Comparative Efficacy of a High-Dose vs Standard-Dose Hepatitis B Revaccination Schedule Among Patients With HIV: A Randomized Clinical Trial.

Importance: Active immunization for hepatitis B virus (HBV) infection is recommended in patients living with HIV. Limited evidence is available about the most appropriate regimen of HBV vaccination among those who have not responded to an initial schedule. Objective: To determine the efficacy of a high-dose schedule compared with a standard dose of HBV vaccination. Design, Setting, and Participants: This double-masked, parallel-group, randomized controlled trial included patients living with HIV at a single outpatient HIV and hepatology clinic in Chile for whom previous HBV vaccination had failed. Patients with hepatitis B surface antibody (anti-HBs) titers less than 10 IU/L after an initial HBV vaccination regimen were included. Consecutive patients were recruited between December 2013 and March 2018. Data were analyzed in June 2018 using intention-to-treat analysis. Intervention: The high-dose HBV vaccination group consisted of 3 doses of 40 µg recombinant hepatitis B vaccine at 0, 1, and 2 months. The standard-dose group received 3 doses 20 µg each at 0, 1, and 2 months. Main Outcomes and Measures: Primary outcome was the serologic response to HBV vaccination (anti-HBs greater than 10 IU/L) 4 to 8 weeks after completion of the schedule. Secondary outcomes were anti-HBs greater than 100 IU/L and seroprotective anti-HBs at 1 year follow up. Results: A total of 107 patients underwent randomization (55 to the standard-dose group, 52 to the high-dose group); 81 (75.7%) were men, and the mean (SD) patient age was 47.0 (13.3) years. Nearly all patients were receiving antiretroviral therapy (105 patients [98%]) and 92 patients (86%) had an undetectable HIV viral load. Mean (SD) CD4 count was 418 (205) cells/mm3. There were no differences in baseline characteristics between groups. Serological response in the high-dose group was found in 36 of 50 patients (72%; 95% CI, 56.9%-82.9%) compared with 28 of 55 patients in the standard-dose group (51%; 95% CI, 37.1%-64.6%) (odds ratio, 2.48; 95% CI, 1.02-6.10; P = .03). Mean (SD) anti-HB levels were 398.0 (433.4) IU/L in the high-dose group and 158.5 (301.4) IU/L in the standard-dose group (P < .001). Of patients with a serological response in the high-dose group, 29 of 36 (80.6%) had anti-HBs titers greater than 100 IU/L compared with 14 of 28 responders (50.0%) in the standard-dose group (P = .02). At 1-year follow-up, 20 of 25 patients (80.0%) with a serological response in the high-dose group had protective anti-HBs vs 9 of 23 patients (39.1%) in the standard-dose group (P = .01). Conclusions and Relevance: The results of this randomized clinical trial suggest that use of a high-dose regimen for HBV revaccination for patients with HIV achieves a higher and longer-lasting serological response as compared with a standard-dose regimen. Trial Registration: ClinicalTrials.gov Identifier: NCT02003703.

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. METHODS: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. RESULTS: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. CONCLUSIONS: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

CD4/CD8 ratio as a predictor of the response to HBV vaccination in HIV-positive patients: A prospective cohort study.

BACKGROUND: Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) share transmission mechanisms and thus coinfection is frequent. Active immunization against HBV is essential in HIV patients. Reports using standard and reinforced HBV vaccination schedules vary widely in seroconversion rates depending on the characteristics of the included patients. Regional data concerning HBV vaccination in HIV patients are scarce. We aim to determine the serological response to HBV vaccination using standard schedule in HIV-positive patients and to evaluate characteristics that predict seroconversion. MATERIALS AND METHODS: We performed a single centre prospective study of HBV vaccination with standard schedule in HIV-positive patients. Adults with negative markers of HBV infection were included between November 2012 and December 2014. Anti-HBs titres were measured 4-8 weeks after completion of vaccination schedule. Clinical, laboratory values and HIV characteristics were analyzed to determine their association with seroconversion and adherence to the HBV vaccination schedule. RESULTS: The study included 245 HIV-positive patients, 68.9% were male and the mean age was 42.1 years. A total of 80.7% of the patients had undetectable HIV viral loads, 86.1% had CD4 counts >200, and 94.7% were on HAART. The response to vaccination was positive in 62% (95% CI, 56-68%) and mean anti-HBs titres of 646 IU/ml. 85.5% of the responders had anti-HBs titres >100 IU/ml. An age less than 45 years, no tobacco use and a CD4/CD8 ratio >0.4 were associated with seroconversion in multivariate analysis. The seroconversion rates were 86% in the subgroup of patients who met these criteria. A total of 97.9% of the study population completed the vaccination schedule. CONCLUSION: The CD4/CD8 ratio was the primary factor associated with positive serological conversion in the multivariate analysis. The seroconversion rates were higher in a selected group of patients who were particularly suitable for the use of the standard HBV vaccination schedule.

