Prevalence of menopausal symptoms and severity related factors among mid-aged Paraguayan women as measured with the 10-item Cervantes Scale.

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.

Insights from the clinical phenotype of subjects with Laron syndrome in Ecuador.

The Ecuadorian cohort of subjects with LS has taught us valuable lessons since the late 80's. We have learned about migration of Sephardic Jews to our country, their isolation in remote hamlets and further inbreeding. These geographical, historical and social determinants induced dissemination of a growth hormone (GH) receptor mutation which widely occurred in those almost inaccessible villages. Consequently, the world's largest Laron syndrome (LS) cohort emerged in Loja and El Oro, two of the southern provinces of Ecuador. We have been fortunate to study these patients since 1987. New clinical features derived from GH insensitivity, their growth patterns as well as treatment with exogenous insulin-like growth factor I (IGF-I) have been reported. Novel biochemical characteristics in the field of GH insensitivity, IGFs, IGF binding proteins (BP) and their clinical correlates have also been described. In the last few years, studies on the morbidity and mortality of Ecuadorian LS adults surprisingly demonstrated that despite obesity, they had lower incidence of diabetes and cancer than their relatives. These events were linked to their metabolic phenotype of elevated but ineffective GH concentrations and low circulating IGF-I and IGFBP-3. It was also noted that absent GH counter-regulation induces a decrease in insulin resistance (IR), which results in low but highly efficient insulin levels which properly handle metabolic substrates. We propose that the combination of low IGF-I signaling, decreased IR, and efficient serum insulin concentrations are reasonable explanations for the diminished incidence of diabetes and cancer in these subjects.

Antenatal and Perioperative Mechanisms of Global Neurological Injury in Congenital Heart Disease.

Congenital heart defects (CHD) is one of the most common types of birth defects. Thanks to advances in surgical techniques and intensive care, the majority of children with severe forms of CHD survive into adulthood. However, this increase in survival comes with a cost. CHD survivors have neurological functioning at the bottom of the normal range. A large spectrum of central nervous system dysmaturation leads to the deficits seen in critical CHD. The heart develops early during gestation, and CHD has a profound effect on fetal brain development for the remainder of gestation. Term infants with critical CHD are born with an immature brain, which is highly susceptible to hypoxic-ischemic injuries. Perioperative blood flow disturbances due to the CHD and the use of cardiopulmonary bypass or circulatory arrest during surgery cause additional neurological injuries. Innate patient factors, such as genetic syndromes and preterm birth, and postoperative complications play a larger role in neurological injury than perioperative factors. Strategies to reduce the disability burden in critical CHD survivors are urgently needed.

Polymorphism of the THOC5 of the transcription/export multiprotein complex and its correlation with the lipid and metabolic profile in middle-aged women.

The transcription/export complex (TREX) is formed by a core called THO. These are necessary for the transcription and packaging of messenger RNA and its subsequent nuclear exportation. Studies have correlated THO-specific polymorphisms with abnormalities of HDL-C metabolism. To correlate lipid and metabolic parameters with the genetic variants of the rs8135828 polymorphism of the THOC5 gene in middle-aged women. DNA was extracted from the whole blood of 183 women aged 40-65 and tested for the rs8135828 polymorphism of the THOC5 gene using real-time PCR. HDL-C, LDL-C, triglyceride, and total cholesterol levels, as well as other metabolic parameters, were correlated with the polymorphism genotypes: GG, AG, and AA. Mean age of women was 50.6 ± 6.3 years, 54.6% were postmenopausal and 16.4% had the metabolic syndrome. GG was the most frequently determined genotype (62.3%). There were no differences in lipid levels according to genotypes; although there was a trend for lower HDL-C levels for the AA and AG + AA genotypes. Those with the AG and AG + AA genotypes displayed significantly higher glucose levels (p = .02 and p = .002, respectively); with a trend toward a higher metabolic syndrome prevalence and increased abdominal perimeters in both variants (AG and AG + AA). The AG genotype was related to higher glucose levels but not with abnormal lipid parameters. There is a need for more research in this regard.

The use of information and communication technologies in Latin American dentists: a cross-sectional study from Ecuador.

