Short-term neuropsychiatric outcomes and quality of life in COVID-19 survivors.

BACKGROUND: The general medical impacts of coronavirus (COVID-19) are increasingly appreciated. However, its impact on neurocognitive, psychiatric health and quality of life (QoL) in survivors after the acute phase is poorly understood. We aimed to evaluate neurocognitive function, psychiatric symptoms and QoL in COVID-19 survivors shortly after hospital discharge. METHODS: This was a cross-sectional analysis of a prospective study of hospitalized COVID-19 survivors followed up for 2 months after discharge. A battery of standardized instruments evaluating neurocognitive function, psychiatric morbidity and QoL (mental and physical components) was administered by telephone. RESULTS: Of the 229 screened patients, 179 were included in the final analysis. Amongst survivors, the prevalence of moderately impaired immediate verbal memory and learning was 38%, delayed verbal memory (11.8%), verbal fluency (34.6%) and working memory (executive function) (6.1%), respectively. Moreover, 58.7% of patients had neurocognitive impairment in at least one function. Rates of positive screening for anxiety, depression and post-traumatic stress disorder were 29.6%, 26.8% and 25.1%, respectively. In addition, 39.1% of the patients had psychiatric morbidity. Low QoL for physical and mental components was detected in 44.1% and 39.1% of patients respectively. Delirium and psychiatric morbidity were associated with neurocognitive impairment, and female gender was related with psychiatric morbidity. CONCLUSION: Hospitalized COVID-19 survivors showed a considerable prevalence of neurocognitive impairment, psychiatric morbidity and poor QoL in the short term. It is uncertain if these impacts persist over the long term.

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.

Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKß1. In addition, we used an RNAi strategy to silence the expression of the second AMPKß subunit in worms, namely aakb-2/AMPKß2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKß2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.

Stem cell paracrine actions in tissue regeneration and potential therapeutic effect in human endometrium: a retrospective study.

OBJECTIVE: Determining genetic and paracrine mechanisms behind endometrial regeneration in Asherman's syndrome and endometrial atrophy (AS/EA) patients after autologous CD133+ bone marrow-derived stem cell (CD133+ BMDSC) transplantation. DESIGN: Retrospective study using human endometrial biopsies and mouse models. SETTING: Fundación-IVI, IIS-La Fe, Valencia, Spain. SAMPLES: Endometrial biopsies collected before and after CD133+ BMDSC therapy, from eight women with AS/EA (NCT02144987) from the uterus of five mice with only left horns receiving CD133+ BMDSC therapy. METHODS: In human samples, haematoxylin and eosin (H&E) staining, RNA arrays, PCR validation, and neutrophil elastase (NE) immunohistochemistry (IHQ). In mouse samples, PCR validation and protein immunoarrays. MAIN OUTCOME MEASURES: H&E microscopic evaluation, RNA expression levels, PCR, and growth/angiogenic factors quantification, NE IHQ signal. RESULTS: Treatment improved endometrial morphology and thickness for all patients. In human samples, Jun, Serpine1, and Il4 were up-regulated whereas Ccnd1 and Cxcl8 were down-regulated after treatment. The significant decrease of NE signal corroborated Cxcl8 expression. Animal model analysis confirmed human results and revealed a higher expression of pro-angiogenic cytokines (IL18, HGF, MCP-1, MIP2) in treated uterine horns. CONCLUSIONS: CD133+ BMDSC seems to activate several factors through a paracrine mechanism to help tissue regeneration, modifying endometrial behaviour through an immunomodulatory milieu that precedes proliferation and angiogenic processes. Insight into these processes could bring us one step closer to a non-invasive treatment for AS/EA patients. TWEETABLE ABSTRACT: CD133+ BMDSC therapy regenerates endometrium, modifying the immunological milieu that precedes proliferation and angiogenesis.

Anastomotic leakage after colon cancer resection: does the individual surgeon matter?

