Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Original Form in Combination With Methotrexate in Patients With Rheumatoid Arthritis: A Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

BACKGROUND: Enerceptan (EtaBS) has been developed as a proposed biosimilar of etanercept. METHODS: This randomized, multicenter, evaluator-blinded, noninferiority study conducted in Argentina included adults with active, moderate, and severe rheumatoid arthritis with inadequate response to methotrexate. Subjects were randomly assigned to 32 weeks treatment with EtaBS (n = 99) or etanercept (n = 51) at a weekly 50-mg dose administered subcutaneously. Patients were categorized according to prior use of biologic disease-modifying antirheumatic drugs and concomitant use of steroids. The primary efficacy endpoint was ACR20 response rate at week 32. Safety, immunogenicity, and steady-state concentration of both drugs were evaluated. The noninferiority margin for ACR20 was estimated at 12%. RESULTS: In the per-protocol population, 85 subjects (92.4%) treated with EtaBS and 44 subjects (93.6%) treated with etanercept achieved ACR20 (difference, -1.2%; 95% confidence interval, -10.1% to 7.6%). Frequent adverse drug reactions occurred in 34.3% and 38% of subjects treated with EtaBS and etanercept, respectively. The most common reaction was upper respiratory tract infection. Six and 3 serious adverse events occurred in 4 and 3 subjects treated with EtaBS and etanercept, respectively. Injection site reactions occurred in 67.7% and 66.0% of subjects treated with EtaBS and etanercept, respectively. Two subjects treated with EtaBS and 1 subject treated with etanercept developed antibodies by week 32. CONCLUSIONS: Efficacy outcomes for EtaBS were noninferior to original etanercept in patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate. Safety and immunogenicity results were comparable between the two. This study is a major step toward improving access to biologics in Latin America.

Relationship between serum lithium concentration and kidney damage in a preclinical model.

OBJECTIVES: The aim of the present study was to assess whether there is a relationship between serum lithium concentrations and the magnitude of kidney damage in a preclinical model. METHODS: Thirty Wistar male rats were randomized into three groups: control group fed ad libitum powered standard diet for 3 months; and experimental groups fed ad libitum the same diet supplemented with 30 or 60 mmol/kg diet for 3 months (LowLi and HighLi groups respectively). Laboratory parameters were assessed at months 1 and 3 and histopathological changes were evaluated after 3 months. RESULTS: Serum lithium levels in experimental rats were within therapeutic range used in humans throughout the entire experiment. After 3 months of treatment, lithium levels were statistically higher in HighLi group. Rats of the LowLi group showed dilation of cortical tubules although with similar clearance of creatinine. Rats from the HighLi group had greater histopathological damage in addition to lower creatinine clearance than the other two groups. CONCLUSIONS: Our study suggests that during long-term treatments, even with serum lithium levels within the therapeutic range used in humans, the risk of kidney damage could increase proportionally to the serum lithium concentration.

Access to pathology and laboratory medicine services: a crucial gap.

As global efforts accelerate to implement the Sustainable Development Goals and, in particular, universal health coverage, access to high-quality and timely pathology and laboratory medicine (PALM) services will be needed to support health-care systems that are tasked with achieving these goals. This access will be most challenging to achieve in low-income and middle-income countries (LMICs), which have a disproportionately large share of the global burden of disease but a disproportionately low share of global health-care resources, particularly PALM services. In this first in a Series of three papers on PALM in LMICs, we describe the crucial and central roles of PALM services in the accurate diagnosis and detection of disease, informing prognosis and guiding treatment, contributing to disease screening, public health surveillance and disease registries, and supporting medical-legal systems. We also describe how, even though data are sparse, these services are of both insufficient scope and inadequate quality to play their key role in health-care systems in LMICs. Lastly, we identify four key barriers to the provision of optimal PALM services in resource-limited settings: insufficient human resources or workforce capacity, inadequate education and training, inadequate infrastructure, and insufficient quality, standards, and accreditation.