BACKGROUND: The use of information and communication technologies (ICTs) provide the tools for enabling fast and reliable real-time communications, as well as the transfer of information between dental professionals and their patients. However, little is known about the frequency and preference of ICTs among Latin-American dentists. Our study aims to fill this gap by assessing different aspects related to ICTs, mainly the frequency of use, perceptions, and barriers among Ecuadorian dentists. METHODS: An anonymous, cross-sectional survey-based study was conducted among 342 Ecuadorian dentists. The final questionnaire included 13 items related to the frequency of use, perceptions, and barriers of ICTs. Bivariate analysis was performed by using chi-squared testing to explore the association between the independent variables and the intended use of ICTs, as well as to characterize the perceptions and barriers related to ICTs. RESULTS: In general, most participants reported the use of ICTs to communicate with colleagues (99.7%), and patients (96.2%), while only 63.5% reported using ICTs to obtain academic information in their daily practice. WhatsApp was rated as the most used ICT for communicating with colleagues and patients. A majority of participants considered that ICTs can be useful for facilitating continuing dental education (92.1%), searching new work opportunities (91.5%), promoting health (90.1%), working with colleagues and other health professionals (91.2%), promoting their professional services (90.6%), and for resolving clinical cases (87.7%). On the subject of barriers, privacy and security concerns about personal and/or patient information was the biggest concern among dentists (65%), followed by lack of time to learn how to use and/or use ICTs (48%), lack of mobile internet access (28.1%), and lack of internet access at work (24.9%). CONCLUSION: In our study, we found that Ecuadorian dentists had a high usage rate of ICTs, mainly for communicating with other colleagues and patients, while the academic use of technology remains a comparatively underused application. Most of the participants surveyed had a positive perception towards ICTs, while privacy and security concerns were identified as the main barrier. Older age was associated with a less favourable perception toward ICTs, as well as an increased likelihood of reporting barriers related to the use of technology.

The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia.

AIM: Despite advances in perinatal management, there is a flat trend in incidences of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants. The main feature of BPD development in preterm infants is an imbalance between increased exposure to free radicals and inadequate antioxidant defences. We investigated the associations between BPD and lipid hydro-peroxide (LOOH) and glutathione (GSH) concentrations in bronchoalveolar lavage fluid (BALF). METHODS: In this prospective study, BALF samples were collected from 44 preterm infants with RDS and oxidative stress markers were measured in 11 with BPD and 33 controls without BPD. RESULTS: LOOH levels were significantly higher (p < 0.01) in the BPD group (median 16.35; 25th-75th centile 13.75-17.05 nmol/mL) than in the no BPD group (median 13.18; 25th-75th centile 12.92-13.63 nmol/mL). Conversely, GSH levels were significantly lower in the BPD group (p < 0.01) (median 11.52; 25th-75th centile 6.95-13.85 µmol/mg) than the no BPD group (median: 18.69; 25th-75th centile: 13.89-23.64 µmol/mg). Multiple regression analysis showed significant correlations between BPD and mechanical ventilation time (p < 0.01) and LOOH levels (p < 0.05). CONCLUSION: Early LOOH level increases in preterm infants developing BPD suggest that lung biochemical monitoring of sick infants might be possible and BPD could be predicted early by evaluating biomarkers.

Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in the placenta of pregnancies complicated with preeclampsia.

BACKGROUND: Preeclampsia has been related to single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate reductase (MTHFR) gene; however, data regarding the placenta are still lacking. OBJECTIVE: To determine the frequency of C677T and A1298C SNPs of the MTHFR gene in the placenta of preeclamptic pregnancies and healthy controls. METHODS: Genotyping of C677T and A1298C polymorphisms of the MTHFR gene using RFLP-PCR was performed to the placenta of 100 gestations (n = 50 complicated with preeclampsia and n = 50 normal controls matched for parity and maternal age). RESULTS: Gestational age at birth and neonatal and placental weight were significantly lower in women with preeclampsia as compared to controls. The TT genotype of the C677T polymorphism was threefold more prevalent in preeclamptic placentas as compared to the placenta of controls (24.0% versus 8.0%, p = 0.001). Upon pooled analysis (n = 100), placental and neonatal weights were significantly lower in placentas displaying this genotype (TT, C677T) as compared with the CC genotype. CONCLUSION: This study found that the frequency of the TT mutant genotype of the C677T polymorphism was higher in the placenta of pregnancies complicated with preeclampsia. There is a need for further research in this matter.

Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia.

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 whole-genome 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.

Cerebellar cytokine expression in a rat model for fetal asphyctic preconditioning and perinatal asphyxia.

Asphyctic brain injury is a major cause of neuronal inflammation in the perinatal period. Fetal asphyctic preconditioning has been shown to modulate the cerebral inflammatory cytokine response, hereby protecting the brain against asphyctic injury at birth. This study was designated to examine the effects of perinatal asphyxia and fetal asphyctic preconditioning on the inflammatory cytokine response in the cerebellum. Fetal asphyxia was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global perinatal asphyxia was induced by placing the uterine horns in saline for 19 min. Pro- and anti-inflammatory cytokine expression were assessed by real-time PCR and immunohistochemistry in cerebella of newborn rats. We found that tumor necrosis factor alpha and interleukin-10 mRNA were increased 12 h after fetal asphyxia, while the inflammatory cytokine response was decreased 96 h postfetal asphyxia. When applied as preconditioning stimulus, fetal asphyxia attenuates the cerebellar cytokine response. These results indicate that sublethal fetal asphyxia may protect the cerebellum from perinatal asphyxia-induced damage via inhibition of inflammation.