AIM: Anastomotic leakage is one of the most feared complications after colonic resection. Many risk factors for anastomotic leakage have been reported, but the impact of an individual surgeon as a risk factor has scarcely been reported. The aim of this study was to assess if the individual surgeon is an independent risk factor for anastomotic leakage in colonic cancer surgery. METHOD: This was a retrospective analysis of prospectively collected data from patients who underwent elective resection for colon cancer with anastomosis at a specialized colorectal unit from January 1993 to December 2010. Anastomotic leaks were diagnosed according to standardized criteria. Patient and tumour characteristics, surgical procedure and operating surgeons were analysed. A logistic regression model was used to discriminate statistical variation and identify risk factors for anastomotic leakage. RESULTS: A total of 1045 patients underwent elective colon cancer resection with primary anastomosis. Anastomotic leakage occurred in 6.4% of patients. Ileocolic anastomosis had an anastomotic leakage rate of 7.2%, colo-colonic/colorectal anastomosis 5.2% and ileorectal anastomosis 12.7%, with intersurgeon variability. The independent risk factors associated with anastomotic leakage were the use of perioperative blood transfusion (OR 2.83, CI 1.59-5.06, P < 0.0001) and the individual surgeon performing the procedure (OR up to 8.44, P < 0.0001). CONCLUSION: In addition to perioperative blood transfusion, the individual surgeon was identified as an important risk factor for anastomotic leakage. Efforts should be made to reduce performance variability amongst surgeons.

Obstetric and neonatal outcome of pregnancies fathered by males on immunosuppression after solid organ transplantation.

Immunosuppressive drugs may influence spermatogenesis, but little is known about outcome of pregnancies fathered by transplanted males. We estimated risk of adverse outcomes in pregnancies (with data after the first trimester) fathered by males that had undergone organ transplantation and were treated with immunosuppression. A population-based study, linking data from the Norwegian transplant registry and the Medical Birth Registry of Norway during 1967-2009 was designed. All Norwegian men undergoing solid organ transplantation were included. Odds ratios for major malformations, preeclampsia, preterm delivery (<37 weeks) and small-for-gestational-age were obtained using logistic regression. A total of 2463 transplanted males, fathering babies of 4614 deliveries before and 474 deliveries after transplantation were identified. The risk of preeclampsia was increased (AOR: 7.4, 95% CI: 1.1-51.4,) after transplantation compared to prior to transplantation. No increased risk was found for congenital malformations or other outcomes when compared with pregnancies before transplantation or with the general population (2 511 506 births). Our results indicate an increased risk of preeclampsia mediated through the transplanted and immunosuppressed father. Importantly, no increased risk was found for other adverse obstetric outcomes or malformations, which may reassure male transplant recipients planning to father children.

Solar radiation and water vapor pressure to forecast chickenpox epidemics.

The clear seasonality of varicella infections in temperate regions suggests the influence of meteorologic conditions. However, there are very few data on this association. The aim of this study was to determine the seasonal pattern of varicella infections on the Mediterranean island of Mallorca (Spain), and its association with meteorologic conditions and schooling. Data on the number of cases of varicella were obtained from the Network of Epidemiologic Surveillance, which is composed of primary care physicians who notify varicella cases on a compulsory basis. From 1995 to 2012, varicella cases were correlated to temperature, humidity, rainfall, water vapor pressure, atmospheric pressure, wind speed, and solar radiation using regression and time-series models. The influence of schooling was also analyzed. A total of 68,379 cases of varicella were notified during the study period. Cases occurred all year round, with a peak incidence in June. Varicella cases increased with the decrease in water vapor pressure and/or the increase of solar radiation, 3 and 4 weeks prior to reporting, respectively. An inverse association was also observed between varicella cases and school holidays. Using these variables, the best fitting autoregressive moving average with exogenous variables (ARMAX) model could predict 95 % of varicella cases. In conclusion, varicella in our region had a clear seasonality, which was mainly determined by solar radiation and water vapor pressure.

Can meteorological factors forecast asthma exacerbation in a paediatric population?

BACKGROUND: Asthma exacerbations attended in emergency departments show a marked seasonality in the paediatric age. This seasonal pattern can change from one population to another and the factors involved are poorly understood. OBJECTIVES: To evaluate the association between meteorological factors and schooling with asthma exacerbations in children attended in the paediatric emergency department of a district hospital. METHODS: We conducted a retrospective review of the medical records of children 5-14 years of age attended for asthma exacerbations during a 4-year period (2007-2011). Climatic data were obtained from a weather station located very close to the population studied. The number of asthma exacerbations was correlated to temperature, barometric pressure, relative humidity, rainfall, wind speed, wind distance, solar radiation, water vapour pressure and schooling, using regression analyses. RESULTS: During the study period, 371 children were attended for asthma exacerbations; median age was eight years (IQR: 6-11), and 59% were males. Asthma exacerbations showed a bimodal pattern with peaks in spring and summer. Maximum annual peak occurred in week 39, within 15 days from school beginning after the summer holidays. A regression model with mean temperature, water vapour pressure, relative humidity, maximum wind speed and schooling could explain 98.4% (p<0.001) of monthly asthma exacerbations. CONCLUSIONS: The combination of meteorological factors and schooling could predict asthma exacerbations in children attended in a paediatric emergency department.