High-fat diet abolishes the cardioprotective effects of ischemic postconditioning in murine models despite increased thioredoxin-1 levels.

Ischemic postconditioning (PostC) reduces infarct size in healthy experimental models. However, if protective effects of PostC are abolished during early stages of atherosclerotic and if this is related with a disbalance in mitochondrial energetics and alterations in thioredoxin-1 (Trx1) is still unknown. The objectives were to generate a murine high-fat diet (HFD)-fed model that developed in a phenotype consistent with early stages of atherosclerosis to then evaluate whether HFD exposure increased oxidative stress and consequently abolished the cardioprotection conferred by PostC. We used C57/BL6 mice fed with control diet (CD) or HFD for 12 weeks. Isolated mice hearts were subjected to 30 min of ischemia and 120 min of reperfusion (I/R group). For PostC group, after ischemia, six cycles of reperfusion/ischemia were performed (10 s per cycle) at the onset of reperfusion. In CD group, the PostC reduced infarct size (CD-I/R: 52.14 ± 2.8 vs. CD-PostC: 36.58 ± 1.8, P < 0.05) and increased phosphorylation of GSK3ß (CD-PostC: 2.341 ± 1.03 vs. CD-Baseline: 0.923 ± 0.41 AUOD, P < 0.05), and this cardioprotection was abolished in HFD-exposed mice. HFD increased hydrogen peroxide levels, produced a shift towards an oxidized intracellular environment (GSSG/GSH2), and increased Trx1 expression with higher fractions of oxidized protein. State 3 mitochondrial oxygen consumption in basal conditions decreased 24% in HFD-exposed mice and PostC improved state 3 values only in CD mice. Cellular redox state and mitochondrial bioenergetics were altered in HFD-exposed mice. We demonstrated that alterations in redox state at early stages of atherosclerosis abolished cardioprotective mechanisms, such as those induced by PostC, even with increased Trx1 levels.

Low molecular weight hyaluronan induces migration of human choriocarcinoma JEG-3 cells mediated by RHAMM as well as by PI3K and MAPK pathways.

Hyaluronan (HA) is the major glycosaminoglycan present in the extracellular matrix. It is produced by some tumours and promotes proliferation, differentiation and migration among others cellular processes. Gestational trophoblastic disease (GTD) is composed by non-tumour entities, such as hydatidiform mole (HM), which is the most common type of GTD and also malignant entities such as choriocarcinoma (CC) and placental site trophoblastic tumour (PSTT), being CC the most aggressive tumour. Although there is a growing understanding of GTD biology, the role of HA in the pathogenesis of this group of diseases remains largely unknown. The aim of this work was to study the role of HA in the pathogenesis of GTD by defining the expression pattern of HA and its receptors CD44 and RHAMM, as well as to determine if HA can modulate proliferation, differentiation and migration of CC cells. Receptors and signalling pathways involved were also analyzed. We demonstrated that HA and RHAMM are differently expressed among GTD entities and even among trophoblast subtypes. We also showed that HA is able to enhance the expression of extravillous trophoblast markers and also to induce migration of JEG-3 cells, the latter mediated by RHAMM as well as PI3K and MAPK pathways. These findings indicate a novel regulatory mechanism for CC cell biology and also contribute to the understanding of GTD pathophysiology.

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes.

Type 1 diabetes (T1D) originates from autoimmune ß-cell destruction. IMT504 is an immunomodulatory oligonucleotide that increases mesenchymal stem cell cloning capacity and reverts toxic diabetes in rats. Here, we evaluated long-term (20 doses) and short-term (2-6 doses) effects of IMT504 (20 mg·kg(-1)·day(-1) sc) in an immunodependent diabetes model: multiple low-dose streptozotocin-injected BALB/c mice (40 mg·kg(-1)·day(-1) ip for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. IMT504 reduced glycemia, induced ß-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased ß-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression; preproinsulin-2, proglucagon, somatostatin, nestin, regenerating gene-1, and C-X-C motif ligand-1 cytokine (Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated platelet endothelial cell adhesion molecule-1 (Pecam1) in islets from control and diabetic mice, whereas it increased regenerating gene-2 (Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate ß-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.

