Decoding the Versatile Landscape of Autophagic Protein VMP1 in Cancer: A Comprehensive Review across Tissue Types and Regulatory Mechanisms.

Autophagy, a catabolic process orchestrating the degradation of proteins and organelles within lysosomes, is pivotal for maintaining cellular homeostasis. However, its dual role in cancer involves preventing malignant transformation while fostering progression and therapy resistance. Vacuole Membrane Protein 1 (VMP1) is an essential autophagic protein whose expression, per se, triggers autophagy, being present in the whole autophagic flux. In pancreatic cancer, VMP1-whose expression is linked to the Kirsten Rat Sarcoma Virus (KRAS) oncogene-significantly contributes to disease promotion, progression, and chemotherapy resistance. This investigation extends to breast cancer, colon cancer, hepatocellular carcinoma, and more, highlighting VMP1's nuanced nature, contingent on specific tissue contexts. The examination of VMP1's interactions with micro-ribonucleic acids (miRNAs), including miR-21, miR-210, and miR-124, enhances our understanding of its regulatory network in cancer. Additionally, this article discusses VMP1 gene fusions, especially with ribosomal protein S6 kinase B1 (RPS6KB1), shedding light on potential implications for tumor malignancy. By deciphering the molecular mechanisms linking VMP1 to cancer progression, this exploration paves the way for innovative therapeutic strategies to disrupt these pathways and potentially improve treatment outcomes.

Autophagy in Inflammatory Response against SARS-CoV-2.

The coronavirus disease pandemic, which profoundly reshaped the world in 2019 (COVID-19), and is currently ongoing, has affected over 200 countries, caused over 500 million cumulative cases, and claimed the lives of over 6.4 million people worldwide as of August 2022. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Depicting this virus' life cycle and pathogenic mechanisms, as well as the cellular host factors and pathways involved during infection, has great relevance for the development of therapeutic strategies. Autophagy is a catabolic process that sequesters damaged cell organelles, proteins, and external invading microbes, and delivers them to the lysosomes for degradation. Autophagy would be involved in the entry, endo, and release, as well as the transcription and translation, of the viral particles in the host cell. Secretory autophagy would also be involved in developing the thrombotic immune-inflammatory syndrome seen in a significant number of COVID-19 patients that can lead to severe illness and even death. This review aims to review the main aspects that characterize the complex and not yet fully elucidated relationship between SARS-CoV-2 infection and autophagy. It briefly describes the key concepts regarding autophagy and mentions its pro- and antiviral roles, while also noting the reciprocal effect of viral infection in autophagic pathways and their clinical aspects.

Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells.

Autophagy is a tightly regulated catabolic process involved in the degradation and recycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin-proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin-RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor-cell-therapy resistance.

Incidence and case-fatality rate of stroke in General Villegas, Buenos Aires, Argentina. The EstEPA population study.

OBJECTIVES: Stroke epidemiology varies among different populations. The burden of stroke is high in low- and middle-income countries. Reliable population data is needed to assess the impact of stroke and to develop policies aimed to improve stroke care in our region. EstEPA is a population-based project assessing prevalence, incidence, mortality and burden of stroke in General Villegas Department, Buenos Aires, Argentina (pop=30,864 inhabitants). We determined incidence of stroke (first-ever and recurrent stroke) and stroke case-fatality rate from 2017 to 2020. METHODS: First-ever strokes, recurrent strokes and transient ischemic attacks were ascertained and case-fatality rate was obtained. Diagnoses were based on standard AHA/WHO definitions. Study population included all persons residing in General Villegas during the three-year period. Hospitals, households, nursing homes, death certificates and several overlapping sources were surveyed. RESULTS: We assessed 92,592 person-years. There were 155 cerebrovascular events aged 70 years (SD ± 13 years), of which 115 were first-ever strokes (74%), 21 recurrent strokes (13.5%) and 19 transient ischemic attacks (12.5%). The crude overall incidence rate of first-ever strokes was 124.2 per 100,000 population (86.9 per 100,000 [95% CI 58.5-115.2] when standardized by WHO World population and 109.7 per 100,000 [95% CI 89.7-129.8] when standardized by Argentine population) and 317.0 per 100,000 population in subjects older than 40 years. Case fatality rate at 30 days of first-ever strokes was 27%. CONCLUSION: In this population-based comprehensive stroke epidemiological study in Argentina, first-ever stroke incidence in an urban population was 124.2 per 100,000 population (86.9 per 100,000 adjusted by the WHO World population). This is lower than the incidence in other countries in the region and similar to a recent incidence study in Argentina. It is also comparable to reported incidence in most middle- and high-income countries. Stroke case-fatality rate was comparable to other population-based Latin-American studies.