Exploring the role of information and communication technologies in allergic rhinitis in specialist centers: Patient perspectives on usefulness, value, and impact on healthcare.

INTRODUCTION: Information and communication technologies (ICTs) improve patient-centered care and are routinely used in Allergic Rhinitis (AR), but patients' preferences and attitudes are unexplored. This study examines AR-related information preferences and ICT use by AR patients. METHODS: A survey-based cross-sectional study was carried out in Ecuador from July to September 2019 in seven centers of reference for allergic disease. Participants were 18 years or older, diagnosed with AR and had access to ICT and the Internet. Descriptive and binomial logistic regressions were performed. A value of less than 0.05 was considered statistically significant. RESULTS: 217 patients were included. 47% (n = 102) used ICTs to learn about AR, of which 38.2% (n = 83) found it useful. Most of participants (75%, n = 164) did not think that ICTs reduce their need to see a doctor. Individuals with poorer quality of life were more likely to utilize ICTs to contact their doctor (OR 1.27, 95% CI 1.04-1.55), and more likely to be interested in AR-related content (OR 1.23, 95% CI 1.00-1.52). Patients with long-term AR or other allergies were less likely to use ICTs (OR 0.92 and OR 0.40 respectively). Higher education and lower quality of life may increase AR apps adoption (OR 4.82, 95% CI 1.11-21.00). Academic preparation five-fold increased ICT use for health provider communication (OR 5.29, 95% CI 1.18-23.72). Mild-persistent AR enhanced the probabilities of using ICTs to share experiences and communicate with other patients (OR 12.59, 95% CI 1.32-120.35). CONCLUSIONS: Our study emphasizes the importance of tailoring digital resources to patient needs by considering factors such as quality of life, education, and specific subgroups within the AR patient population. Additionally, the findings suggest that while ICTs can play a valuable role in patient education and support, they should complement, rather than replace, traditional medical care for many AR patients.

Fetal asphyxia induces acute and persisting changes in the ceramide metabolism in rat brain.

Fetal asphyctic preconditioning, induced by a brief episode of experimental hypoxia-ischemia, offers neuroprotection to a subsequent more severe asphyctic insult at birth. Extensive cell stress and apoptosis are important contributing factors of damage in the asphyctic neonatal brain. Because ceramide acts as a second messenger for multiple apoptotic stimuli, including hypoxia/ischemia, we sought to investigate the possible involvement of the ceramide pathway in endogenous neuroprotection induced by fetal asphyctic preconditioning. Global fetal asphyxia was induced in rats by clamping both uterine and ovarian vasculature for 30 min. Fetal asphyxia resulted in acute changes in brain ceramide/sphingomyelin metabolic enzymes, ceramide synthase 1, 2, and 5, acid sphingomyelinase, sphingosine-1-phosphate phosphatase, and the ceramide transporter. This observation correlated with an increase in neuronal apoptosis and in astrocyte number. After birth, ceramide and sphingomyelin levels remained high in fetal asphyxia brains, suggesting that a long-term regulation of the ceramide pathway may be involved in the mechanism of tolerance to a subsequent, otherwise lethal, asphyctic event.

Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep.

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.

Fetal brain genomic reprogramming following asphyctic preconditioning.

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.

Elevated Activin A urine levels are predictors of intraventricular haemorrhage in preterm newborns.

AIM: Intraventricular haemorrhage (IVH) is the most common variety of cerebral haemorrhage and cause of neurological disabilities in preterm newborns. We evaluated the usefulness of urine Activin A concentrations for the early detection of perinatal IVH. METHODS: We conducted a case-control study on 100 preterm newborns (20 with IVH and 80 without IVH) in whom urine Activin A was measured at five predetermined time-points in the first 72 h after birth. IVH diagnosis and the extension of the lesion were performed by ultrasound scanning within the first 72 h and at 1 week after birth, respectively. RESULTS: Urine Activin A in infants who developed IVH was significantly higher than in controls at all monitoring time-points (p < 0.01 for all), increasing progressively from first urination to 24 h when it reached the highest peak (p < 0.001). At a cut-off 0.08 ng/L, at the first void, Activin A sensitivity and specificity were 68.7% (CI: 41.3-89%) and 84.5% (CI: 75-91.5%). CONCLUSION: Activin A measurements in urine soon after birth can constitute a promising tool for identifying preterm infants at risk of IVH.

