefaléia, infecções respiratórias recorrentes e elevação intermitente de transaminases. Os anticorpos anti-DNA e anticardiolipina IgG e IgM foram identificados e a biópsia renal evidenciou glomerulonefrite lúpica de classe III. A paciente foi tratada com pulso de metilprednisolona, prednisona, azatioprina e hidroxicloroquina. Após dois anos, na vigência de pneumonia apresentou abdome agudo e convulsões, evoluindo para o choque hemorrágico fatal após esplenectomia, que evidenciou infarto esplênico e infiltração maciça por macrófagos hemofagocíticos CD163+. CONCLUSÃO: A revisão do desfecho sugere a SAM precipitada por infecção e sobreposta a atividade inflamatória do lúpus com febre persistente, citopenias, disfunção hepática, hepatomegalia e esplenomegalia, como efeitos do excesso de produção de citocinas. Os anticorpos anticardiolipina podem ter tido papel precipitante na coagulopatia, que resultou infarto esplênico e choque hemorrágico.

A contagem de plaquetas pré-operatória é fator de risco em pacientes cirróticos com hepatocarcinoma submetidos a hepatectomia?: revisão sistemática e metanálise de estudos coorte

Pós-graduação em Bases Gerais da Cirurgia - FMB

Analisi dei meccanismi patogenetici alla base del danno vascolare Hiv-indotto

L'infezione da HIV-1 resta ancora oggi una delle principali problematiche nell'ambito della sanità mondiale, con circa 35 milioni di individui infetti in tutto il mondo. L'introduzione della terapia antiretrovirale combinata (cART) ha drasticamente modificato l’evoluzione di questa infezione, che da patologia a sviluppo terminale dopo alcuni anni dalla trasmissione, è diventata una patologia cronica con una lunga aspettativa di vita per i pazienti. Tuttavia, la cART non è in grado di eradicare l’infezione e nei pazienti HIV-infetti trattati è possibile notare un aumento della comparsa di comorbidità, tra le quali le più frequentemente riscontrate sono lesioni al sistema nervoso centrale, ai reni, al tessuto osseo, al fegato e al sistema cardiovascolare. I danni al sistema cardiocircolatorio derivano da una serie di concause virologiche, comportamentali, ambientali e farmacologiche che alterano la parete vascolare, il metabolismo dei lipidi e la regolazione della coagulazione, inducendo la formazione di lesioni strutturali di tipo aterosclerotico che sono alla base dell’aumentata incidenza di infarti, ictus e alterazioni del circolo osservabili nei pazienti HIV-positivi. Dalla recente letteratura è emerso come l’omeostasi del tessuto endoteliale sia regolata anche a livello delle cellule staminali mesenchimali (MSC) presenti nella parete vascolare. Per questo abbiamo voluto analizzare possibili effetti dell’infezione di HIV, delle sue proteine e di alcune molecole antiretrovirali sulla vitalità e sul differenziamento delle MSC purificate dalla parete arteriosa umana. I risultati ottenuti indicano come l’infezione da HIV e l’azione delle proteine gp120 e Tat attivino il meccanismo di apoptosi nelle MSC e una profonda alterazione nel differenziamento verso la filiera adipocitaria e verso quella endoteliale. Inoltre, alcune molecole ad azione antiretrovirale (in particolare specifici inibitori della proteasi virale) sono in grado bloccare il differenziamento delle MSC verso le cellule endoteliali. Dall’insieme di queste osservazioni emergono nuovi meccanismi patogenetici correlati al danno cardiovascolare riscontrato nei pazienti HIV-positivi.