Stroke Epidemiology in Argentina. Design of a Population-Based Study in General Villegas (EstEPA).

BACKGROUND: Epidemiological data on stroke is scarce in Latin America. Estudio Epidemiológico Poblacional sobre Accidente Cerebrovascular (EstEPA) is a population-based program planned to assess prevalence, incidence, mortality, and burden of disease for stroke in the Department of General Villegas, province of Buenos Aires, Argentina. METHODS AND DESIGN: Prevalence study will consist of a two-phase survey approach in the urban area of General Villegas. First, trained social workers with a structured questionnaire will collect data in 2000 randomly selected housing units. Those subjects screened positive for possible strokes will be interviewed and examined by stroke neurologists to confirm diagnosis. The incidence study will be performed according to the methodology of WHO STEPS stroke surveillance manual and will detect all new strokes in the department during a 5-year period. General and disease-specific mortality rates will be assessed monthly during a 5-year period, using different sources of information. To assess the overall burden of cerebrovascular disease, disability adjusted life years will be calculated. DISCUSSION: EstEPA will assess for the first time all aspects of stroke epidemiology in Argentina. Its results will help to implement population-based interventions and to properly allocate public health resources.

[Severe asthma]. / Asma grave.

The objectives of this work were to investigate the frequency of severe asthma (SA) according to WHO definition and to compare SA patients' characteristics with those of non-severe asthma (NSA); secondly, to investigate the level of control reached throughout a period of regular treatment. Between 1-1-2005 and 12-31-2014, 471 medical records from patients with bronchial asthma assisted in Buenos Aires City were analyzed. SA frequency was 40.1% (189/471), being significantly higher among patients from the public health system (47.7%, 108/226 vs. 33%, 81/245, p = 0.001). SA patients were older than NSA ones (51.3 ± 17.4 vs. 42.6 ± 17.1 years, p = 0.000), presented longer time since onset of the disease (median 30 vs. 20 years, p = 0.000), lower educational levels (secondary level or higher 41.7% vs. 58.1%, p = 0.000), lower frequency of rhinitis (47% vs. 60.6%, p = 0.004), more severe levels of airway obstruction (FEV% 50.2 ± 13.7 vs. 77.7 ± 12.4, p = 0.000), more frequent antecedents of Near Fatal Asthma (11.1% vs. 2.8%, p = 0.000), higher levels of serum IgE (median of 410 vs. 279 UI/l, p = 0.01) and higher demand of systemic steroids requirements and hospitalizations (68.7% vs. 50.7%, p = 0.000 and 37.5% vs. 15.9%, p = 0.000, respectively). A 30.6% of SA patients (58/189) reached a follow-up period of 12 months, 13 (22.5%) of whom reached the controlled asthma level. The frequency of SA found seems to be considerable. Multicenter studies to investigate the levels of control reached by SA patients with access to proper treatment are recommended.

Treatment of hyponatremic encephalopathy with a 3% sodium chloride protocol: a case series.