Changes in CNS cells in hyperammonemic portal hypertensive rats.

Rats with pre-hepatic portal hypertension because of partial portal vein ligation develop minimal hepatic encephalopathy (MHE) with hyperammonemia, impaired blood-brain barrier, mild brain edema, and severe mitochondrial changes in the hippocampus. The aim of this study was to evaluate changes of different neural cells in the cerebral cortex and the hippocampus. Animals were divided into two groups, MHE and sham. Astrocytes were studied by immunostaining with glial fibrillary acidic protein and S100ß protein; neurons were immunostained with neuronal nuclear marker, microtubule associated protein-2, and NF-200 and capillaries with Nestin. The hypoxia-inducible factor 1α (HIF-1α) and its downstream proteins, P-glycoprotein (P-gp) and erythropoietin receptor (Epo-R), were also evaluated. Astrocytes were increased in area and number only in the hippocampus, while S100ß increased in both brain areas in MHE animals. Microtubule associated protein-2 and NF-200 immunoreactivities (-ir) were significantly reduced in both areas. Hippocampal Nestin-ir was increased in MHE animals. These cellular changes were similar to those described in ischemic conditions, thus HIF-1α, P-gp, and Epo-R were also evaluated. A high expression of HIF-1α in cortical neurons was observed in the MHE group. It is likely that this hypoxia-like state is triggered via ammonia occupying the binding domain of HIF-1α and thereby preventing its degradation and inducing its stabilization, leading to the over-expression of P-gp and the Epo-R.

A simple method to determine proteolytic activity of snake venoms.

In this work, we describe an easy, simple, and cost-effective method to assess the proteolytic activity of snake venoms. The method is based on measuring the hydrolytic halo formed by gelatin radial hydrolysis following the incubation of venoms on a solid gelatin-agarose plate. Venoms from Bothrops (B.) alternatus, B. diporus, B. neuwiedi, B. jararaca, B. jararacussu, Crotalus atrox, and Trimeresurus albolabris were tested. A dose-response relationship was observed for each venom tested, with proteolytic capacity values, determined as GD (gelatinolytic dose, the dose causing a 15 mm hydrolytic halo) ranging from 21 to 222 µg. A correlation between hydrolysis and hemorrhagic activity in rat skin (minimal hemorrhagic dose) was found, with an r2 value of 0.8774 (p < 0.0001). The venoms' hydrolytic activity was significantly, though not completely, inhibited by EDTA. This methodology was also deployed to assess venom neutralization by antivenoms on the hydrolytic activity of the different venoms, demonstrating its usefulness in evaluating antivenom neutralizing capacity. The method presented is simple, cheap and useful for preliminary screening of venom proteolytic activity and its inhibition and may also predict gross differences in hemorrhagic activity, contributing to the reduction of the number of animals used for these determinations.

Biosimilar Versus Originator Pegfilgrastim for Preventing Chemotherapy-Induced Neutropenia: A Phase III Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