Effect of remifentanil on mitochondrial oxygen consumption of cultured human hepatocytes

During sepsis, liver dysfunction is common, and failure of mitochondria to effectively couple oxygen consumption with energy production has been described. In addition to sepsis, pharmacological agents used to treat septic patients may contribute to mitochondrial dysfunction. This study addressed the hypothesis that remifentanil interacts with hepatic mitochondrial oxygen consumption. The human hepatoma cell line HepG2 and their isolated mitochondria were exposed to remifentanil, with or without further exposure to tumor necrosis factor-α (TNF-α). Mitochondrial oxygen consumption was measured by high-resolution respirometry, Caspase-3 protein levels by Western blotting, and cytokine levels by ELISA. Inhibitory κBα (IκBα) phosphorylation, measurement of the cellular ATP content and mitochondrial membrane potential in intact cells were analysed using commercial ELISA kits. Maximal cellular respiration increased after one hour of incubation with remifentanil, and phosphorylation of IκBα occurred, denoting stimulation of nuclear factor κB (NF-κB). The effect on cellular respiration was not present at 2, 4, 8 or 16 hours of incubation. Remifentanil increased the isolated mitochondrial respiratory control ratio of complex-I-dependent respiration without interfering with maximal respiration. Preincubation with the opioid receptor antagonist naloxone prevented a remifentanil-induced increase in cellular respiration. Remifentanil at 10× higher concentrations than therapeutic reduced mitochondrial membrane potential and ATP content without uncoupling oxygen consumption and basal respiration levels. TNF-α exposure reduced respiration of complex-I, -II and -IV, an effect which was prevented by prior remifentanil incubation. Furthermore, prior remifentanil incubation prevented TNF-α-induced IL-6 release of HepG2 cells, and attenuated fragmentation of pro-caspase-3 into cleaved active caspase 3 (an early marker of apoptosis). Our data suggest that remifentanil increases cellular respiration of human hepatocytes and prevents TNF-α-induced mitochondrial dysfunction. The results were not explained by uncoupling of mitochondrial respiration.

"Rapid two-stage" Norwood operation in a child with multiorgan failure

The Norwood I operation continues to be a procedure with significant operative mortality. One well-accepted risk factor for death after the first step of the Norwood operation is critical preoperative status. We describe herein a new concept for the treatment of patients with hypoplastic left heart syndrome (HLHS) in very poor preoperative condition. This is a case report of a child who was born in a rural hospital. On the second day of life he was referred to our center in multiorgan failure. There were signs of liver dysfunction and the child was anuric. Therapy was started immediately with prostaglandin and vasodilators as well as diuretics, milrinone, and dobutamine. However, systemic perfusion continued to be insufficient. Finally, the child was placed on a ventilator. On the fourth day of life, bilateral pulmonary artery (PA) banding was performed and circulation stabilized immediately. Two hours after the operation urine output started. Liver function stabilized over the next couple of days. Two days after PA banding the child was weaned from the ventilator. On the 12th day of life a Norwood operation with PA debanding and a right ventricle-PA conduit was performed, and 2 days postoperatively the child was weaned from the ventilator. Twenty days after the operation he was discharged home. When the boy was 4 months old a bidirectional cavopulmonary anastomosis was performed. In selected cases of patients with HLHS with very poor hemodynamic conditions, a rapid two-stage approach with bilateral banding followed by a Norwood operation after cardiac stabilization can be recommended.

Survivors with bad outcome after hypoxic-ischaemic encephalopathy: full-term neonates compare unfavourably with children

Hypoxic-ischaemic encephalopathy (HIE) is of major importance in neonatal and paediatric intensive care with regard to mortality and long-term morbidity. Our aim was to analyse our data in full-term neonates and children with special regard to withdrawal of life support and bad outcome. PATIENTS: All patients with HIE admitted to our unit from 1992-96 were analysed. Criteria for HIE were presence of a hypoxic insult followed by coma or altered consciousness with or without convulsions. Severity of HIE was assessed in neonates using Sarnat stages, and in children the duration of coma. In the majority of cases staging was completed with electrophysiological studies. Outcome was described using the Glasgow Outcome Scale. Bad outcome was defined as death, permanent vegetative state or severe disability, good outcome as moderate disability or good recovery. RESULTS: In the neonatal group (n = 38) outcome was significantly associated with Sarnat stages, presence of convulsions, severely abnormal EEG, cardiovascular failure, and multiple organ dysfunction (MOD). A bad outcome was observed in 27 cases with 14 deaths and 13 survivors. Supportive treatment was withdrawn in 14 cases with 9 subsequent deaths. In the older age group (n = 45) outcome was related to persistent coma of 24-48 h, severely abnormal EEG, cardiovascular failure, liver dysfunction and MOD. A bad outcome was found in 36 cases with 33 deaths and 3 survivors. Supportive treatment was withdrawn in 15 instances, all followed by death. CONCLUSIONS: Overall, neonates and older patients did not differ with regard to good or bad outcome. However, in the neonatal group there were significantly more survivors with bad outcome, either overall or after withdrawal of support. Possible explanations for this difference include variability of hypoxic insult, maturational and metabolic differences, and the more compliant neonatal skull, which prevents brainstem herniation.