BACKGROUND: 3% sodium chloride solution is the accepted treatment for hyponatremic encephalopathy, but evidence-based guidelines for its use are lacking. STUDY DESIGN: A case series. SETTING & PARTICIPANTS: Adult patients presenting to the emergency department of a university hospital with hyponatremic encephalopathy, defined as serum sodium level < 130 mEq/L with neurologic symptoms of increased intracranial pressure without other apparent cause, and treated with a continuous infusion of 500mL of 3% sodium chloride solution over 6 hours through a peripheral vein. PREDICTORS: Hyponatremic encephalopathy defined as serum sodium level < 130 mEq/L with neurologic symptoms of increased intracranial pressure without other apparent cause. OUTCOMES: Change in serum sodium level within 48 hours, improvement in neurologic symptoms, and clinical evidence of cerebral demyelination, permanent neurologic injury, or death within 6 months' posttreatment follow-up. RESULTS: There were 71 episodes of hyponatremic encephalopathy in 64 individuals. Comorbid conditions were present in 86% of individuals. Baseline mean serum sodium level was 114.1±0.8 (SEM) mEq/L and increased to 117.9±1.3, 121.2±1.2, 123.9±1.0, and 128.3±0.8 mEq/L at 3, 12, 24, and 48 hours following the initiation of 3% sodium chloride solution treatment, respectively. There was a marked improvement in central nervous system symptoms within hours of therapy in 69 of 71 (97%) episodes. There were 12 deaths, all of which occurred following the resolution of hyponatremic encephalopathy and were related to comorbid conditions, with 75% of deaths related to sepsis. No patient developed neurologic symptoms consistent with cerebral demyelination at any point during the 6-month follow-up period. LIMITATIONS: Lack of a comparison group and follow-up neuroimaging studies. Number of cases is too small to provide definitive assessment of the safety of this protocol. CONCLUSIONS: 3% sodium chloride solution was effective in reversing the symptoms of hyponatremic encephalopathy in the emergency department without producing neurologic injury related to cerebral demyelination on long-term follow-up in this case series.

Diabetic Ketoacidosis in Type 1 Diabetes Onset in Latin American Children.

OBJECTIVE: To describe the patterns of diabetic ketoacidosis (DKA) occurrence in children newly diagnosed with type 1 diabetes (T1DM) across several Latin American pediatric diabetes centers from 2018 to 2022. METHODS: A retrospective chart review included children under 18 with new-onset T1DM from 30 Latin American pediatric diabetes centers (Argentina, Chile, and Peru) between 30 December 2018 and 30 December 2022. Multiple logistic regression models examined the relationships between age, gender, medical insurance, BMI, and DKA at new-onset T1DM. As far as we know, there are no large studies in Latin American countries exploring the patterns of DKA in new-onset T1DM. RESULTS: A total of 2,026 (983 females) children, median age 9.12 (5.8 -11.7) years with new-onset-T1DM were included. Approximately 50% had no medical insurance. Mean glucose values were 467 mg/dL, pH 7.21, bicarbonate 13 mEq/L, HbA1c 11.3%, and BMI 18. The frequency of DKA was 1,229 (60.7%), out of which only 447 (36%) were severe. There was a significant decrease in the frequency of DKA as age increased: 373 (70.2%) in children under 6, 639 (61.6%) in those between 6 and 12, 217 and (47.5%) in those over 12. Children with medical insurance (58.8%) had a significantly lower frequency of DKA than those without (62.7%). The multiple logistic regression models showed that DKA was significantly and inversely associated with age [OR, 0.72 (95% CI 0.60-0.86)], BMI [OR, 0.95 (95% CI 0.92-0.99)], and medical insurance [OR, 0.75 (95% CI 0.60-0.94)] adjusted for sex. CONCLUSION: Latin American children with new-onset T1DM exhibited a substantial occurrence of DKA. Younger ages and the lack of medical insurance were significantly associated with DKA in new-onset T1DM.

Pharmacokinetic and pharmacodynamic study of three products of epoetin alfa as single subcutaneous dose in healthy volunteers.

Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980s and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40 000 IU of Eprex/Erypo® and Hemax® PFS. This clinical trial was conceived following an open-label, randomized, three-way three-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. To analyze similarity between Hemax® PFS and the innovator product, Eprex®, area under the curve (AUC) and Cmax of both products have been compared. The 90% CI lower limit for the geometric mean ratios was higher than 80% for any comparisons, and the 90% CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. The comparison between Hemax® PFS and Eprex® resulted in similar 90% CI for Cmax , AUC(0-120 h) and AUC(0-inf) ratios, all of them within the 80-125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with Tmax close to 15 h), absorption extent, and elimination (with an elimination half-life close to 25-30 h for each formulation).

Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death.

Autophagy has recently elicited significant attention as a mechanism that either protects or promotes cell death, although different autophagy pathways, and the cellular context in which they occur, remain to be elucidated. We report a thorough cellular and biochemical characterization of a novel selective autophagy that works as a protective cell response. This new selective autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration to sequester and degrade potentially deleterious activated zymogen granules. We have coined the term "zymophagy" to refer to this process. The autophagy-related protein VMP1, the ubiquitin-protease USP9x, and the ubiquitin-binding protein p62 mediate zymophagy. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. Zymophagy is activated by experimental pancreatitis in genetically engineered mice and cultured pancreatic acinar cells and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. Together, these data reveal a novel selective form of autophagy mediated by the VMP1-USP9x-p62 pathway, as a cellular protective response.

Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells.

Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2-3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs.

Alerting network dysfunction in early multiple sclerosis.

The objective of this study is to assess attention in recently diagnosed relapsing-remitting multiple sclerosis patients. Twenty-seven patients with early multiple sclerosis and low clinical disability scores (EDSS<2) and 27 sex-, age-, and education-matched healthy controls underwent attention assessment using the Attentional Network Test, a computerized task designed to measure efficiency independently in 3 attentional networks (Alerting, Orienting and Executive Control). MS patients had significantly less efficiency in the Alerting network (p = .006). In contrast, in the Orienting and Executive Control networks, they did not differ from controls. A significant interaction between Alerting and Executive Control was also found in the MS patients (p = .007). Early relapsing-remitting multiple sclerosis particularly affects the Alerting domain of attention, whereas the Orienting and Executive Control domains are not affected.

Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template bleeding time in a single-center prospective study.

BACKGROUND: Patients with heightened platelet reactivity in response to antiplatelet agents are at an increased risk of recurrent ischemic events. However, there is a lack of diagnostic criteria for increased response to combined aspirin/clopidogrel therapy. The challenge is to identify patients at risk of bleeding. This study sought to characterize bleeding tendency in patients treated with aspirin and clopidogrel. PATIENTS/METHODS: In a single-center prospective study, 100 patients under long-term aspirin/clopidogrel treatment, the effect of therapy was assayed by template bleeding time (BT) and the inhibition of platelet aggregation (IPA) by light transmission aggregometry (LTA). Arachidonic acid (0.625 mmol/L) and adenosine diphosphate (ADP; 2, 4, and 8 µmol/L) were used as platelet agonists. RESULTS: Bleeding episodes (28 nuisance, 2 hematuria [1 severe], 1 severe proctorrhagia, 1 severe epistaxis) were significantly more frequent in patients with longer BT. Template BT ≥ 24 min was associated with bleeding episodes (28 of 32). Risk of bleeding increased 17.4% for each 1 min increase in BT. Correlation was found between BT and IPAmax in response to ADP 2 µmol/L but not to ADP 4 or 8 µmol/L. CONCLUSION: In patients treated with dual aspirin/clopidogrel therapy, nuisance and internal bleeding were significantly associated with template BT and with IPAmax in response to ADP 2 µmol/L but not in response to ADP 4 µmol/L or 8 µmol/L.

Protein expression in exocrine pancreatic diseases. Focus on VMP1 mediated autophagy.

The exocrine pancreas produces enzymes involved in the digestive process whereas endocrine pancreas mainly regulates glucose metabolism. Diseases of the exocrine pancreas are characterized by high morbidity and mortality. Acute pancreatitis is a painful disease in which pancreatic secretory proteins are prematurely activated causing the digestion of the gland. Pancreatic adenocarcinoma is one of the most malignant cancers due to its resistance to treatment, its late diagnosis and high capacity for metastasis. Autophagy is a catabolic process that aims at degrading cytoplasmic contents and damaged organelles, to preserve cell viability and homeostasis. VMP1 is a transmembrane protein that plays a key role in triggering autophagy and being part of the autophagosome membrane. A specific type of selective autophagy pathway called zymophagy protects the pancreas against self-digestion in the setting of acute pancreatitis by sequestering intracellularly activated zymogen granules. Mitophagy is also responsible for maintaining pancreatitis as a mild disease by preserving mitochondrial function. Dysregulation of these selective autophagic processes by pancreatitis itself constitutes a risk factor for development of severe disease. In pancreatic adenocarcinoma, VMP1 mediated autophagy promotes cancer cell survival and resistance to chemotherapy. Therefore, it is relevant to highlight a role for controlling VMP1 expression and targeting VMP1 molecular pathways to improve exocrine pancreatic diseases prognosis.

Association between hepcidin and type 2 diabetes markers in indigenous Argentinean children living at high altitude.