PURPOSE: This study evaluated the efficacy, safety, and immunogenicity of biosimilar pegfilgrastim (PegFilBS) and originator pegfilgrastim (PegFilOR) in patients with stage 2-4 breast cancer. METHODS: This phase III randomized, multicenter, evaluator-blinded, noninferiority study recruited women with stage 2-4 breast cancer in Argentina who were scheduled to receive chemotherapy. Stratification was based on the breast cancer stage. The primary end point was the duration of severe neutropenia (DSN, noninferiority margin: 1 day) in the first chemotherapy cycle. Secondary end points assessed were incidence of severe neutropenia, grade 3 neutropenia, febrile neutropenia, infections, postchemotherapy hospitalization and duration, and the incidence of adverse drug reactions (ADRs). RESULTS: A total of 120 patients were randomly assigned to receive PegFilBS (58 patients) or PegFilOR (62 patients). Severe neutropenia occurred in 52 of 283 cycles (18.4%) for 27 patients who received PegFilBS and in 48 of 297 cycles (16.2%) for 20 patients who received PegFilOR (P = .48). During the first cycle, severe neutropenia occurred in 16 patients who received PegFilBS (DSN: 0.78 ± 1.53 days) and in 11 patients who received PegFilOR (DSN: 0.53 ± 1.25 days; 95% CI, -0.26 to 0.76 days). In the intention-to-treat analysis, the mean DSN values were 0.90 ± 1.79 days for the PegFilBS group and 0.50 ± 1.21 for the PegFilOR group (95% CI, -0.15 to 0.95 days). No significant differences were observed for the secondary efficacy end points. Three patients experienced seven ADRs in the PegFilBS group while 10 patients experienced 31 ADRs in the PegFilOR group. The most common ADR was myalgia. CONCLUSION: Relative to PegFilOR, PegFilBS provided noninferior efficacy outcomes in Argentinian women with stage 2-4 breast cancer who were treated using myelosuppressive chemotherapy.

Chronic exposure to polluted urban air aggravates myocardial infarction by impaired cardiac mitochondrial function and dynamics.

Air pollution exposure positively correlates with increased cardiovascular morbidity and mortality rates, mainly due to myocardial infarction (MI). Herein, we aimed to study the metabolic mechanisms underlying this association, focusing on the evaluation of cardiac mitochondrial function and dynamics, together with its impact over MI progression. An initial time course study was performed in BALB/c mice breathing filtered air (FA) or urban air (UA) in whole-body exposure chambers located in Buenos Aires City downtown for up to 16 weeks (n = 8 per group and time point). After 12 weeks, lung inflammatory cell recruitment was evident in UA-exposed mice. Interestingly, impaired redox metabolism, characterized by decreased lung SOD activity and increased GSSG levels and NOX activity, precede local inflammation in this group. At this selected time point, additional mice were exposed to FA or UA (n = 12 per group) and alveolar macrophage PM uptake and nitric oxide (NO) production was observed in UA-exposed mice, together with increased pro-inflammatory cytokine levels (TNF-α and IL-6) in BAL and plasma. Consequently, impaired heart tissue oxygen metabolism and altered mitochondrial ultrastructure and function were observed in UA-exposed mice after 12 weeks, characterized by decreased active state respiration and ATP production rates, and enhanced mitochondrial H2O2 production. Moreover, disturbed cardiac mitochondrial dynamics was detected in this group. This scenario led to a significant increase in the area of infarcted tissue following myocardial ischemia reperfusion injury in vivo, from 43 ± 3% of the area at risk in mice breathing FA to 66 ± 4% in UA-exposed mice (n = 6 per group, p < 0.01), together with a sustained increase in LVEDP during myocardial reperfusion. Taken together, our data unravel cardiac mitochondrial mechanisms that contribute to the understanding of the adverse health effects of urban air pollution exposure, and ultimately highlight the importance of considering environmental factors in the development of cardiovascular diseases.

High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia.

Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in non-alcoholic fatty liver disease (NAFLD) is not well understood. We evaluated the molecular mechanisms that may be involved in the regulation of liver mtDNA content in a high-fat-induced rat model of NAFLD. In particular, we tested the hypothesis that liver mtDNA copy number is associated with liver expression of HIF-1α. Rats were given either standard chow diet (SCD, n = 10) or high-fat diet (HFD, n = 15) for 20 weeks. Subsequently, mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using real time quantitative PCR. HFD induced a significant increase in liver mtDNA/nDNA ratio, which significantly correlated with the liver triglyceride content (R: 0.29, P < 0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1α mRNA (R: 0.37, P < 0.001); liver HIF-1α mRNA was significantly higher in the HFD group. In addition, liver cytochrome c oxidase subunit IV isoform 1 (COX4I1) mRNA expression was also positively correlated with liver mtDNA content. The hepatic expression of mRNA of transcriptional factors that regulate mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PGC-1ß, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor δ and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1α-mediated increase in mtDNA copy number. In conclusion, we found that HFD promotes an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1α, probably to enhance the mitochondrial function as well as to accommodate the metabolic load.

