Severe Ovarian Hyperstimulation Syndrome in the Setting of In Vitro Fertilization Treatment.

Ovarian hyperstimulation syndrome (OHSS) is one of the complications of pharmacological ovarian stimulation used in fertility treatments. This syndrome is characterized by increased vascular permeability secondary to stimulation, resulting in a fluid shift from the intravascular space to the third-space compartments. Patients developing OHSS can experience severe complications, including ascites, pleural effusions, and shock. Here, we present a case of OHSS in the setting of recent transvaginal oocyte retrieval, leading to severe ascites, pleural effusion, and hypotension requiring urgent intervention.

Congenital diaphragmatic hernia: phosphodiesterase-5 and Arginase inhibitors prevent pulmonary vascular hypoplasia in rat lungs.

BACKGROUND: Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. OBJECTIVE: To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. METHODS: Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring's lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I-II expression, and activity. RESULTS: In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. CONCLUSION: These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. IMPACT: This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments' synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.

Accurate characterization of dynamic microbial gene expression and growth rate profiles.

Genetic circuits are subject to variability due to cellular and compositional contexts. Cells face changing internal states and environments, the cellular context, to which they sense and respond by changing their gene expression and growth rates. Furthermore, each gene in a genetic circuit operates in a compositional context of genes which may interact with each other and the host cell in complex ways. The context of genetic circuits can, therefore, change gene expression and growth rates, and measuring their dynamics is essential to understanding natural and synthetic regulatory networks that give rise to functional phenotypes. However, reconstruction of microbial gene expression and growth rate profiles from typical noisy measurements of cell populations is difficult due to the effects of noise at low cell densities among other factors. We present here a method for the estimation of dynamic microbial gene expression rates and growth rates from noisy measurement data. Compared to the current state-of-the-art, our method significantly reduced the mean squared error of reconstructions from simulated data of growth and gene expression rates, improving the estimation of timing and magnitude of relevant shapes of profiles. We applied our method to characterize a triple-reporter plasmid library combining multiple transcription units in different compositional and cellular contexts in Escherichia coli. Our analysis reveals cellular and compositional context effects on microbial growth and gene expression rate dynamics and suggests a method for the dynamic ratiometric characterization of constitutive promoters relative to an in vivo reference.

Efectividad del tocilizumab intravenoso en la práctica clínica usual de una cohorte de pacientes costarricenses con artritis reumatoide / Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis

Objetivo: Determinar la efectividad y la incidencia de eventos adversos graves del tocilizumab (TCZ) en una cohorte de pacientes costarricenses con artritis reumatoide (AR). Pacientes y métodos: Se realizó un análisis retrospectivo de 45 pacientes con AR, refractarios al uso previo de fármacos modificadores de la enfermedad reumática (FAME), que utilizaron TCZ a una dosis inicial de 4mg/kg intravenoso (IV) cada 4 semanas en asociación con metotrexato o leflunomida. La medida de efectividad fue la incidencia de remisión clínica, determinada cada 3 meses y definida por un puntaje de actividad de la enfermedad en 28 articulaciones con velocidad de sedimentación globular (DAS28-VSG) menor de 2,6. La seguridad del fármaco se evaluó mediante la tasa de incidencia de eventos adversos severos. Se realizó un modelo de regresión logística uni- y multivariado para determinar las variables asociadas con la probabilidad de remisión a los 3 meses de iniciado el tratamiento. Resultados: A los 3 meses de tratamiento un total de 22 pacientes (48,9%; intervalo de Confianza [IC] del 95%: 34,3-63,5%) alcanzaron remisión, en tanto que a los 12 meses de terapia con TCZ el valor aumentó a 34 pacientes (75%; IC 95%: 62,3-87,6%). Un total de 18 pacientes (40%; IC 95%: 25,7-54,3%) requirieron aumento de dosis del TCZ de 4 a 8mg/kg ante la ausencia de remisión. La tasa de incidencia de eventos adversos severos fue de 0,98 por 100 pacientes/año, correspondiendo todos ellos a cuadros infecciosos que resolvieron sin ningún desenlace fatal. Solo el DAS28-VSG inicial se asoció de forma independiente con la probabilidad de remisión a los 3 meses. Conclusiones: El uso de TCZ IV a una dosis inicial de 4mg/kg en pacientes costarricenses con AR es efectivo y seguro en la práctica clínica.(AU)