Presence of anti-HBc is associated to high rates of HBV resolved infection and low threshold for Occult HBV Infection in HIV patients with negative HBsAg in Chile.

HBV-HIV coinfection is prevalent. Frequently, anti-HBc is the only serological marker of HBV, which can be indicative of HBV resolved infection, when found together with anti-HBs reactivity; or present as "isolated anti-HBc," related to HBV occult infection with presence of detectable DNA HBV, more prevalent in HIV-positive individuals. Regional data about this condition are scarce. Anti-HBc rapid test has been used as screening, but its performance has not been described in HIV-positive patients. The aim of this study was determine prevalence of anti-HBc in HIV-positive patients, serological pattern of HBV resolved infection and isolated anti-HBc, evaluating presence of HBV occult infection. Assess anti-HBc rapid test compared to ECLIA. Methods included measurement of anti-HBc and anti-HBs in HIV-positive patients with negative HBsAg. Serum HBV DNA quantification and HBV booster vaccination to "isolated anti-HBc" individuals. Detection of anti-HBc by rapid test and ECLIA. In 192 patients, prevalence of anti-HBc was 42.7% (82/192); associated to male gender, drug use, men-sex-men, positive-VDRL, and longer time HIV diagnosis. 34.4% (66/192) had presence of anti-HBs, mean titers of 637 ui/ml. Isolated anti-HBc in 8.3% (16/192), associated to detectable HIV viral load and no-use of HAART; in them, HBV DNA was undetectable, and 60% responded to HBV vaccination booster. Anti-HBc rapid test showed low sensibility (32.9%) compared to ECLIA. These results show that prevalence of anti-HBc in HIV-positive individuals is high, in most cases accompanied with anti-HBs as HBV resolved infection. Low prevalence of "isolated anti-HBc," with undetectable HBV DNA, and most had anamnestic response to HBV vaccination; suggest low possibility of occult HBV infection. Anti-HBc rapid test cannot be recommended as screening method for anti-HBc.

Screening transesterifiable lipid accumulating bacteria from sewage sludge for biodiesel production.

Sewage sludge was evaluated as high available and low cost microbial oils feedstock for biodiesel production. Samples from four different wastewater treatment plants from La Araucanía Region in Southern Chile presented total lipids content ranging between 7.7 and 12.6%, being Vilcún sewage sludge that with the highest transesterifiable lipids content of about 50% of the total extracted lipids. The most relevant identified bacteria present in sludge samples were Acinetobacter, Pseudomonas and Bacillus, being Bacillus sp. V10 the strain with the highest transesterfiable lipids content of 7.4%. Bacillus sp. V10 was cultured using urban wastewater supplemented with glucose to achieve nitrogen depleted medium and using milk processing wastewater as a low-cost carbon source. Bacillus sp. V10 lipid profile indicates that low degree unsaturated long chain fatty acids such as C18:1 may account for approximately 50% of the lipids content, indicating its suitability to be used as raw material for biodiesel production.

Impacto del uso de antibióticos en el valor de PSA, previo a la biopsia de prostata / Impact of antibiotic use in prostate-specific antigen levels before prostate biopsy

Existen observaciones clínicas sobre el uso empírico de antibióticos en pacientes con alto nivel de PSA, sin síntomas de infecciones del tracto urinario y con indicación de biopsia prostática. El uso indiscriminado de antibióticos puede llevar a la resistencia bacteriana y diversos efectos secundarios; pero sobre todo, esto puede ser una acción médica injustificada. El objetivo de esta investigación es determinar el impacto del uso de antibióticos en los valores de PSA antes de la biopsia prostática y en la decisión de si hacer o no una biopsia prostática en pacientes con sospecha de neoplasia prostática. Estudio de casos y controles de 63 pacientes menores de 80 años de edad, con tacto rectal normal, sin infección urinaria y los valores de PSA alterado con indicación de biopsia. El grupo de control no recibió medicamento y el grupo de casos recibió cotrimoxazol (80/400 mg) cada 12 horas durante 10 días. Quince días más tarde los niveles de PSA se evaluaron de nuevo y los resultados se analizaron estadísticamente. No se encontraron diferencias significativas entre ambos grupos en relación con la edad, tacto rectal o el valor de PSA. La variación de la PSA después del uso de la terapia con antibióticos no fue significativa (p = 0,588). El uso de la terapia antimicrobiana para disminuir los valores de PSA antes de una biopsia de próstata es controvertido y no hay evidencia científica para el tratamiento de una prostatitis asintomática que pueden estar alterando los valores de PSA. Los resultados de nuestro estudio muestran la necesidad de una investigación más compleja que puede confirmar que la terapia antimicrobiana no tiene un papel terapéutico en esta situación específica y común...

