Tobramycin Inhalation Powder™:a novel drug delivery system for treating chronic Pseudomonas aeruginosa infection in cystic fibrosis

Lung disease in cystic fibrosis (CF) is typified by the development of chronic airways infection culminating in bronchiectasis and progression to end-stage respiratory disease. Pseudomonas aeruginosa, a ubiquitous gram-negative bacteria, is the archetypical CF pathogen and is associated with an accelerated clinical decline. The development and widespread use of chronic suppressive aerosolized antibacterial therapies, in particular Tobramycin Inhalation Solution (TIS), in CF has contributed to reduced lung function decline and improved survival. However, the requirement for the aerosolization of these agents through nebulizers has been associated with increased treatment burden, reduced quality of life and remain a barrier to broader uptake. Tobramycin Inhalation Powder (TIP™) has been developed by Novartis with the express purpose of delivering the same benefits as TIS in a time-effective manner. Administered via the T-326™ (Novartis) Inhaler in four individual 28-mg capsules, TIP can be administered in a quarter of the time of traditional nebulizers and is inherently portable. In clinical studies, TIP has been shown to be safe, result in equivalent or superior reductions in P. aeruginosa sputum density and produce similar improvements in pulmonary function. TIP offers significant advantages in time saving, portability and convenience over traditional nebulized TIS with comparable clinical outcomes for individuals with CF.

Liver Depurative Techniques: A Single Liver Transplantation Center Experience

In a liver transplant (LT) center, treatments with Prometheus were evaluated. The main outcome considered was 1 and 6 months survival. Methods. During the study period, 74 patients underwent treatment with Prometheus; 64 were enrolled,with a mean age of 51 13 years; 47men underwent 212 treatments (mean, 3.02 per patient). The parameters evaluated were age, sex, laboratorial (liver enzymes, ammonia) and clinical (model for end-stage liver disease and Child-Turcotte-Pugh score) data. Results. Death was verified in 23 patients (35.9%) during the hospitalization period, 20 patients (31.3%) were submitted to liver transplantation, and 21 were discharged. LT was performed in 4 patients with acute liver failure (ALF, 23.7%), in 7 patients with acute on chronic liver failure (AoCLF, 43.7%), and in 6 patients with liver disease after LT (30%). Seven patients who underwent LT died (35%). In the multivariate analysis, older age (P ¼ .015), higher international normalized ratio (INR) (P ¼ .019), and acute liver failure (P ¼ .039) were independently associated with an adverse 1-month clinical outcome. On the other hand, older age (P ¼ .011) and acute kidney injury (P ¼ .031) at presentation were both related to worse 6-month outcome. For patients with ALF and AoCLF we did not observe the same differences. Conclusions. In this cohort, older age was the most important parameter defining 1- and 6-month survival, although higher INR and presence of ALF were important for 1-month survival and AKI for 6-month survival. No difference was observed between patients who underwent LT or did not have LT.

Epithelial-Mesenchymal-Transition : a proposed mechanism in the development of Bronchiolitis Obliterans

La transplantation pulmonaire pour les patients avec une maladie pulmonaire en phase terminale est leur seul espoir de survie. Malheureusement, certains greffés du poumon rencontrent des difficultés après la transplantation du poumon, dont l'un est le rejet chronique du greffon pulmonaire également connu histologiquement comme la bronchiolite oblitérante et cliniquement comme syndrome de bronchiolite oblitérante. L'étiologie exacte de la BO reste mal comprise. Certaines hypothèses suggèrent l'implication des cellules épithéliales dans le processus de remodelage des voies respiratoires, conduisant à l'obstruction des voies aériennes. Un des mécanismes proposés est un processus de transition, connue sous le nom de transition épithéliale-mésenchymateuse (TEM). Lors de ce processus, les cellules perdent leurs propriétés épithéliales, acquièrent un phénotype mésenchymateux et deviennent plus mobiles et envahissantes. Cette transformation leur permet de participer activement au processus de remodelage bronchique dans la bronchiolite oblitérante. L’induction de la TEM peut être due à certains facteurs tels que l'inflammation et l'apoptose. Le principal objectif de ce travail de maîtrise est de détecter in vivo la présence de la TEM dans des biopsies transbronchiques obtenues chez des greffés et de l’associer à leurs conditions cliniques. Le deuxième objectif est d'induire la TEM in vitro dans les cellules épithéliales des petites voies aériennes à l'aide de milieux conditionnés apoptotiques et non apoptotiques produits par les cellules endothéliales microvasculaires humaines du poumon. D’autre part, nous avons évalué si des médiateurs connus pour participer au processus de TEM tels que le facteur de croissance du tissu conjonctif (CTGF)et le facteur de croissance transformant bêta (TGF-beta) ainsi que le perlecan sont présents dans les milieux conditionnés utilisés.