Objective: To determine the effectiveness and the incidence of severe adverse events in a cohort of Costa Rican patients with Rheumatoid Arthritis (RA) treated with intravenous (IV) tocilizumab (TCZ). Patients and methods: A retrospective analysis was carried out in 45 patients that were unresponsive to disease-modifying antirheumatic drugs (DMARDs). The study included patients who received IV TCZ every 4 weeks (4mg/kg) along with methotrexate or leflunomide. Effectiveness was measured through the incidence of clinical remission according to a disease activity score - erythrocyte sedimentation rate (DAS28-ESR) less than 2.6. Safety was assessed by the incidence rate of serious adverse events. An univariate and multivariate logistic regression analysis was performed to assess the association of potential variables with the probability of achieving remission during the first 3 months of TCZ therapy. Results: During the 3rd month of TCZ therapy, a total of 22 patients (48.9%; 95% Confidence Interval (CI) 34.3-63.5%) achieved remission. The cumulative incidence of patients with remission at month 12 was 75.0% (n=34) (95% CI: 62.3-87.6%). A total of 18 patients (40%; 95% CI: 25.7-54.3%) were switched to a 8mg/kg dose due to the absence of remission. The incidence rate of serious adverse events was .98 per 100 patients/year, all of them due to infectious diseases with no fatal events reported. Only basal DAS28-ESR was associated with the probability of achieving remission at month 3. Conclusions: IV TCZ (4mg/kg) is an effective and safe treatment for RA patients in a clinical setting in Costa Rica.(AU)

Mycoremediation of oxytetracycline by marine fungi mycelium isolated from salmon farming areas in the south of Chile.

Antibiotics are extensively used for growth promotion purposes in intensive aquaculture. In Chile, the use of antibiotics in salmon farming is excessive, approximately 62 times more than is used in Norway. In the salmon industry, antibiotics such as oxytetracycline (OTC) are administered in the diet, both in the juvenile stage in freshwater and in the fattening process of salmon in marine sectors. We have investigated the fjords of Chile, where many salmon farms are located, searching for fungi able to degrade this tetracycline antibiotic. We have evaluated the OTC degradation ability of the following; Penicillium commune, Epicoccum nigrum, Trichoderma harzianum, Aspergillus terreus and Beauveria bassiana, isolated from sediments in salmon farms from southern Chile. In all these fungal strains, the amount of OTC decreased in the culture medium, as adsorbed in the mycelia, after the third day of exposure. These strains were capable of degrading OTC at remarkable rates up to 78%, by the 15th day. This is the first study showing that the mycelium of these fungal strains has the ability to degrade OTC. We believe the knowledge produced by these results has the potential to serve as a basis for implementing a bioremediation process in the near future.

Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa Rican patients with rheumatoid arthritis. / Efectividad del tocilizumab intravenoso en la práctica clínica usual de una cohorte de pacientes costarricenses con artritis reumatoide.