There is a clinical observation about the empiric use of antibiotics on patients with high PSA level, without symptoms of urinary tract infections and with indication for prostatic biopsy. The indiscriminate use of antibiotics may lead to bacterial resistance and various others side effects as well; but above all, this may be an unjustified medical action. The objective of this research is to determinate the impact of antibiotic use on PSA values before prostatic biopsy and on the decision whether make or not a prostatic biopsy in patients suspected of having prostatic cancer. Case and control study of 63 patients younger than 80 years old, with normal rectal tact, without symptoms of urinary tract infection and PSA values altered with biopsy indication. Control group did not receive medicament and the case group received Cotrimoxazole (80/400 mg) every 12 hours for 10 days. 15 days later PSA levels were evaluated again and the results were statistically analyzed. No significant differences were found between both groups in relation to age or PSA value. The variation of the PSA after the use of antibiotic therapy was no significant (p=0,588). The use of antimicrobial therapy to decrease the values of PSA before a prostate biopsy is controversial and there isn’t scientific evidence to treat a possible asyntomatic prostatitis that may be altering the PSA values. The results of our study shows the need of a more complex research that can confirm that the antimicrobial therapy has no therapeutic role on this specific and common situation...

[Vascular endothelial growth factor in malignant and non malignant prostatic tissue: Association with tumor recurrence at one year after prostatectomy]. / Identificación de factor de crecimiento vascular endotelial en células glandulares de tejido prostético maligno y benigno. Relación con la recidiva tumoral al año de la prostatectomía.

BACKGROUND: Prostate cancer (PC) is the second cause of death by cancer in men in Chile. Its behavior is so variable that it is necessary to search reliable prognostic markers. Vascular Endothelial Growth Factor (VEGF) is one of the most powerful pro-angiogenic factors. There is no agreement on its validity as a diagnostic or prognostic factor. AIM: To search for VEFG in prostatic tissue. MATERIAL AND METHODS: This study was performed in prostatectomy tissue coming from 41 patients with PC and 39 patients with benign prostatic hyperplasia (BPH). Specimens were studied using immunohistochemical staining for VEGF. The percentage of stained glandular cells per patient was calculated and associated with pathological diagnosis in cancer patients. RESULTS: PC biopsies had a mean of 82% of VEGF (+) stained cells, while BPH had only 1.6% (p < 0.01). No relationship was found between the percentage of staining and recurrence at one year of follow-up in the case of PC. CONCLUSIONS: These results would rule out VEGF as a prognostic factor in this series of patients.

Identificación de factor de crecimiento vascular endotelial en células glandulares de tejido prostético maligno y benigno: Relación con la recidiva tumoral al año de la prostatectomía / Vascular endothelial growth factor in malignant and non malignant prostatic tissue: Association with tumor recurrence at one year after prostatectomy

Background: Prostate cancer (PC) is the second cause of death by cancer in men in Chile. Its behavior is so variable that it is necessary to search reliable prognostic markers. Vascular Endothelial Growth Factor (VEGF) is one of the most powerful pro-angiogenic factors. There is no agreement on its validity as a diagnostic or prognostic factor. Aim: To search for VEFG in prostatic tissue. Material and Methods: This study was performed in prostatectomy tissue coming from 41 patients with PC and 39 patients with benign prostatic hyperplasia (BPH). Specimens were studied using immunohistochemical staining for VEGF. The percentage of stained glandular cells per patient was calculated and associated with pathological diagnosis in cancer patients. Results: PC biopsies had a mean of 82% of VEGF (+) stained cells, while BPH had only 1.6% (p < 0.01). No relationship was found between the percentage of staining and recurrence at one year of follow-up in the case of PC. Conclusions: These results would rule out VEGF as a prognostic factor in this series of patients.