Urine S100 BB and A1B dimers are valuable predictors of adverse outcome in full-term asphyxiated infants.

AIM: To investigate whether S100A1B and BB dimers are predictors of early perinatal death in newborns with perinatal asphyxia (PA). METHODS: The study compared 38 full-term newborns with PA [neonatal death n = 11; hypoxic ischaemic encephalopathy (HIE): n = 27] with a control group of 38 healthy infants. Clinical and laboratory parameters were recorded at eight time points and urine collected for S100B assessment. Multivariate analysis was performed in order to analyse the influence of various clinical parameters on the occurrence of neonatal death. RESULTS: A1B and BB in PA nonsurvivor infants were significantly higher (p < 0.001) than in controls at all monitoring time points. BB at first void (cut-off>42 ng/L) was the best predictor of early neonatal death (p < 0.05) of all the clinical and laboratory parameters studied. CONCLUSION: These results suggest that S100s are valuable predictors of adverse outcome in PA infants. It is also suggested that these biomarkers be used in daily clinical practice, due to their low cost and stress, reproducibility and the possibility of longitudinal monitoring.

Tidal volume optimization and heart rate response during stabilization of very preterm infants.

AIM: To verify the added value of respiratory function monitor (RFM) to assess ventilation and the heart rate (HR) changes during stabilization of preterm infants. METHODS: Preterm infants <32 weeks' gestation, bradycardic at birth and in need for positive pressure ventilation (PPV) were included. The first 15 min of stabilization was monitored with RFM. Three time points were identified according to HR values (T0 the start of mask PPV; T1 the HR rise >100 bpm; T2 the delivery of the last PPV). For each inflation, PIP, PEEP, MAP, expired tidal volume/kg (Vte/kg), and mean dynamic compliance (Cdyn) were analyzed. RESULTS: PIP and MAP values were significantly higher at T1 (27.09 ± 5.37 and 17.47 ± 3.85 cmH2 O) and at T2 (24.7 ± 3.86 and 15.2 ± 3.78 cmH2 O) compared to T0 (24.05 ± 2.27 and 15.85 ± 2.77 cmH2 O). PEEP at T1 was significantly higher (6.27 ± 2.17 cmH2 O) compared to T2 (5.61 ± 1.50 cmH2 O). Vte/kg showed significantly lower T0 values (3.57 ± 2.14 ml/kg) compared to T1 (6.18 ± 2.51 ml/kg) and T2 (6.89 ± 2.40 ml/kg). There was a significant effect of time on Cdyn. CONCLUSIONS: A clear correspondence between HR rise and adequate Vte/kg during stabilization of very preterm infants was highlighted. RFM might be useful to tailor ventilation, following real-time changes of lung compliance.

Cancer in growth hormone excess and growth hormone deficit.

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 insulin-like 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 hypo-insulinemia, 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.

Cancer in Ecuadorian subjects with Laron syndrome (ELS).

Meta-analyses from 2018-2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.

Divergent metabolic phenotypes in two genetic syndromes of low insulin secretion.

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.

Intra-amniotic LPS and antenatal betamethasone: inflammation and maturation in preterm lamb lungs.

The proinflammatory stimulus of chorioamnionitis is commonly associated with preterm delivery. Women at risk of preterm delivery receive antenatal glucocorticoids to functionally mature the fetal lung. However, the effects of the combined exposures of chorioamnionitis and antenatal glucocorticoids on the fetus are poorly understood. Time-mated ewes with singleton fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) either preceding or following maternal intramuscular betamethasone 7 or 14 days before delivery, and the fetuses were delivered at 120 days gestational age (GA) (term = 150 days GA). Gestation matched controls received intra-amniotic and maternal intramuscular saline. Compared with saline controls, intra-amniotic LPS increased inflammatory cells in the bronchoalveolar lavage and myeloperoxidase, Toll-like receptor 2 and 4 mRNA, PU.1, CD3, and Foxp3-positive cells in the fetal lung. LPS-induced lung maturation measured as increased airway surfactant and improved lung gas volumes. Intra-amniotic LPS-induced inflammation persisted until 14 days after exposure. Betamethasone treatment alone induced modest lung maturation but, when administered before intra-amniotic LPS, suppressed lung inflammation. Interestingly, betamethasone treatment after LPS did not counteract inflammation but enhanced lung maturation. We conclude that the order of exposures of intra-amniotic LPS or maternal betamethasone had large effects on fetal lung inflammation and maturation.