OBJECTIVE: To determine the effectiveness and the incidence of severe adverse events in a cohort of Costa Rican patients with Rheumatoid Arthritis (RA) treated with intravenous (IV) tocilizumab (TCZ). PATIENTS AND METHODS: A retrospective analysis was carried out in 45 patients that were unresponsive to disease-modifying antirheumatic drugs (DMARDs). The study included patients who received IV TCZ every 4 weeks (4mg/kg) along with methotrexate or leflunomide. Effectiveness was measured through the incidence of clinical remission according to a disease activity score - erythrocyte sedimentation rate (DAS28-ESR) less than 2.6. Safety was assessed by the incidence rate of serious adverse events. An univariate and multivariate logistic regression analysis was performed to assess the association of potential variables with the probability of achieving remission during the first 3 months of TCZ therapy. RESULTS: During the 3rd month of TCZ therapy, a total of 22 patients (48.9%; 95% Confidence Interval (CI) 34.3-63.5%) achieved remission. The cumulative incidence of patients with remission at month 12 was 75.0% (n=34) (95% CI: 62.3-87.6%). A total of 18 patients (40%; 95% CI: 25.7-54.3%) were switched to a 8mg/kg dose due to the absence of remission. The incidence rate of serious adverse events was .98 per 100 patients/year, all of them due to infectious diseases with no fatal events reported. Only basal DAS28-ESR was associated with the probability of achieving remission at month 3. CONCLUSIONS: IV TCZ (4mg/kg) is an effective and safe treatment for RA patients in a clinical setting in Costa Rica.

Dietary Potassium Downregulates Angiotensin-I Converting Enzyme, Renin, and Angiotensin Converting Enzyme 2.

BACKGROUND: The importance of dietary potassium in health and disease has been underestimated compared with that placed on dietary sodium. Larger effort has been made on reduction of sodium intake and less on the adequate dietary potassium intake, although natural food contains much more potassium than sodium. The benefits of a potassium-rich diet are known, however, the mechanism by which it exerts its preventive action, remains to be elucidated. With the hypothesis that dietary potassium reduces renal vasoconstrictor components of the renin-angiotensin system in the long-term, we studied the effect of high potassium diet on angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2. METHODS: Sprague Dawley male rats on a normal sodium diet received normal potassium (0.9%, NK) or high potassium diet (3%, HK) for 4 weeks. Urine was collected in metabolic cages for electrolytes and urinary volume measurement. Renal tissue was used to analyze angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2 expression. Protein abundance analysis was done by Western blot; gene expression by mRNA levels by RT-qPCR. Renal distribution of angiotensin-I converting enzyme and renin was done by immunohistochemistry and morphometric analysis in coded samples. RESULTS: High potassium diet (4 weeks) reduced the levels of renin, angiotensin-I converting enzyme, and angiotensin converting enzyme 2. Angiotensin-I converting enzyme was located in the brush border of proximal tubules and with HK diet decreased the immunostaining intensity (P < 0.05), decreased the mRNA (P < 0.01) and the protein levels (P < 0.01). Renin localization was restricted to granular cells of the afferent arteriole and HK diet decreased the number of renin positive cells (P < 0.01) and renin mRNA levels (P < 0.01). High potassium intake decreased angiotensin converting enzyme 2 gene expression and protein levels (P < 0.01).No morphological abnormalities were observed in renal tissue during high potassium diet.The reduced expression of angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2 during potassium supplementation suggest that high dietary potassium intake could modulate these vasoactive enzymes and this effects can contribute to the preventive and antihypertensive effect of potassium.

Recomendaciones médicas para uveítis no infecciosas en adultos

Justificación: Las uveítis no infecciosas constituyen una importante causa de pérdida visual a nivel mundial; por su complejidad y gravedad de complicaciones requieren un abordaje temprano y multidisciplinario. En Costa Rica se desconoce hasta el momento la incidencia global de estas entidades y todavía no existe ningún consenso en cuanto a su manejo. Objetivos: Resumir las recomendaciones terapéuticas vigentes para uveítis no infecciosas en adultos y ofrecer una guía adaptada a la realidad costarricense. Métodos: Se efectuó una revisión no sistemática de bibliografía médica indexada en las plataformas PubMed y Scielo, sobre el manejo médico de las uveítis no infecciosas. De igual manera, se compararon los esquemas terapéuticos recomendados actualmente en América y Europa con el abordaje realizado en los centros hospitalarios costarricenses, para crear una guía adaptada a la realidad nacional. En la elaboración de estas recomendaciones participaron médicos especialistas de todas las clínicas multidisciplinarias especializadas en uveítis del país. Conclusiones: En Costa Rica se cuenta con la mayoría de las opciones disponibles para el tratamiento de uveítis idiopáticas en el sistema público de salud. Se logró la creación de algoritmos de tratamiento para las diferentes patologías.