Identificación de factor de crecimiento endotelial vascular (VEGF) en cáncer de próstata / Identification of vascular endotelial growth factor (VEGF) in prostate cancer

El cáncer de próstata (Ca P) es la segunda causa de muerte en hombres y su comportamiento es tan heterogéneo que se ha sido necesario buscar factores pronósticos que sean fiables. Entre ellos, se está investigando la angiogénesis, proceso necesario para el crecimiento y desarrollo de metástasis del cáncer. El factor de crecimiento endotelial vascular (VEGF), es uno de los factores proangiogénicos más potentes encontrados. No se ha llegado a un consenso internacional en cuanto a su validez como factor pronóstico y tampoco hay estudios en Chile que demuestren una diferencia en su presencia entre el cáncer prostático y la hiperplasia benigna prostática (HBP). Se propuso investigar ambas relaciones en nuestro medio pues contamos con la alternativa de efectuar inmunohistoquímica a pesar de nuestras clásicas limitaciones tecnológicas. Se contaron con 66 biopsias obtenidas de cirugía prostática, de las cuales 30 eran prostatectomías radicales por cáncer prostático clínicamente localizado y 36 eran HBP obtenidas por técnica transvesical. Se les realizó inmunohistoquímica para VEGF y se obtuvo el porcentaje de marcaje de células glandulares por paciente. Se encontró una relación estadísticamente significativa en el porcentaje de marcaje entre cáncer yHBP, ya que el marcaje está prácticamente ausente en la HBP. Cuando se intento correlacionar la intensidad del marcaje con la evolución y el pronóstico de los tumores no se encontró relación entre el porcentaje de marcaje y el mal pronóstico de los tumores operados como en el caso de los cánceres que evolucionaron con recidiva bioquímica definida comoPSA mayor de 0,2 ng/ml. Como expectativas de utilidad clínica podemos plantear que en el futuro el VEGF podría tener utilidad en facilitar el diagnóstico de cáncer y un eventual uso como criterio para optar por una terapia antiangiogénica.

Introduction. Prostate cancer (PCa) is the second cause of death in men and its behavior is so versatile that it has been necessary to search for reliable prognostic factors and therapeutical targets, such as angiogenesis. The Vascular Endothelial Growth Factor (VEGF) is one of the most powerful proangiogenic factors. There is no agreement on its validity as a prognostic factor. Material and methods. A case control study was performed in patients with PCa age matched with patients with benign hyperplasia (BPH). Specimens from prostatectomies were studied using immunohistochemical staining of VEGF in prostate gland cells. The percentage of stained glandular cells per patient was calculated, and associated with diagnosis and recurrence. Prostatic Specific Antigen (PSA) over 0.2 ng/ml at 1 year after the surgery was considered as a recurrence. Results. Sixty biopsies were available, obtained by radical prostatectomy, of which 30 were PCa and 30 were BPH. PCa biopsies had a proportion of VEGF stained cells of 79.5 per cent, while BPH had a 0.86 per cent of stained cells (p<0.0001). However, association between staining percentage and recurrence of the PCa was not found. Discussion: Glandular cells in prostatic cancer show a significantly different pattern of VEGF than in non neoplasic prostates. VEGF could be useful to make PCa diagnosis in cases of dubious biopsies, through positive or negative staining for VEGF. Further studies are necessary to evaluate whether VEGF pattern correlates with aggresiveness of prostate cancer.

Brotes epizoóticos de triquinosis en dos criaderos de cerdos de la Región Metropolitana, Chile / Epizootic outbreaks of trichinosis in 2 pig farms from the Metropolitan Region, Chile

In Chile swine trichinosis has presented a progressive decreasing in the last two decades of XX century. T. spiralis pig infection descended from an average of 0,683 per 1000 in 1980-1984 to 0,315 in 1985-1989 and to 0,115 in 1990-1996. In the particular case of Metropolitan Region this decreasing has been more marked: from an average of 0,058 per 1000 in 1990-1994 to 0,003 in 1995-1999. Between the end of june 1999 and middle january 2000 in Metropolitan Region abattoirs T. spiralis was detected in 15 (4,9 percent) out of 306 swine from two pigsties located in El Monte (E.M) and Padre Hurtado (P.H) 45 and 30 km south-west from Santiago. In the same period another four pigs from the same premises were found infected in abattoirs of other regions. During inspection visits it was stated that both pig farms had deficient sanitary conditions. Phototrichinoscopy was positive in three out of five rattus norvegicus collected in E.M. In pigsty PH the examination of diaphragm samples of 25 dogs and 17 cats resulted negative. In the premises originating T. spirali infected swine the Metropolitan Environmetal Health Service Abattoirs Program carries out and epidemiological vigilance consisting in the follow-up of animls destined for slaughtering in order to initiate prophylactic actions oriented to eliminate eventual sources of trichinosis infection for human and rearing pigs