Renal Damage During Continuous Versus Intermittent Treatment with Lithium.

The aim of this study was to evaluate renal damage in animals treated with lithium continuously versus intermittently. Rats were randomized into three groups: control group fed ad libitum powered standard diet for 3 months and two experimental groups, one of them fed ad libitum the same diet or the same diet supplemented with 60 mmol of lithium/kg diet every alternate week, for 3 months and the other fed ad libitum powered standard diet for one and a half month and the same diet supplemented with 60 mmol of lithium/kg diet for the last month and a half. Lithemias in experimental groups were within therapeutic range used in humans. At the end of the protocol, diuresis was higher in experimental groups compared to control group. There was no difference in serum creatinine and creatinine clearance. Both experimental groups showed hypertrophy, hyperplasia, and dilatation of cortical collecting tubules although dilatation was greater in continuous group. Longer studies are necessary to clarify the evolution of renal damage. Our preliminary study shows that histopathological damage associated with the use of lithium occurs during both continuous and intermittent treatment, but it seems to be somewhat greater in the continuous group.

Efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) vs. Gonal-f® in women undergoing ovarian stimulation for IVF: A randomized, multicenter, evaluator-blinded, non-inferiority study.

OBJECTIVE: We compared the efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) with Gonal-f® in women undergoing ovarian stimulation for in-vitro fertilization. METHODS: This randomized (1:1), multicenter, assessor-blinded, non-inferiority, parallel-group, controlled study conducted at four infertility clinics in Argentina included infertile normogonadotropic women with ages below 39 years, with menstrual cycles of 25/35 days and a body mass index of 18-32 kg/m2 undergoing assisted reproductive technology therapy. During a 5-day fixed-dose phase, the women received 225 IU/day of Folitime® (n=49) or Gonal-f® (n=44), followed by a dose-adaptation phase up to a maximum of 450 IU/day. The non-inferiority margin for oocyte retrieval was estimated at -4 oocytes (one-sided test). Immunogenicity was investigated on days 9 and 84, following the start of treatment. RESULTS: The mean number of oocytes retrieved was 12.6 (SD 7.4) in the Folitime® group and 13.4 (SD 6.9) in the Gonal-f® group (per protocol analysis, 95% confidence interval = -3.82; 2.33), within the non-inferiority margin. Pregnancy rate at week 10 was 24.4% among subjects treated with Folitime® and 19.5% for subjects treated with Gonal-f®. One serious adverse drug reaction-late mild ovarian hyper stimulation syndrome and deep venous thrombosis in the left deep jugular vein-occurred in a subject treated with Folitime®. None of the subjects developed antibodies against the study drugs. There were no unexpected safety findings. CONCLUSIONS: Folitime® is non-inferior to Gonal-f®, with no differences in the safety profile and has been approved as a biosimilar in Argentina.

Chronic progressive nephropathy: functional, morphological, and morphometrical studies.