Summary Background: Noninfectious uveitis represents an important cause of visual loss worldwide, which in view of the severity and complexity of complications demands an early and multidisciplinary approach to therapy. In Costa Rica there is no statistical records of incidence nor consensus of management of these entities to this date. Objectives: To summarize the therapeutic recommendations for non-infectious uveítis according to the scientific evidence and adapt them to the Costa Rican conditions. Methods: A non-systematic review of medical literature indexed on PubMed and Scielo, concerning medical and surgical management of non-infectious uveitis was carried out. Likewise, the recommended therapeutic schemes in America and Europe were compared to the approach used in the Costa Rican hospital centers. In the elaboration of these recommendations participated physicians, specialists of all multidisciplinary clinics for uveitis of the country. Conclusions: In Costa Rica, the majority of alternatives available for the treatment of idiopathic uveitis in the public health system are available. It was possible to create therapeutic algorithms for the different diseases.

Recaída bioquímica en cáncer de próstata de bajo riesgo tratados con prostatectomía radical y linfadenectomía pélvica / Biochemical Relapse in Low Risk Prostate Cáncer Treated with Radial Prostatectomy and Pelvic Lymphadenectomy

Objetivo La linfadenectomía pélvica ampliada es el método más confiable para identificar compromiso ganglionar en cáncer de próstata, sin embargo, la morbilidad, el tiempo quirúrgico, el papel terapéutico y las complicaciones, han sido temas de debate. El objetivo del estudio fue describir las características clínicas y patológicas de acuerdo con la presentación de recaída bioquimíca de los pacientes con cáncer de próstata de bajo riesgo tratados con prostatectomía radical más linfadenectomía pélvica ampliada. Métodos Estudio descriptivo longitudinal retrospectivo en una cohorte de pacientes con cáncer de próstata de bajo riesgo tratados quirúrgicamente, entre enero 2006 hasta diciembre 2016. Se revisaron 210 historias clínicas, 178 cumplían los criterios de inclusión: PSA < 10 ng/mL; Gleason < 6, cT1­cT2a, revisión de las biopsias de próstata y procedimientos quirúrgicos realizados en la misma institución. Las variables a evaluar: porcentaje de compromiso tumoral, invasión linfovascular, concordancia de gleason, numero de ganglios resecados, ganglios positivos, densidad ganglionar, recaída bioquímica. Resultados 178 pacientes con: 64 años, 62% T1c, psa de 6,37, compromiso de biopsia 23%. El 47% estaban subestadificados por gleason, con un promedio de ganglios resecados de 21, el compromiso ganglionar se encontró en un 3%, los bordes positivos en un 34% y la recaída bioquímica en un 19%. De los 33 pacientes con recaída bioquímica, el 6% tenían ganglios positivos y el 79% tenían bordes positivos, comparado con los que no recayeron: el 1% tenían ganglios positivos y el 23% eran R1, mientras que la invasión linfovascular solo estuvo presente en el 6% vs el 1% sin recaída. El tiempo a la recaída fue de 26 meses. Conclusiones El compromiso ganglionar en cáncer de próstata es bajo, pero la subestadificación es alta. En el grupo de recaída bioquímica se observó que la mayoría de los pacientes presentaban bordes positivos y una subestadificacion del Gleason.