Hallazgos radiológicos de la enfermedad pulmonar en pacientes Colombianos con esclerodermia

La esclerosis sistémica (ES) es una enfermedad autoinmune multisistémica que afecta principalmente la piel, los pulmones, el tracto gastrointestinal, el corazón y los riñones. La enfermedad pulmonar, presente en casi el 100% de los casos, es el factor con mayor influencia en la mortalidad. El propósito de este estudio es realizar un análisis detallado de la enfermedad pulmonar por tomografía computarizada de alta resolución(TCAR) en pacientes Colombianos con ES, para lo cual se realizó un estudio de prevalencia analítica en 44 pacientes con ES valorados en el Hospital Universitario Mayor Méderi en los últimos 7 años. Los resultados mostraron características demográficas y clínicas similares a las previamente descritas. La prevalencia de enfermedad pulmonar intersticial fue alta, y los hallazgos de fibrosis pulmonar como vidrio esmerilado y panal de abejas se asociaron con la presencia del autoanticuerpo antiSCL70. La medida del diámetro esofágico por TCAR fue mayor en los pacientes con disfagia, antiSCL 70 y linfopenia, los cuales son marcadores de mal pronóstico.

Incidencia y factores asociados a infecciones bacterianas en el primer mes postrasplante hepático en la Fundación Cardioinfantil

Introducción: El trasplante hepático ortotópico es la colocación de un nuevo hígado en la misma ubicación del explantado. El objetivo es prolongar la duración y la calidad de vida en pacientes con enfermedades hepáticas terminales. Sin embargo, las infecciones bacterianas son una complicación en los pacientes receptores del trasplante, comprometiendo el éxito del procedimiento. El objetivo fue determinar los factores asociados a infecciones bacterianas en el primer mes tras realizada la intervención y describir las características demográficas de esa población. De 332 trasplantes realizados, que 262 cumplieron criterios para el análisis. Métodos: Se realizó un estudio observacional analítico de casos y controles anidado en una cohorte, en mayores de 18 años, receptores de trasplante hepático primario, de la FCI-IC de 2005 a 2014; excluyendo trasplante combinado hígado riñón, retrasplantes o fallecidos por causa diferente a la infecciosa durante el primer mes. Resultados: Se encontró que la ventilación mecánica por más de 1 día, el catéter venoso central mayor de 3 días son los principales factores de riesgo para infecciones bacterianas. La albúmina mayor de 2,6gr/dl se asoció a menor infección. Los agentes etiológicos predominantes fueron gérmenes gram negativos como E. coli, K. pneumonia y E. cloacae. Mientras que bacteremia, infección urinaria y peritonitis fueron las infecciones más frecuentes. La incidencia de infección bacteriana en esta población fue 24%. Discusión: Se recomienda por tanto extubación antes de 24 horas, uso de catéter central menor de 3 días y limitar el uso del catéter vesical.

Characteristics of Acute Kidney Injury in Patients Infected with the 2009 Influenza A (H1N1) Virus

Background and objectives: There have been few studies investigating acute kidney injury (AKI) in patients infected with the 2009 pandemic influenza A (H1N1) virus. Therefore, the objective of this study was to identify the factors associated with AKI in H1N1-infected patients. Design, setting, participants, & measurements: This was a study of 47 consecutive critically ill adult patients with reverse transcriptase-PCR-confirmed H1N1 infection in Brazil. Outcome measures were AKI (as defined by the Risk, Injury, Failure, Loss, and End-stage renal failure [RIFLE] criteria) and in-hospital death. Results: AKI was identified in 25 (53%) of the 47 H1N1-infected patients. AKI was associated with vasopressor use, mechanical ventilation, high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and severe acidosis as well as with higher levels of C-reactive protein and lactic dehydrogenase upon intensive care unit (ICU) admission. A nephrology consultation was requested for 16 patients (64%), and 8 (50%) required dialysis. At ICU admission, 7 (15%) of the 25 AKI patients had not yet progressed to AKI. However, by 72 hours after ICU admission, no difference in RIFLE score was found between AKI survivors and nonsurvivors. Of the 47 patients, 9 (19%) died, all with AKI. Mortality was associated with mechanical ventilation, vasopressor use, dialysis, high APACHE II score, high bilirubin levels, and a low RIFLE score at ICU admission. Conclusions: Among critically ill H1N1-infected patients, the incidence of AKI is high. In such patients, AKI is mainly attributable to shock. Clin J Am Soc Nephrol 5: 1916-1921, 2010. doi: 10.2215/CJN.00840110

Labile Plasma Iron Generation After Intravenous Iron is Time-dependent and Transitory in Patients Undergoing Chronic Hemodialysis