Some aspects of the functional, morphological, and morphometrical characteristics of chronic progressive nephropathy occurring in 18- to 26-month-old male rats and in 3-month-old control rats were studied. Rats with chronic progressive nephropathy were proteinuric and showed a slight increase in serum creatinine and no changes in blood pressure. The morphological changes were studied by light microscopy, high-resolution light microscopy, and electron microscopy. They showed focal and segmental or global glomerulosclerosis, the three types of atrophic tubules ("classic," "thyroid-like," and "endocrine") described by Nadasdy et al, as well as interstitial fibrosis with mononuclear cell infiltrates. On certain occasions, small vessels showed hyalinosis. Glomerular morphometrical studies showed a biphasic pattern in the glomeruli progressing toward obsolescence. Vascular morphometrical studies showed significant increase in media wall thickness and media cross-sectional area in the 18- to 26-month-old rats. These results support the hypothesis that changes in the vascular system are not of utmost importance in the pathogenesis of chronic progressive nephropathy, and that glomerular sequential changes seem to be of paramount significance in the progression of the disease.

Toxicological study of bee venom (Apis mellifera mellifera) from different regions of the province of Buenos Aires, Argentina.

Samples of Apis mellifera mellifera venom from different hives in two regions of the Buenos Aires province and its pool were analyzed for their lethal potency, myotoxic, defibrinogenating, hemolytic and inflammatory-edematizing activity and for the histological alterations they produce in the heart, lungs, kidneys, skeletal muscle and liver of mice. In vitro studies focused on the venom's hemolytic activity in different systems and species (horse, man, sheep and rabbit), the cytotoxicity in cellular lines, and on the proteolytic and coagulant activity in plasma and fibrinogen. Hemolytic activity, either observed in vitro or in vivo, showed similar toxicity levels for all samples. Erythrocytes of different species varied in their sensitivity to the venom pool, equines being the most sensitive and sheep the most resistant to direct hemolytic action. Local and systemic myotoxicity was evidenced by either the elevation of serum creatine kinase and/or histopathological lesions, observed in different muscles. All samples caused significant pathological alterations; pulmonary, cardiac, renal and skeletal muscle lesions were substantive and can be related to the pathophysiological mechanisms of envenomation. The venoms from different apiaries and regions of the Buenos Aires province showed very similar toxicological characteristics. These results suggest that severity of envenomation in case of a swarming could therefore be more related to the number of bees than to the differential toxicity of the venom from different regions of the province. This is the first study on the toxicity and toxicological characteristics of Apis mellifera venom in Argentina.

A new venomous scorpion responsible for severe envenomation in Argentina: Tityus confluens.

In Argentina the scorpions of medical importance belong to the genus Tityus (T.), particularly the species T. trivittatus, the only scorpion whose sting is recognized to be associated with severe human envenoming and death. This genus is distributed from the north of the Patagonian region to the center and some provinces in the north of the country. During the period 2003-2006 four children died following scorpion stings, of which one was certainly and three were probably by T. confluens. In 2006, in the province of Tucumán, a girl died by scorpion envenoming and the scorpion responsible for the death, found in her shoe, was T. confluens. We thus studied the toxicity of venom gland homogenates from T. confluens from the provinces of Jujuy and Catamarca, and of crude venom from specimens from Catamarca and the province of La Rioja. The lethal potencies of the telson homogenates were 7.0 and 18.6microg/g for Jujuy and Catamarca, respectively, while the lethal potency of the crude venom was 0.7microg/g. Injected mice showed generalized congestion and hepatic lesions. Pancreatic damage was observed in some animals. Lungs showed congestion and foci of hemorrhage and mild edema. The heart showed injury in the muscular fibers. The venom showed high reactivity against anti-T. trivittatus antivenom and against two anti-T. serrulatus antivenoms. The anti-T. trivittatus antivenom neutralized the lethal activity of T. confluens venom. In addition, the venom reacted very slightly against an anti-Centruroides antivenom. Therefore, the stings of this scorpion must be considered of risk for humans to the same degree as the stings of T. trivittatus.