Objective Extended pelvic lymphadenectomy is the most reliable method to identify lymph node involvement in prostate cancer, however, the morbidity, surgical time, therapeutic role and complications have been debated. The objective of this study was to describe the clinical and pathological characteristics according to the presentation of biochemical relapse in patients with low-risk prostate cancer treated with radical prostatectomy and extended pelvic lymphadenectomy. Methods A retrospective longitudinal descriptive study in a cohort of patients with low-risk prostate cancer treated surgically, from January 2006 to December 2016. 210 clinical records were reviewed, 178 met the inclusion criteria: PSA <10 ng / mL; Gleason <6, cT1 - cT2a, review of prostate biopsies and surgical procedures performed in the same institution. The variables to be evaluated: percentage of tumor commitment, lymphovascular invasion, gleason score, number of resected nodes, positive lymph nodes, lymph node density, biochemical relapse. Results 178 patients with: 64 years, 62% T1c, psa of 6.37, commitment of biopsy 23%. 47% were understaged by gleason, with an average of 21 resected nodes, nodal involvement was found in 3%, positive edges in 34% and biochemical relapse in 19%. Of the 33 patients with biochemical relapse, 6% had positive lymph nodes and 79% had positive margins, compared with those who did not relapse: 1% had positive lymph nodes and 23% were R1, whereas lymphovascular invasion was only present in 6% vs 1% without relapse. The time to relapse was 26 months. Conclusions The lymph node involvement in prostate cancer is low, but sub-staging is high. Patients with biochemical relapse they had positive borders and a sub-staging of the Gleason

Potassium Intake Prevents the Induction of the Renin-Angiotensin System and Increases Medullary ACE2 and COX-2 in the Kidneys of Angiotensin II-Dependent Hypertensive Rats.

In angiotensin II (Ang II)-dependent hypertensive rats there is an increased expression of proximal tubule angiotensinogen (AGT), collecting duct renin and angiotensin converting enzyme (ACE), which contributes to intratubular Ang II formation. Ang II acts on Ang II type 1 receptors promoting sodium retention and vasoconstriction. However concurrently, the ACE2-Ang-(1-7) axis and the expression of kallikrein and medullary prostaglandins counteract the effects of Ang II, promoting natriuresis and vasodilation. Human studies demonstrate that dietary potassium (K+) intake lowers blood pressure. In this report we evaluate the expression of AGT, ACE, medullary prorenin/renin, ACE2, kallikrein and cyclooxygenase-2 (COX-2) in Ang II-infused rats fed with high K+ diet (2%) for 14 days. Dietary K+ enhances diuresis in non-infused and in Ang II-infused rats. The rise in systolic blood pressure in Ang II-infused rats was attenuated by dietary K+. Ang II-infused rats showed increased renal protein levels of AGT, ACE and medullary prorenin and renin. This effect was attenuated in the Ang II + K+ group. Ang II infusion decreased ACE2 compared to the control group; however, K+ diet prevented this effect in the renal medulla. Furthermore, medullary COX-2 was dramatically induced by K+ diet in non-infused and in Ang II infused rats. Dietary K+ greatly increased kallikrein immunostaining in normotensive rats and in Ang II-hypertensive rats. These results indicate that a high K+ diet attenuates Ang II-dependent hypertension by preventing the induction of ACE, AGT and collecting duct renin and by enhancing medullary COX-2 and ACE2 protein expression in the kidney.

Cardiotoxicidad tardía por antraciclinas usadas en el tratamiento de la leucemia linfoblástica aguda en la edad pediátrica / Late cardiotoxicity by anthracyclines used for treatment of acute lymphoblastic leukemia in pediatric age