Automated low flow pump system for the treatment of refractory ascites: A multi-center safety and efficacy study

BACKGROUND & AIMS: Refractory ascites (RA) affects 10% of patients with advanced cirrhosis and ascites. Usual therapy includes large volume paracentesis, and in selected patients, a transjugular portosystemic shunt (TIPS). These therapies may be associated with increased morbidity: paracentesis may induce circulatory dysfunction and impair quality of life and TIPS may induce encephalopathy and is associated with increased mortality in patients with severe liver dysfunction. We present the results of a multicenter, non-randomized trial to assess the safety and efficacy of a new automated pump system for treatment of RA. METHODS: Forty patients at 9 centers (February 2010-June 2011) received an implanted pump for the automated removal of ascites from the peritoneal cavity into the bladder, from where it was eliminated through normal urination. Patients were followed-up for 6months. The primary study outcome was safety. Secondary outcomes included recurrence of tense ascites and pump performance. RESULTS: Surgical complications occurred early in the study and became less frequent. The pump system removed 90% of the ascites and significantly reduced the median number of large volume paracentesis per month [3.4 (range 1-6) vs. 0.2 (range 0-4); p <0.01]. Cirrhosis-related adverse events decreased along follow-up. CONCLUSIONS: The automated pump seems an efficacious tool to move out ascites from the peritoneal cavity to the bladder. Its safety is still moderate, but a broad use in different countries will improve the surgical technique as well as the medical surveillance. A prospective randomized clinical trial vs. large volume paracentesis is underway to confirm these preliminary results.

A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly

We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. What is Known: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.

Anaesthetic induction with etomidate in cardiac surgery: A randomised controlled trial.

BACKGROUND Etomidate is perceived as preserving haemodynamic stability during induction of anaesthesia. It is also associated with adrenocortical dysfunction. The risk/benefit relationship is controversial. OBJECTIVES We tested the hypotheses that single-dose etomidate increases cumulative vasopressor requirement, time to extubation and length of stay in the ICU. DESIGN Double-blind randomised controlled trial. SETTING Bern University Hospital, Switzerland, from November 2006 to December 2009. PATIENTS There were 90 patients undergoing coronary artery bypass grafts (CABG) and 40 patients undergoing mitral valve surgery (MVS). Reasons for noninclusion were known adrenocortical insufficiency, use of etomidate or propofol within 1 week preoperatively, use of glucocorticoids within 6 months preoperatively, severe renal or liver dysfunction, or carotid stenosis. INTERVENTIONS CABG patients were allocated randomly to receive either etomidate 0.15 mg kg with placebo, propofol 1.5 mg kg with placebo or etomidate 0.15 mg kg with hydrocortisone (n = 30 in each arm). Risk stratification (low vs. high) was achieved by block randomisation. MVS patients received either etomidate 0.15 mg kg or propofol 1.5 mg kg (n = 20 in each arm). MAIN OUTCOME MEASURES Cumulative vasopressor requirements, incidence of adrenocortical insufficiency, length of time to extubation and length of stay in ICU. RESULTS Cumulative vasopressor requirements 24 h after induction did not differ between treatments in patients who underwent CABG, whereas more noradrenaline was used in MVS patients following propofol induction (absolute mean difference 5.86 μg kg over 24 h P = 0.047). The incidence of relative adrenocortical insufficiency was higher after etomidate alone than propofol (CABG 83 vs. 37%, P < 0.001; MVS: 95 vs. 35%, P < 0.001). The time to extubation, length of stay in ICU and 30-day mortality did not differ among treatments. Within low and high-risk subgroups, no differences in vasopressor use or outcomes were found. CONCLUSION In elective cardiac surgery, laboratory indicators of etomidate-induced adrenal insufficiency do not translate into increased vasopressor requirement or inferior early outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT 00415701.