La administración de N-acetilcisteína atenúa el remodelado post infarto de miocardio / Administration of N-acetylcysteine Attenuates Post-Myocardial Infarction Remodeling

RESUMEN Introducción: La cardiopatía isquémica es la principal causa de muerte en la República Argentina. La forma de presentación que prevalece es el infarto de miocardio (IM), caracterizado por insuficiente perfusión sanguínea, muerte celular y pérdida de masa contráctil. La evolución del remodelado ventricular provoca dilatación ventricular, deterioro hemodinámico, insuficiencia cardíaca y disminución de la sobrevida. Durante este proceso existe un estrés oxidativo miocárdico que podría ser atenuado mediante la administración de N-acetil cisteína (NAC), a través de un aumento de los niveles de glutatión. Objetivos: Evaluar el efecto de la NAC sobre el remodelado post IM. Material y métodos: Se estudiaron durante 28 días conejos neozelandeses en tres grupos experimentales: Control, IM e IM+NAC. Bajo anestesia general se realizó una toracotomía izquierda y, en los grupos con IM, ligadura de una rama de la coronaria izquierda. Al finalizar el período de seguimiento posterior al infarto, se realizaron estudios ecocardiográficos, hemodinámicos y morfológicos del ventrículo izquierdo (VI). Resultados: En los grupos IM e IM+NAC los infartos estaban ubicados en la pared libre del VI y tuvieron tamaños similares. La administración de NAC evitó el adelgazamiento de la zona no infartada y disminuyó la dilatación provocada por el infarto. También pudo observarse que preservó las funciones sistólica y diastólica del VI, con atenuación del deterioro que las mismas sufrieron como consecuencia del infarto. Conclusión: Estos resultados sugieren que la administración de NAC es una terapéutica promisoria para mitigar los efectos desfavorables del remodelado post IM.

ABSTRACT Background: Ischemic heart disease is the main cause of death in Argentina. The prevailing form of presentation is myocardial infarction (MI), characterized by insufficient blood perfusion, cell death and loss of contractile mass. The evolution of ventricular remodeling causes ventricular dilation, hemodynamic impairment, heart failure, and decreased survival. The oxidative stress occurring during this process could be attenuated by the administration of N-acetyl cysteine (NAC) through increased glutathione levels. Objectives: The aim of this study was to evaluate the effect of NAC administration on post-MI remodeling. Methods: New Zealand rabbits were divided into three experimental groups: Control, MI and MI+NAC. A left thoracotomy was performed under general anesthesia, and in the MI groups a branch of the left coronary artery was ligated. Echocardiographic, hemodynamic and morphological studies of the left ventricle were performed at the end of the 28-day post infarction follow-up period. Results: In the MI and MI+NAC groups, the infarcts were located in the left ventricular free wall and had similar sizes. The administration of NAC prevented non-infarcted area thinning and decreased the dilation caused by the infarction. It also preserved left ventricular systolic and diastolic functions, attenuating the impairment that they suffered as a consequence of the infarction. Conclusion: These results suggest that NAC administration is a promising therapy to mitigate the unfavorable effects of post-MI remodeling.

Role of Oxidative Stress in Lithium-Induced Nephropathy.

Long-term lithium treatment was associated with chronic kidney disease and renal failure although the underlying pathogenic mechanisms are not certainty known. The aim of this study was to evaluate changes in oxidative stress measures as well as renal functional and structural alterations associated with chronic use of lithium in rats. Forty Wistar male rats were randomized into four groups: control groups fed ad libitum powered standard diet for 1 and 3 months and experimental groups fed ad libitum the same diet supplemented with 60 mmol/kg diet for 1 and 3 months. Histopathological changes, laboratory parameters, and oxidative stress measurements were assessed at months 1 and 3. The experimental animals showed alteration of the cortical tubules from the first month of lithium-treatment and a decrease in the glomerular filtration rate and in the glomerular area at the third month. There was an increase in thiobarbituric acid reactive substances and carbonyls, as well as an increase in reduced glutathione, in the kidney of rats exposed to lithium. These changes were evident from the first month of treatment and remained throughout the experiment. Our results suggest that, oxidative stress could be one of the pathogenic mechanisms involved in the structural and functional alterations of the kidney associated with prolonged use of lithium. The study of the pathogenic mechanisms involved in lithium-induced nephropathy is a critical issue for the development of new strategies for prevention and/or early detection.