Introducción: las leucemias linfoblásticas agudas diagnosticadas en la edad prediátrica se tratan con antraciclinas con buenos resultados. Sin embargo estos fármacos producen cardiotoxicidad, lo que limita su uso. Objetivo: identificar las alteraciones subclínicas de cardiotoxicidad tardía causadas por las antraciclinas usadas en los enfermos de leucemia linfoblástica aguda en edad pediátrica.Método: se realizó un preexperimento con posprueba entre septiembre de 2015 y diciembre de 2016. La población en estudio estuvo constituida por 18 enfermos tratados en el Departamento de Oncología del Hospital Pediátrico de Camagüey, a los que se les realizó electrocardiograma y ecocardiograma bidimensional, Doppler y de flujo en color y se calculó la dosis acumulada de antraciclinas en mg/m2 de superficie corporal.Resultados: predominó el sexo femenino (61,11 por ciento), la casi totalidad de los pacientes tenían 10 o más años de edad, 83,33 por ciento presentó signos de cardiotoxicidad tardía. Prevalecieron las alteraciones electrocardiográficas (86,67 por ciento) por taquicardia sinusal, sobre las ecocardiográficas (13,33 por ciento) por incremento del diámetro diastólico del ventrículo izquierdo. Se identificó cardiotoxicidad incluso en los que recibieron dosis más bajas (180 mg/m2 y 240 mg/m2) y en todos los que recibieron el tratamiento por dos años o más. Los signos ecocardiográficos aparecieron con las dosis más elevadas (600 mg/m2 a 720 mg/m2) mientras los signos electrocardiográficos se presentaron para las demás dosis de la droga.Conclusiones: las alteraciones electrocardiográficas predominaron sobre las ecocardiográficas. La cardiotoxicidad se presentó cuando el tiempo de exposición a la droga fue corto y las dosis eran bajas(AU)

Introduction: the acute lymphoblastic leukemias diagnosed in prediatric age are treated with anthracyclines which offers good results. However, these drugs produce cardiotoxicity, which limits their use.Objective : to identify the subclinical alterations of late cardiotoxicity caused by anthracyclines used in patients with acute lymphoblastic leukemia in pediatric age.Method: a preexperiment was carried out with post-test between September 2015 and December 2016. The population under study was constituted by the 18 patients treated in the Oncology Department of the Pediatric Hospital in Camagüey, who underwent an electrocardiogram and two-dimensional echocardiogram, Doppler and color flow, and calculated the cumulative dose of anthracyclines in mg/m2 of body surface area.Results: the female sex predominated (61,11 percent), almost all patients were 10 or more years old, 83,33 percent showed signs of late cardiotoxicity. Electrocardiographic alterations prevailed (86,67 percent) due to sinus tachycardia, on echocardiography (13,33 percent) due to an increase in diastolic diameter of the left ventricle. Cardiotoxicity was identified even in those who received the lowest dose (180 mg/m2 and 240 mg/m2 ) and in all those who received the treatment for two years or more. The echocardiographic signs appeared with the highest doses (600 mg/m2 to 720 mg/m2) while the electrocardiographic signs appeared for the other doses of the drug.Conclusions: the electrocardiographic alterations prevailed over echocardiography. Cardiotoxicity occurred even when the time of exposure to the drug was short and the doses were low(AU)

Imbalance in Renal Vasoactive Enzymes Induced by Mild Hypoxia: Angiotensin-Converting Enzyme Increases While Neutral Endopeptidase Decreases.

Chronic hypoxia has been postulated as one of the mechanisms involved in salt-sensitive hypertension and chronic kidney disease (CKD). Kidneys have a critical role in the regulation of arterial blood pressure through vasoactive systems, such as the renin-angiotensin and the kallikrein-kinin systems, with the angiotensin-converting enzyme (ACE) and kallikrein being two of the main enzymes that produce angiotensin II and bradykinin, respectively. Neutral endopeptidase 24.11 or neprilysin is another enzyme that among its functions degrade vasoactive peptides including angiotensin II and bradykinin, and generate angiotensin 1-7. On the other hand, the kidneys are vulnerable to hypoxic injury due to the active electrolyte transportation that requires a high oxygen consumption; however, the oxygen supply is limited in the medullary regions for anatomical reasons. With the hypothesis that the chronic reduction of oxygen under normobaric conditions would impact renal vasoactive enzyme components and, therefore; alter the normal balance of the vasoactive systems, we exposed male Sprague-Dawley rats to normobaric hypoxia (10% O2) for 2 weeks. We then processed renal tissue to identify the expression and distribution of kallikrein, ACE and neutral endopeptidase 24.11 as well as markers of kidney damage. We found that chronic hypoxia produced focal damage in the kidney, mainly in the cortico-medullary region, and increased the expression of osteopontin. Moreover, we observed an increase of ACE protein in the brush border of proximal tubules at the outer medullary region, with increased mRNA levels. Kallikrein abundance did not change significantly with hypoxia, but a tendency toward reduction was observed at protein and mRNA levels. Neutral endopeptidase 24.11 was localized in proximal tubules, and was abundantly expressed under normoxic conditions, which markedly decreased both at protein and mRNA levels with chronic hypoxia. Taken together, our results suggest that chronic hypoxia produces focal kidney damage along with an imbalance of key components of the renal vasoactive system, which could be the initial steps for a long-term contribution to salt-sensitive hypertension and CKD.

Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice: differential effects for B1 and B2 receptors.

The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-fibrotic effects in renal and cardiac models of fibrosis; and the inducible B1 receptor (B1R), whose expression is induced by damage and inflammation. Inflammation and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), therefore we hypothesized that the KKS may play a role in this disease. To evaluate this hypothesis we used the mdx mouse a model for DMD. We blocked the endogenous activity of the KKS by treating mdx mice with B2R antagonist (HOE-140) or B1R antagonist (DesArgLeu8BK (DALBK)) for four weeks. Both antagonists increased damage, fibrosis, TGF-ß and Smad-dependent signaling, CTGF/CCN-2 levels as well as the number of CD68 positive inflammatory cells. B2R blockade also reduced isolated muscle contraction force. These results indicate that the endogenous KKS has a protective role in the dystrophic muscle. The KKS may be a new target for future therapies to reduce inflammation and fibrosis in dystrophic muscle.

The impact of Andean Patagonian mycoflora in the search for new lead molecules.

Secondary metabolites from fungi have become a major source of chemical innovation in programs searching for lead molecules with bioactivities, especially over the last 50 years. In this review, we discuss the fundamental considerations in the discovery of molecules for agricultural and medicinal uses. This group of organisms possesses a strong potential for scientific and industrial communities. Recently, the incorporation of new technologies for the artificial cultivation of fungi and the use of better equipment to isolate and identify active metabolites has allowed the discovery of leading molecules for the design of new and safer drugs and pesticides. The geographical region including the Patagonian Andes mountains harbors a wide diversity of fungi, many of them still unknown and so far associated with Chilean-Argentinian Andean endemic forests. There have been very few chemical studies of the fungi located in this region. However, those few studies have allowed the discovery of new molecules. We argue that the richness of fungal biodiversity in this region offers an interesting source for the discovery of bioactive molecules for the basic and applied sciences.

Inhibition on cholinesterase and tyrosinase by alkaloids and phenolics from Aristotelia chilensis leaves.

It is reported in this study the effect of isolates from leaves of Aristotelia chilensis as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes. The aim of the paper was to evaluate the activity of A. chilensis towards different enzymes. In addition to pure compounds, extracts rich in alkaloids and phenolics were tested. The most active F5 inhibited AChE (79.5% and 89.8% at 10.0 and 20.0 µg/mL) and against BChE (89.5% and 97.8% at 10.0 and 20.0 µg/mL), showing a strong mixed-type inhibition against AChE and BChE. F3 (a mixture of flavonoids and phenolics acids), showed IC50 of 90.7 and 59.6 µg/mL of inhibitory activity against AChE and BChE, inhibiting the acetylcholinesterase competitively. Additionally, F3 showed and high potency as tyrosinase inhibitor with IC50 at 8.4 µg/mL. Sample F4 (anthocyanidins and phenolic composition) presented a complex, mixed-type inhibition of tyrosinase with a IC50 of 39.8 µg/mL. The findings in this investigation show that this natural resource has a strong potential for future research in the search of new phytotherapeutic treatments for cholinergic deterioration ailments avoiding the side effects of synthetic drugs. This is the first report as cholinesterases and tyrosinase inhibitors of alkaloids and phenolics from A. chilensis leaves.