Estudo do potencial imunomodulador de Dehidroepiandrosterona (DHEA) na inflamação intestinal experimental

As Doenças inflamatórias intestinais (DII) são multifatoriais e sua etiologia envolve susceptibilidade genética, fatores ambientais, disbiose e ativação exacerbada do sistema imunológico no intestino. Essas doenças também tem sido relacionadas a baixos níveis de dehidroepiandrosterona (DHEA), um hormônio precursor de diversos esteroides e relacionado à modulação das respostas imunes. Porém, os mecanismos precisos que relacionam as ações deste hormônio com a proteção ou susceptibilidade à doença de Crohn ou colite ulcerativa ainda não são totalmente conhecidos. Sendo assim, este projeto buscou entender o papel imunomodulador do DHEA exógeno in vitro e in vivo durante a inflamação intestinal experimental induzida por dextran sulfato de sódio (DSS) em camundongos C57BL/6. Inicialmente, in vitro, DHEA inibiu a proliferação de células do baço de forma dose dependente nas concentrações de 5?M, 50?M ou 100?M, com diminuição da produção de IFN-?. Este hormônio não foi tóxico para células de linhagem mieloide, embora tenha causado necrose em leucócitos nas doses mais elevada (50 ?M e 100?M), o que pode ter influenciado a diminuição das citocinas in vitro. Nos ensaios in vivo, os camundongos tratados com DHEA (40 mg/Kg) foram avaliados na fase de indução da doença (dia 6) e durante o reparo tecidual, quando os animais expostos ao DSS e ao DHEA por 9 dias foram mantidos na ausência destas drogas até o dia 15. Houve diminuição do escore pós-morte, melhora no peso e nos sinais clínicos da inflamação intestinal, com redução de monócitos no sangue periférico com 6 dias e aumento de neutrófilos circulantes na fase de reparo tecidual (15 dias). Ainda, a suplementação com DHEA levou à redução da celularidade da lâmina própria (LP) e ao restabelecimento do comprimento normal do intestino. O uso deste hormônio também diminuiu a expressão do RNAm de IL-6 e TGF-?, enquanto aumentou a expressão de IL-13 no colón dos animais durante a fase de indução da doença, o que provavelmente ajudou na atenuação da inflamação intestinal. Além disso, houve acúmulo de linfócitos CD4+ e CD8+ no baço e diminuição apenas de linfócitos CD4+ nos linfonodos mesentéricos (LNM), indicando retenção das células CD4+ no baço após uso do DHEA. O tratamento foi também capaz de aumentar a frequência de células CD4 produtoras de IL-4 e diminuir CD4+IFN-?+ no baço, além de reduzir a frequência de CD4+IL-17+ nos LNM, sugerindo efeito do DHEA no balanço das respostas Th1/Th2/Th17 relacionadas à colite. Em adição, as células de baço dos animais tratados com DHEA e expostos ao DSS se tornaram hiporresponsivas, como visto pela diminuição da proliferação após re-estímulos in vitro. Finalmente, DHEA foi capaz de atuar no metabolismo dos camundongos tratados, levando à diminuição de colesterol total e da fração LDL no soro durante a fase de indução da doença, sem gerar quaisquer disfunções hepáticas. Com isso, podemos concluir que o DHEA atua por meio do balanço das respostas imunes exacerbadas, minimizando os danos locais e sistêmicos causados pela inflamação intestinal induzida por DSS.

Long-evolution ascites in a patient with constrictive pericarditis

Constrictive pericarditis (CP) is an uncommon disease resulting from chronic pericardial inflammation, fibrosis and calcification. Since there are atypical forms of presentation, with subtle or nonexistent cardiorespiratory symptoms, diagnosis may be challenging and difficult. Recurrent ascites in patients with congestive hepatopathy due to constrictive pericarditis is, in most cases, reversible after pericardiectomy. Nevertheless, development of persistent liver dysfunction may be a long-term complication. The present case describes a 23 years old man with growth delay, dyspnoea and long evolution ascites, whose exhaustive etiological investigation led to diagnosis. Afterwards the patient underwent elective surgery with symptom and general condition improvement. Ascites differential diagnosis and its association with constrictive pericarditis are briefly reviewed in this article.