BACKGROUND: Hepcidin is a protein that regulates the metabolism of iron. In addition, a high iron load can cause insulin resistance and subsequent diabetes. OBJECTIVE: To investigate the association between hepcidin levels and glucose, insulin, lipids, HOMA-IR, and inflammatory markers, C reactive protein (CRP), ferritin, Lp (a), and leucocytes, in indigenous school children living at 4000 m above sea level. Data were collected cross-sectionally from the four schools in San Antonio de los Cobres (SAC). BMI, glucose, insulin, lipids, CRP, hemoglobin, leucocytes, iron, ferritin, transferrin, and hepcidin levels were obtained. RESULTS: Three hundred and seventy-six children (170 males) aged 9.6 ± 2.3 y were included. Fifty-five(15.2 %) children were underweight, 28 (7.4 %) overweight and 10 (2.7 %) obese. Univariate analysis showed a significant inverse correlation between hepcidin and glucose (r = -0.14) and HOMA-IR (r = -0.30). Furthermore, hepcidin was found to be directly and significantly correlated with Lp(a) (r = 0.18), leucocytes (r = 0.24,) CRP (r = 0.32), and ferritin (r = 0.32). Multiple linear regression analysis indicated that hepcidin was significantly and inversely associated with glucose and BMI and directly with Lp(a), CRP, leucocytes, and ferritin; adjusted for age and gender (R2 0.26). CONCLUSION: In this study, which included indigenous children living at high altitudes (4000 m), hepcidin was significantly and inversely associated with glucose and BMI and directly associated with inflammatory markers such as CRP, Lp(a), leucocytes, and ferritin, suggesting that hepcidin could be a reliable marker of future type 2 diabetes.

Ability of TyG Index as a Marker of Insulin Resistance in Argentinean School Children.

Objective: To determine if the triglycerides and glucose index (TyG) can be used as a marker for insulin resistance (IR) in Argentinean schoolchildren according to age and sex. Methods: Anthropometric data, blood glucose levels, lipid profiles, and insulin levels were measured. The TyG index was defined by Ln [fasting triglyceride (mg/dL)* fasting glucose (mg/dL)/2]. A comparison of the ability of TyG to identify children with IR was performed using receiver operating characteristic (ROC) curves and the area under the ROC (AUROC) curve. IR was defined as HOMA-IR > III quartile. Results: A total of 915 (528, 57.7% males) apparently healthy schoolchildren, aged 9.3 ± 2.2, were evaluated. The AUROC using the HOMA-IR > III quartile as the dichotomous variable showed that TyG was a fair marker to identify IR (0.65, 95% CI, 0.61-0.69; p < 0.01). There was a significantly higher TyG AUROC in males (0.69, 95% CI, 0.63-0.75; p < 001) than in females (0.60, 95% CI, 0.54-0.66; p < 0.01). When children were divided according to age into two groups (5.0-9.9 and 10.0-14.9-year-olds); younger children (0.64, 95% CI, 0.58-0.69; p < 0.011) and older children (0.62, 95% CI, 0.55-0.68; p = 0.01) had a similar and fair AUROC. However, when children were divided by age and sex, females older than ten had a non-significant AUROC (0.53, 95% CI, 0.42-0.63; p = 0.61). The TyG index compared with HOMA-IR had low sensitivity and specificity, ranging from 0.62 to 0.56. Conclusion: The TyG index had a fair AUROC with low sensitivity and specificity, indicating poor discrimination in identifying IR in apparently healthy Argentinean children. The ability to use TyG for screening purposes seems limited in Argentinean schoolchildren.

Cost-effectiveness of a hypertension management programme in an elderly population: a Markov model.