Should IFN-γ, IL-17 and IL-2 be considered predictive biomarkers of acute rejection in liver and kidney transplant? Results of a multicentric study.

Acute rejection (AR) remains a major challenge in organ transplantation, and there is a need for predictive biomarkers. In the present multicenter study, we prospectively examined a series of biomarkers in liver and kidney recipients. Intracellular expression of IFN-γ, IL-17 and IL-2 and IL-17 soluble production were evaluated both pre-transplantation and post-transplantation (1st and 2nd week, 1st, 2nd and 3rd month). 142 transplant patients (63 liver/79 kidney) were included in the study. Twenty-eight recipients (14 liver/14 kidney) developed AR. Pre- and post-transplantation intracellular expression of %IFN-γ(+) in CD4(+)CD69(+) and in CD8(+)CD69(+) and soluble IL17 identified liver and kidney transplant patients at high risk of AR. Pre-transplantation, %IL-2(+) in CD8(+)CD69(+) also identified kidney patients at high risk. We constructed pre- and post-transplantation risk prediction models, based on a composite panel of biomarkers, which could provide the basis for future studies and will be a useful tool for the selection and adjustment of immunosuppressive treatments.

Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG).

BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.

Are hospitalizations for rotavirus gastroenteritis associated with meteorologic factors?

Local climatic factors might explain seasonal patterns of rotavirus infections, but few models have been proposed to determine the effects of weather conditions on rotavirus activity. Here, we study the association of meteorologic factors with rotavirus activity, as determined by the number of children hospitalized for rotavirus gastroenteritis on the Mediterranean island of Mallorca (Spain). We conducted a retrospective review of the medical records of children aged 0-5 years admitted for rotavirus gastroenteritis between January 2000 and December 2010. The number of rotavirus hospitalizations was correlated to temperature, humidity, rainfall, atmospheric pressure, water vapor pressure, wind speed, and solar radiation using regression and time-series techniques. A total of 311 patients were hospitalized for rotavirus gastroenteritis in the 11-year study period, with a seasonal pattern from December to June, and a peak incidence in February. After multiple regressions, weekly rotavirus activity could be explained in 82 % of cases (p < 0.001) with a one-week lag meteorologic model. Rotavirus activity was negatively associated to temperature and positively associated to atmospheric pressure, solar radiation, and wind speed. Temperature and solar radiation were the factors that contributed most to the model, with a peak rotavirus activity at 9 °C and 800 10KJ/m(2), respectively. In conclusion, hospitalization for rotavirus was strongly associated with mean temperature, but an association of rotavirus activity with solar radiation, atmospheric pressure, and wind speed was also demonstrated. This model predicted more than 80 % of rotavirus hospitalizations.

Specific IgE levels to Dermatophagoides pteronyssinus are associated with meteorological factors.

BACKGROUND: Dermatophagoides pteronyssinus specific IgE (sIgE) measurement is a major diagnostic test for the detection of sensitization to that allergen. METHODS: To investigate the effect of climate on the seasonal variations of D.pteronyssinus sIgE, we studied the tests performed in an insular population during a 10-year period. The association with meteorological factors was evaluated with multiple regression analyses. RESULTS: Of 24,879 tests performed for D. pteronyssinus sIgE, 16,719 (67.2%) were D. pteronyssinus sIgE positive; 24.5% were tested for asthma and 46.07% for rhinitis. D. pteronyssinus sIgE levels showed a seasonal pattern with an annual peak in November. In the multivariate analyses solar radiation (r = -0.94) and relative humidity (r = 0.86) were independent factors associated with D. pteronyssinus sIgE levels. The resulting model could explain 93% (p < 0.001) of D. pteronyssinus sIgE variability. CONCLUSIONS: Our population showed a seasonal pattern of D. pteronyssinus sIgE explained by relative humidity and solar radiation.

Epidemiology of hospitalization for acute bronchiolitis in children: differences between RSV and non-RSV bronchiolitis.