Clinical Outcomes and Genetic Expression Profile in Human Liver Graft Dysfunction During Ischemia/Reperfusion Injury

Introduction. This study aims to compare the molecular gene expression during ischemia reperfusion injury. Several surgical times were considered: in the beginning of the harvesting (T0), at the end of the cold ischemia period (T1), and after reperfusion (T2) and compared with graft dysfunction after liver transplant (OLT). Methods. We studied 54 patients undergoing OLT. Clinical, laboratory data, and histologic data (Suzuki classification) as well as the Survival Outcomes Following Liver Transplantation (SOFT) score were used and compared with the molecular gene expression of the following genes: Interleukin (IL)-1b, IL-6, tumor necrosis factor-a, perforin, E-selectin (SELE), Fas-ligand, granzyme B, heme oxygenase-1, and nitric oxide synthetase. Results. Fifteen patients presented with graft dysfunction according to SOFT criteria. No relevant data were obtained by comparing the variables graft dysfunction and histologic variables. We observed a statistically significant relation between SELE at T0 (P ¼ .013) and IL-1b at T0 (P ¼ .028) and early graft dysfunction. Conclusions. We conclude that several genetically determined proinflammatory expressions may play a critical role in the development of graft dysfunction after OLT.

Inflammation-induced atherogenesis, liver alterations, and cardiovascular outcome

Cardiovascular diseases, which presently are considered inflammatory diseases, affect millions of people worldwide. Chronic infections may contribute to the systemic inflammation suggested to increase the risk for cardiovascular diseases. Such chronic infections are periodontitis and Chlamydia pneumoniae infection. They are highly prevalent as approximately 10% of adult population and 30% of people over 50 years old are affected by severe periodontitis and 70-80% of elderly people are seropositive for C. pneumoniae. Our general aim was to investigate the role of infection and inflammation in atherosclerosis both in animal and human studies. We aimed to determine how the two pathogens alter the atherosclerosis-associated parameters, and how they affect the liver inflammation and lipid composition. Furthermore, we evaluated the association between matrix metalloproteinase-8 (MMP-8), a proteinase playing a major role in inflammation, and the future cardiovascular diseases (CVD) events in a population-based cohort. For the animal experiments, we used atherosclerosis-susceptible apolipoprotein E deficient (apoE-/-) mice. They were kept in germ free conditions and fed with a normal chow diet. The bacteria were administered either intravenously (A. actinomycetemcomitans) or intranasally (C. pneumoniae). Several factors were determined from serum as well as from aortic and hepatic tissues. We also determined how cholesterol efflux, a major event in the removal of excess cholesterol from the tissues, and endothelial function were affected by these pathogens. In the human study, serum MMP-8 and its tissue inhibitor (TIMP-1) concentrations were measured and their associations during the follow-up time of 10 years with CVD events were determined. An infection with A. actinomycetemcomitans increased concentrations of inflammatory mediators, MMP production, and cholesterol deposit in macrophages, decreased lipoprotein particle size, and induced liver inflammation. C. pneumoniae infection also elicited an inflammatory response and endothelial dysfunction, as well as induced liver inflammation, microvesicular appearance and altered fatty acid profile. In the population-based cohort, men with increased serum MMP-8 concentration together with subclinical atherosclerosis (carotid artery intima media thickness > 1mm) had a three-fold increased risk for CVD death during the follow-up. The results show that infections with A. actinomycetemcomitans and C. pneumoniae induce proatherogenic changes, as well as affect the liver. These data therefore support the concept that common infections have systemic effects and could be considered as cardiovascular risk factors. Furthermore, our data indicate that, as an independent predictor of fatal CVD event, serum MMP-8 could have a clinical significance in diagnosing cardiovascular diseases.