Iron supplementation in hemodialysis patients is fundamental to erythropoiesis, but may cause harmful effects. We measured oxidative stress using labile plasma iron (LPI) after parenteral iron replacement in chronic hemodialysis patients. Intravenous iron saccharate (100 mg) was administered in patients undergoing chronic hemodialysis (N = 20). LPI was measured by an oxidant-sensitive fluorescent probe at the beginning of dialysis session (T0), at 10 min (T1), 20 min (T2), and 30 min (T3) after the infusion of iron and at the subsequent session; P < 0.05 was significant. The LPI values were significantly raised according to the time of administration and were transitory: -0.02 +/- 0.20 mu mol/L at the beginning of the first session, 0.01 +/- 0.26 mu mol/L at T0, 0.03 +/- 0.23 mu mol/L at T1, 0.09 +/- 0.28 mmol/L at T2, 0.18 +/- 0.52 mmol/L at T3, and -0.02 +/- 0.16 mmol/L (P = 0.001 to 0.041) at the beginning of the second session. The LPI level in patients without iron supplementation was -0.06 +/- 0.16 mmol/L. Correlations of LPI according to time were T1, T2, and T3 vs. serum iron (P = 0.01, P = 0.007, and P = 0.0025, respectively), and T2 and T3 vs. transferrin saturation (P = 0.001 and P = 0.0003, respectively). LPI generation after intravenous saccharate administration is time-dependent and transitorily detected during hemodialysis. The LPI increment had a positive correlation to iron and transferrin saturation.

Inflammation and Overweight in Peritoneal Dialysis: Is There an Association?

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

High-Volume Peritoneal Dialysis in Acute Kidney Injury: Indications and Limitations

Background and objectives Peritoneal dialysis is still used for AKI in developing countries despite concerns about its limitations. The objective of this study was to explore the role of high-volume peritoneal dialysis in AM patients in relation to metabolic and fluid control, outcome, and risk factors associated with death.Design, setting, participants, & measurements A prospective study was performed on 204 AKI patients who were assigned to high-volume peritoneal dialysis (prescribed Kt/V=0.60/session) by flexible catheter and cycler; 150 patients (80.2%) were included in the final analysis.Results Mean age was 63.8 +/- 15.8 years, 70% of patients were in the intensive care unit, and sepsis was the main etiology of AKI (54.7%). BUN and creatinine levels stabilized after four sessions at around 50 and 4 mg/dl, respectively. Fluid removal and nitrogen balance increased progressively and stabilized around 1200 ml and -1 g/d after four sessions, respectively. Weekly delivered Kt/V was 3.5 +/- 0.68. Regarding AKI outcome, 23% of patients presented renal function recovery, 6.6% of patients remained on dialysis after 30 days, and 57.3% of patients died. Age and sepsis were identified as risk factors for death. In urine output, increase of 1 g in nitrogen balance and increase of 500 ml in ultrafiltration after three sessions were identified as protective factors.Conclusions High-volume peritoneal dialysis is effective for a selected AKI patient group, allowing adequate metabolic and fluid control. Age, sepsis, and urine output as well as nitrogen balance and ultrafiltration after three high-volume peritoneal dialysis sessions were associated significantly with death. Clin J Am Soc Nephrol 7: 887-894, 2012. doi: 10.2215/CJN.11131111

Glomerulonefrite lúpica: estudo da evolução a longo prazo

OBJETIVO: Estudar a apresentação clínica e a evolução de pacientes portadores de glomerulonefrite lúpica. CASUÍSTICA E MÉTODOS: Foram estudados 37 pacientes portadores de glomerulonefrite lúpica, atendidos pela Disciplina de Nefrologia - Faculdade de Medicina de Botucatu, com seguimento médio de 52,4 ± 13,3 meses. Os dados foram obtidos através do levantamento retrospectivo dos prontuários. RESULTADOS: A idade média foi de 26,05 ± 11,12 anos, com predomínio do sexo feminino (84%) sendo que a glomerulonefrite classe IV foi a mais freqüente (80%). No início do seguimento a média da creatinina sérica foi de 1,74 ± 1,15 mg/dl, e a da proteinúria de 24h foi de 2,62 ± 2.89 g. Cinqüenta e um porcento dos pacientes com creatinina sérica elevada apresentaram, durante o seguimento, diminuição desses valores. Dentre diferentes variáveis estudadas, à época da biopsia renal, (idade, sexo, proteinúria, presença de hipertensão arterial e creatinina sérica) a única que se associou com pior prognóstico foi a elevação da creatinina sérica. Remissão da síndrome nefrótica ocorreu em 65% das vezes. A sobrevida atuarial foi de 96%, 82%, 70% e 70% em 1, 5, 10 e 12 anos. Cinco pacientes desenvolveram insuficiência renal crônica terminal e sete morreram, sendo infecção a principal causa de óbito (57%) CONCLUSÃO: em pacientes com nefropatia lúpica, o aumento da creatinina sérica, à época da biópsia, se associou com o desenvolvimento de insuficiência renal crônica ao fim do seguimento e a principal causa de óbito foi processo infeccioso.