Antifungal activities of secondary metabolites isolated from liquid fermentations of Stereum hirsutum (Sh134-11) against Botrytis cinerea (grey mould agent).

Extracts obtained from liquid mycelial fermentations of the Chilean fungus Stereum hirsutum (Sh134-11) showed antifungal activity against Botrytis cinerea. Two types of extracts were obtained: EtOAc-extract (liquid phase) and MeOH-extract (mycelial phase). Plate diffusion assay showed that EtOAc-extracts were more active than MeOH-extracts. A large-scale fermentation of Sh134-11 and chromatographic methods allowed to isolated four compounds: MS-3, Vibralactone, Vibralactone B and Sterenin D. Only Sterenin D showed antifungal activity against B. cinerea in the tests performed. Effects on the mycelial growth of B. cinerea showed that Sterenin D showed inhibition at 1000-2000 µg/mL reaching 67% and 76% respectively. Sterenin D was more effective to control the sporogenesis, inhibiting in 96% the sporulation at 500 µg/mL. Assays showed that Sterenin D exhibited a minimal fungicidal concentration (MFC) of 50 µg/mL and minimal inhibitory concentration (MIC) at 20 µg/mL. Our study indicated that submerged fermentations of Chilean S. hirsutum (Sh134-11) produced extracts with antifungal activity and Sterenin D is responsible for this activity, which could be used as possible biofungicides alternative to synthetic fungicides.

Metastasectomy of Abdominal Wall Lesions due to Prostate Cancer Detected Through PET/CT Gallium 68-PMSA: First Case Report.

Introducing the topic of abdominal wall metastasis secondary to prostate cancer with a reminder of the disease's rarity, being the first published case. This article is about a 66 year old patient diagnosed with prostate cancer [cT2aNxMx iPSA: 5,6 ng/ml Gleason 3+3, (Grade 1 Group)], treated with radical prostatectomy as well as accompanied with amplified pelvic lymphadenectomy, who subsequently presented metastatic lesions to the abdominal wall diagnosed with PET/CT Gallium 68-PMSA technique and treated with abdominal metastasectomy with adequate short term results.

The chilean superfruit black-berry Aristotelia chilensis (Elaeocarpaceae), Maqui as mediator in inflammation-associated disorders.

The effects of phytochemicals occurred in fractions and extracts of fruits of "Maqui-berry" (Aristotelia chilensis), on the expression of cyclooxygenase-2 (COX-2), inducible-nitric oxide synthases (iNOS) and the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-activated murine macrophage RAW-264 cells, as well as their antioxidant activities. The MeOH extract (A), acetone/methanol extract (B), fractions F3, F4, subfractions (SF4-SF6, SF7, SF8-SF10, SF11-SF15, SF16-SF20), quercetin, gallic acid, luteolin, myricetin, mixtures M1, M2 and M3 exhibited potent anti-inflammatory and antioxidant activities. The results indicated that anthocyanins, flavonoids and its mixtures suppressed the LPS induced production of nitric oxide (NO), through the down-regulation of iNOS and COX-2 protein expressions and showed a potent antioxidant activity against SOD, ABTS, TBARS, ORAC, FRAP and DCFH. The inhibition of enzymes and NO production by selected fractions and compounds was dose-dependent with significant effects seen at concentration as low as 1.0-50.0 (ppm) and 5.0-10.0 µM, for samples (extracts, fractions, subfractions and mixtures) and pure compounds, respectively. Thus, the phenolics (anthocyanins, flavonoids, and organic acids) as the fractions and mixtures may provide a potential therapeutic approach for inflammation associated disorders and therefore might be used as antagonizing agents to ameliorate the effects of oxidative stress.