BACKGROUND: Mounting evidence shows that multi-intervention programmes for hypertension treatment are more effective than an isolated pharmacological strategy. Full economic evaluations of hypertension management programmes are scarce and contain methodological limitations. The aim of the study was to evaluate if a hypertension management programme for elderly patients is cost-effective compared to usual care from the perspective of a third-party payer. METHODS: We built a cost-effectiveness model using published evidence of effectiveness of a comprehensive hypertension programme vs. usual care for patients 65 years or older at a community hospital in Buenos Aires, Argentina. We explored incremental cost-effectiveness between groups. The model used a life-time framework adopting a third-party payer's perspective. Incremental cost-effectiveness ratio (ICER) was calculated in International Dollars per life-year gained. We performed a probabilistic sensitivity analysis (PSA) to explore variable uncertainty. RESULTS: The ICER for the base-case of the "Hypertension Programme" versus the "Usual care" approach was 1,124 International Dollars per life-year gained. PSA did not significantly influence results. The programme had a probability of 43% of being dominant (more effective and less costly) and, overall, 95% chance of being cost-effective. DISCUSSION: Results showed that "Hypertension Programme" had high probabilities of being cost-effective under a wide range of scenarios. This is the first sound cost-effectiveness study to assess a comprehensive hypertension programme versus usual care. This study measures hard outcomes and explores robustness through a probabilistic sensitivity analysis. CONCLUSIONS: The comprehensive hypertension programme had high probabilities of being cost-effective versus usual care. This study supports the idea that similar programmes could be the preferred strategy in countries and within health care systems where hypertension treatment for elderly patients is a standard practice.

Cardiometabolic markers among Argentinean normal weight and overweight children with and without central obesity.

BACKGROUND: The association between central obesity and cardiometabolic complications justifies exploring its association in normal-weight and overweight/obese (OW/OB) schoolchildren. OBJECTIVE: To describe cardiometabolic markers in four groups according to BMI/WC categories: (i) normal weight with central OB; (ii) normal weight without central OB; (iii) OW/OB with central OB and (iv) OW/OB without central OB, in a sample of Argentinean schoolchildren. METHODS: A cross-sectional study of 1264 Argentinean schoolchildren (624 F), aged 9.5 ± 2.2 years was performed between November 2013 and 2015. Children's anthropometric measures, blood pressure (BP), glucose, lipids, and insulin were measured. Children were divided into four groups: (i) normal weight with central OB; (ii) normal weight without central OB; (iii) OW/OB with central OB and (iv) OW/OB without central OB. RESULTS: The prevalence of normal-weight children without central OB was 64.3% (796), normal weight with central OB 5% (66), OW/OB without central OB 11% (137), and OW/OB with central OB 21% (265). Normal weight with central OB had significantly higher triglycerides than normal-weight children without central OB (86 vs 70 mg/dL, respectively) and OW/OB children without central OB (81 vs 77 mg/dL). Multiple linear regression analyses showed that age, systolic BP, HDL-C, triglycerides, and maternal WC were significantly associated with children's WC; R2 = 0.50 as well as children's BMI; R2 = 0.37. CONCLUSION: This study found that children with central OB might be at future higher cardiometabolic risk than those without central OB independently of the presence of OW/OB. However, future longitudinal studies should be performed to confirm these findings.

Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions.

Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.

Association Between High Birth Weight and Later Central Obesity in 9-Year-Old Schoolchildren.

Background and Objective: Studies have suggested that birth weight (BW) is associated with body mass index (BMI), but its association with waist circumference (WC) in children should be further explored. To determine the association between central obesity (OB) in 9-year-old Argentinean schoolchildren and high BW. Methods: Schoolchildren (n = 2567, 1157 males) aged 8.7 ± 2.1 years from 10 elementary schools in 5 states in Argentina were examined between April 2017 and September 2019. Mothers submitted children's BW information. Pediatricians assessed anthropometric measures and blood pressure (BP). Central OB was defined for children as WC ≥90th percentile for age and gender. Results: The prevalence of overweight (OW) and OB (OW/OB) was 42.7% (1095) and that of central OB was 34.8% (856) in 9-year-old children. The prevalence of low BW (<2500 grams) and high BW (>4000 grams) was 6.6% (n = 169) and 7.4% (n = 190), respectively. BW (3.25 vs. 3.36 kg), weight (31.38 vs. 42.88 kg), BMI (17.29 vs. 22.25 kg/m2), BMI z-scores (z-BMI; 0.25 vs. 1.63), systolic BP (96 vs. 98 mmHg), and diastolic BP (59 vs. 60 mmHg) were significantly lower in 9-year-old children without central OB than in those with central OB, respectively. Multiple logistic regression analysis using central OB as the dependent variable showed that high BW [odds ratio, 1.98 (95% confidence interval 1.44-2.73)] was associated with central OB, adjusted for age, gender, and systolic and diastolic BP. Conclusion: This study shows that central OB in 9-year-old children was associated with high BW. Future longitudinal studies should be performed to confirm this finding. Clinical Registration number, IATIMET-08102019.