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The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulinlike growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypoinsulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events. [ABSTRACT FROM AUTHOR]

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Background: Non-invasive ventilation (NIV) significantly changed the management of respiratory distress syndrome (RDS) in preterm infants. Further perspectives for neonatologists regard the assessment of different NIV strategies in terms of availability, effectiveness, and failure. Objective: The aim of the present study is to evaluate the effectiveness of three different NIV strategies: nasal continuous positive airway pressure (N-CPAP), nasal synchronized intermittent positive pressure ventilation (N-SIPPV), and nasal bilevel-CPAP (BiPAP), as first intention treatment for RDS in very low birth-weight infants (VLBW). Methods: A multicenter retrospective study was conducted in three neonatal intensive care unit (NICUs) that enrolled 191 VLBW infants complicated by RDS, who received, as first intention treatment for RDS, three different NIV approaches (N-CPAP: n = 66; N-SIPPV: n = 62, BiPAP: n = 63). We evaluated the performance of different NIV strategies by primary (failure within the first 5 d of life) and some selected secondary end-points. Results: The incidence of NIV failure was significantly higher in the N-CPAP group (22/66) versus N-SIPPV/BiPAP groups (11/62; 11/63) (p < .05 for both), while no difference was observed between N-SIPPV and BiPAP groups. Moreover, no differences were found between the three groups regarding secondary outcomes. Conclusions: The present study shows that first intention N-SIPPV/BiPAP, as NIV support, augment the beneficial effects of N-CPAP contributing to a reduced risk of failure in VLBW infants complicated by RDS. Data open up to further RCTs on a wider population to evaluate NIV effectiveness on long-term outcomes. [ABSTRACT FROM AUTHOR]

Hypoxia-ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic-ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia-ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects. [ABSTRACT FROM AUTHOR]

Background Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and wholegenome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. Results We observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. Conclusions This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic mechanisms are likely to play a role in preconditioning-induced neuroprotection. [ABSTRACT FROM AUTHOR]

Background: Fetal asphyctic (FA) preconditioning is effective in attenuating brain damage incurred by a subsequent perinatal asphyctic insult. Unraveling mechanisms of this endogenous neuroprotection, activated by FA preconditioning, is an important step towards new clinical strategies for asphyctic neonates. Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of preconditioning. Therefore we investigated whole genome differential gene expression in the preconditioned rat brain. FA preconditioning was induced on embryonic day 17 by reversibly clamping uterine circulation. Male control and FA offspring were sacrificed 96 h after FA preconditioning. Whole genome transcription was investigated with Affymetrix Gene1.0ST chip. Results: Data were analyzed with the Bioconductor Limma package, which showed 53 down-regulated and 35 up-regulated transcripts in the FA-group. We validated these findings with RT-qPCR for adh1, edn1, leptin, rdh2, and smad6. Moreover, we investigated differences in gene expression across different brain regions. In addition, we performed Gene Set Enrichment Analysis (GSEA) which revealed 19 significantly down-regulated gene sets, mainly involved in neurotransmission and ion transport. 10 Gene sets were significantly up-regulated, these are mainly involved in nucleosomal structure and transcription, including genes such as mecp2. Conclusions: Here we identify for the first time differential gene expression after asphyctic preconditioning in fetal brain tissue, with the majority of differentially expressed transcripts being down-regulated. The observed down-regulation of cellular processes such as neurotransmission and ion transport could represent a restriction in energy turnover which could prevent energy failure and subsequent neuronal damage in an asphyctic event. Up-regulated transcripts seem to exert their function mainly within the cell nucleus, and subsequent Gene Set Enrichment Analysis suggests that epigenetic mechanisms play an important role in preconditioning induced neuroprotection. [ABSTRACT FROM AUTHOR]

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI. Methods: Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis. Results: Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function. Conclusions: Our data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE. [ABSTRACT FROM AUTHOR]

Background: Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult. Methods: In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines. Results: Prenatally, FA induced acute downregulation in IL-1ß, TNF-a and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls. Conclusions: FA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy. [ABSTRACT FROM AUTHOR]

COVID-19, a highly infectious disease, caused a worldwide pandemic in early 2020. According to the World Health Organization (WHO), COVID-19 has resulted in approximately 774 million cases and around 7 million deaths. The effects of COVID-19 are well known; however, there is a lack of information on the pathophysiological mechanisms underlying the symptoms that comprise Post-Acute COVID-19 Syndrome (PACS) or Long COVID-19. Neurological sequelae are common, with cognitive dysfunction being one of the foremost symptoms. Research indicates that elevated inflammatory levels and increased oxidative stress may play a role in the etiology and severity of PACS. Treatment options are extremely limited, and there is no consensus among the medical and scientific communities on how to manage the disease. Nevertheless, many scientists advocate for using antioxidants for symptomatic therapy and cognitive behavior therapy for supportive care. Additionally, current research aims to ameliorate several aspects of the inflammatory cascade. This review highlights the intracellular and extracellular pathways crucial to the neurological manifestations of PACS, providing valuable information for healthcare professionals and scientists. Given the complex nature of PACS, understanding these pathways is essential for developing new treatment options. Assessing PACS is challenging, and reviewing current therapeutic options while proposing a triad of potential therapeutic elements will add value to clinical assays and guidelines. Current therapeutic strategies, such as antioxidants/vitamin supplements, neurogenic stem cell therapy, and mitochondrial therapy, could be combined to enhance their effectiveness. Future research should focus on validating these approaches and exploring new avenues for the effective treatment of PACS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Andrés Caicedo is the scientific founder and advisor of Dragon Biomed, an entrepreneurial initiative at the Universidad San Francisco de Quito (USFQ). He also serves as a scientific advisor in the Research and Development department of Luvigix. In these roles, he provides scientific guidance and expertise but does not participate in the decision-making processes or operational activities of either company., (© 2024 Zambrano et al.)

Objective: To determine the prevalence of menopausal symptoms and factors related to severity in mid-aged women. Methods: Cross-sectional study in which 216 urban-living women from Asunción-Paraguay (40-60 years) were surveyed with the 10 item Cervantes Scale (CS-10) and a general questionnaire (personal and partner data). Results: Median (interquartile range [IQR]) age of the sample was 48 [9] years, 48.1% were postmenopausal, 8.8% used menopausal hormone therapy, 39.4% psychotropic drugs, 43.5% had hypertension, 6.5% diabetes, 51.9% abdominal obesity, and 89.3% had a partner ( n  = 193). A history of sexual abuse was present in 2.8%. Median total CS-10 score was 8.5 [9.75]. Overall, 93.3% (180/193) of women having a partner were sexually active, with a median coital frequency of 8 times per month. According to the CS-10, the three most prevalent menopausal symptoms were: aching in muscles and/or joints (70.8%), anxiety and nervousness (70.8%) and hot flashes/night sweats (54.2%). Factors associated with higher CS-10 scores were: female age and educational level, marital status, menopausal status, and marital sexual aspects. Partner educational level was inversely correlated (rho Spearman coefficient) with CS-10 total scores. However, multiple linear regression analysis found that higher total CS-10 scores (more severe menopausal symptoms) negatively correlated to coital frequency and positively correlated with peri- and postmenopausal status, parity, sedentary lifestyle and a history of sexual abuse. Conclusion: Menopausal symptoms in this mid-aged urban female Paraguayan sample were related to hormonal, sexual and other female aspects.

Aims: We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS)., Methods: Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP)., Results: Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP., Conclusions: A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)