Hepatitis C Virus NS2 Protein Inhibits DNA Damage Pathway by Sequestering p53 to the Cytoplasm

Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality globally, and often leads to end-stage liver disease. The DNA damage checkpoint pathway induces cell cycle arrest for repairing DNA in response to DNA damage. HCV infection has been involved in this pathway. In this study, we assess the effects of HCV NS2 on DNA damage checkpoint pathway. We have observed that HCV NS2 induces ataxia-telangiectasia mutated checkpoint pathway by inducing Chk2, however, fails to activate the subsequent downstream pathway. Further study suggested that p53 is retained in the cytoplasm of HCV NS2 expressing cells, and p21 expression is not enhanced. We further observed that HCV NS2 expressing cells induce cyclin E expression and promote cell growth. Together these results suggested that HCV NS2 inhibits DNA damage response by altering the localization of p53, and may play a role in the pathogenesis of HCV infection. © 2013 Bitter et al.

Avaliação dos indicadores nutricionais e da composição corporal em hepatopatas crônicos e a relação com a etiologia e gravidade da doença

Pós-graduação em Bases Gerais da Cirurgia - FMB

Low serum potassium levels increase the infectious-caused mortality in peritoneal dialysis patients: a propensity-matched score study

Background and ObjectivesHypokalemia has been consistently associated with high mortality rate in peritoneal dialysis. However, studies investigating if hypokalemia is acting as a surrogate marker of comorbidities or has a direct effect in the risk for mortality have not been studied. Thus, the aim of this study was to analyze the effect of hypokalemia on overall and cause-specific mortality.Design, Setting, Participants and MeasurementsThis is an analysis of BRAZPD II, a nationwide prospective cohort study. All patients on PD for longer than 90 days with measured serum potassium levels were used to verify the association of hypokalemia with overall and cause-specific mortality using a propensity match score to reduce selection bias. In addition, competing risks were also taken into account for the analysis of cause-specific mortality.ResultsThere was a U-shaped relationship between time-averaged serum potassium and all-cause mortality of PD patients. Cardiovascular disease was the main cause of death in the normokalemic group with 133 events (41.8%) followed by PD-non related infections, n=105 (33.0%). Hypokalemia was associated with a 49% increased risk for CV mortality after adjustments for covariates and the presence of competing risks (SHR 1.49; CI95% 1.01-2.21). In contrast, in the group of patients with K < 3.5mEq/L, PD-non related infections were the main cause of death with 43 events (44.3%) followed by cardiovascular disease (n=36; 37.1%). For PD-non related infections the SHR was 2.19 (CI95% 1.52-3.14) while for peritonitis was SHR 1.09 (CI95% 0.47-2.49).ConclusionsHypokalemia had a significant impact on overall, cardiovascular and infectious mortality even after adjustments for competing risks. The causative nature of this association suggested by our study raises the need for intervention studies looking at the effect of potassium supplementation on clinical outcomes of PD patients.

Evidence-based medicine: an update on treatments for peritoneal dialysis-related peritonitis

Peritonitis continues to be a major complication of peritoneal dialysis (PD), and adequate treatment is crucial for a favorable outcome. There is no consensus regarding the optimal therapeutic regimen, and few prospective controlled studies have been published. The objective of this manuscript is to review the results of PD peritonitis treatment reported in narrative reviews, systematic reviews, and proportional meta-analyses. Two narrative reviews, the only existing systematic review and its update published between 1991 and 2014 were included. In addition, we reported the results of a proportional meta-analysis published by our group. Results from systematic reviews of randomized control trials (RCT) and quasi-RCT were not able to identify any optimal antimicrobial treatment, but glycopeptide regimens were more likely to achieve a complete cure than a first generation cephalosporin. Compared to urokinase, simultaneous catheter removal and replacement resulted in better outcomes. Continuous and intermittent IP antibiotic use had similar outcomes. Intraperitoneal antibiotics were superior to intravenous antibiotics in reducing treatment failure. In the proportional meta-analysis of RCTs and the case series, the resolution rate (86%) of ceftazidime plus glycopeptide as initial treatment was significantly higher than first generation cephalosporin plus aminoglycosides (66%) and glycopeptides plus aminoglycosides (75%). Other comparisons of regimens used for either initial treatment or treatment of gram-positive rods or gram-negative rods did not show statistically significant differences. The superiority of a combination of a glycopeptide and a third generation cephalosporin was also reported by a narrative review study published in 1991, which reported an 88% resolution rate.