Study on the obtaining of Tityus trivittatus venom in Argentina.

Envenomation by scorpions of the genus Tityus is an important public health problem in Argentina, involving near 8000 stings and 2 deaths each year. Treatment for envenomation is the use of specific antivenom and intensive hospital care. Antivenom is produced by the Ministry of Health and freely distributed throughout the country. For antivenom production it is necessary to collect scorpion venom, which is a difficult task because although scorpions can be found in Argentina, they are less abundant than in warmer latitudes. For this reason venom collection constitutes a bottleneck for antivenom production. Although in Argentina several species of Tityus can be found, most of the accidents are caused by Tityus trivittatus, and the venom of this scorpion has historically been the venom used for antivenom production. We analyzed retrospectively 26 pools of telson homogenates (6964 telsons) and 37 pools of milked venom obtained by electrical stimulation (equivalent to 6841 milkings). Lethal potencies of samples from different provinces were very similar, although venom from scorpions of Buenos Aires city showed the lowest potency. The venom obtained by milking (median LD50 12.3 µg), provided batches containing LD50s more potent when compared with the venom obtained from telson homogenates (p < 0.0001). Many batches of telson homogenates (30%) showed lower potencies than acceptable for antivenom production and control. In addition to the study of the venom yield, the records of immunization of horses, the potency of the batches and the protein content of each batch of anti-scorpion antivenom produced were analyzed, comparing those produced using milked venom with those using telson homogenates as immunogens. Batches produced using milked venom required a shorter period of immunization (p < 0.0001), rendered higher neutralizing titers (p 0.0350) and possessed lower protein content (p 0.0092). Results clearly showed that the milking of scorpions is a more efficient tool to obtain venom for antivenom production in comparison to the use of telson homogenates.

Metabolic Syndrome and Neuroprotection.

Introduction: Over the years the prevalence of metabolic syndrome (MetS) has drastically increased in developing countries as a major byproduct of industrialization. Many factors, such as the consumption of high-calorie diets and a sedentary lifestyle, bolster the spread of this disorder. Undoubtedly, the massive and still increasing incidence of MetS places this epidemic as an important public health issue. Hereon we revisit another outlook of MetS beyond its classical association with cardiovascular disease (CVD) and Diabetes Mellitus Type 2 (DM2), for MetS also poses a risk factor for the nervous tissue and threatens neuronal function. First, we revise a few essential concepts of MetS pathophysiology. Second, we explore some neuroprotective approaches in MetS pertaining brain hypoxia. The articles chosen for this review range from the years 1989 until 2017; the selection criteria was based on those providing data and exploratory information on MetS as well as those that studied innovative therapeutic approaches. Pathophysiology: The characteristically impaired metabolic pathways of MetS lead to hyperglycemia, insulin resistance (IR), inflammation, and hypoxia, all closely associated with an overall pro-oxidative status. Oxidative stress is well-known to cause the wreckage of cellular structures and tissue architecture. Alteration of the redox homeostasis and oxidative stress alter the macromolecular array of DNA, lipids, and proteins, in turn disrupting the biochemical pathways necessary for normal cell function. Neuroprotection: Different neuroprotective strategies are discussed involving lifestyle changes, medication aimed to mitigate MetS cardinal symptoms, and treatments targeted toward reducing oxidative stress. It is well-known that the routine practice of physical exercise, aerobic activity in particular, and a complete and well-balanced nutrition are key factors to prevent MetS. Nevertheless, pharmacological control of MetS as a whole and pertaining hypertension, dyslipidemia, and endothelial injury contribute to neuronal health improvement. Conclusion: The development of MetS has risen as a risk factor for neurological disorders. The therapeutic strategies include multidisciplinary approaches directed to address different pathological pathways all in concert.