We study the clinical, management and outcome differences between respiratory syncytial virus (RSV) positive and negative bronchiolitis. A retrospective review of the medical records of children ≤ 2 years of age with acute bronchiolitis between January 1995 and December 2006 was done. There were 2,384 patients hospitalized for acute bronchiolitis, and 1,495 (62.7%) were RSV infections. Overall, hospitalization rate was 55/1,000 admissions. Mortality occurred in 0.08% of cases. Bronchiolitis due to RSV was more frequent from November to March (97%). RSV bronchiolitis had longer hospital stays (6 vs. 5 days, P<0.0001), higher risk of intensive care unit (ICU) admission (OR 2.7; 95%CI 1.87-3.9) and more oxygen use (OR 2.2; 95%CI 1.8-2.6). Infants < 2 months had longer median hospital stay (6 vs. 5 days, P <0.0001) and higher risk of ICU admission (OR 3.4; 95%CI 2.5-4.6). Prematures of < 32 gestational weeks, congenital heart disease, and atelectasis/condensation were the main risk factors for ICU admission in both RSV and non-RSV bronchiolitis. The introduction of palivizumab in prematures diminished hospitalization for RSV bronchiolitis, oxygen need, length of hospital stay and mechanical ventilation. In conclusion, this study supports that RSV bronchiolitis seems to be a more severe disease than that caused by other viruses.

How frequent is varicella-associated pneumonia in children?

Varicella is a frequent though mild infection in children, but it can cause important morbidity in adults. The most frequent complication in adults is varicella pneumonia. However, lower airway complications associated to varicella have been scarcely studied in children. We retrospectively reviewed the clinical records of the children hospitalized for varicella-associated pneumonia in the three public hospitals on the Island of Mallorca. We discovered that 17/213 (8%) children hospitalized for varicella were diagnosed of pneumonia. The rate of hospitalization for varicella complication due to pneumonia was 4.3 cases per 10,000 varicella infections. Only one patient was diagnosed of varicella pneumonia, which accounts for 0.3 cases per 10,000 varicella infections. Nine of 17 (53%) cases were classified as bacterial pneumonia. Statistical differences (p < 0.05) in the median time from rash (5.9 vs. 2.4 days) and fever (4.1 vs. 2.2 days) to admission were observed between bacterial and viral pneumonia. However, outcome differences measured by the median length of stay, need for oxygen, and admission to the intensive care unit were not observed. Varicella pneumonia is a very rare complication of varicella in children. Most of the lower airway infections in the course of varicella are associated to other co-infections.

Role of aeroallergen nasal challenge in asthmatic children.

BACKGROUND: The majority of allergic asthmatic patients are sensitised to several aeroallergens. Discrimination of the clinically relevant allergen is essential for the correct use of immunotherapy. OBJECTIVE: To investigate nasal challenge and its role in screening clinically relevant allergens in asthmatic children. METHODS: Aeroallergen nasal challenge was performed in five different groups of patients (asthma; asthma & rhinitis; rhinitis; atopic controls; and non-atopic controls). Differences between groups after challenge were evaluated by means of spirometry and acoustic rhinometry. RESULTS: Nasal challenge was performed in 125 patients, 25 per group. The positive nasal response of immediate type was recorded in 21 patients with asthma only (P<0.001), 18 with asthma and rhinitis (P<0.001), 19 with rhinitis (P<0.001), two atopic control patients and in no healthy control patients. However, no differences were observed between the asthma group and the groups with rhinitis symptoms. The risk of a positive challenge was much higher in the asthma without rhinitis group compared to atopic controls (OR 29.57; 95%CI: 5.47-159.97). CONCLUSION: Aeroallergen nasal challenge is a safe technique in asthmatic children and could be useful in establishing the clinically relevant allergen even in the absence of rhinitis.

Histologic Analysis of Testes from Prepubertal Patients Treated with Chemotherapy Associates Impaired Germ Cell Counts with Cumulative Doses of Cyclophosphamide, Ifosfamide, Cytarabine, and Asparaginase.

Cryopreservation of immature testicular tissue is an experimental strategy for the preservation of fertility in prepubertal boys that will be subjected to a gonadotoxic onset, as is the case of oncologic patients. Therefore, the objective of this study was to assess the impact of chemotherapeutic treatments on the testicular histologic phenotype in prepubertal patients. A total of 56 testicular tissue samples from pediatric patients between 0 and 16 years old (28 with at least one previous chemotherapeutic onset and 28 untreated controls) were histologically analyzed and age-matched compared. At least two 5-µm sections from testis per patient separated by a distance of 100 µm were immunostained for the germ cell marker VASA, the spermatogonial markers UTF1, PLZF, UCHL1, and SALL4, the marker for proliferative cells KI67, and the Sertoli cell marker SOX9. The percentage of tubule cross-sections positive for each marker and the number of positive cells per tubule cross-section were determined and association with the cumulative dose received of each chemotherapeutic drug was statistically assessed. Results indicated that alkylating agents, cyclophosphamide and ifosfamide, but also the antimetabolite cytarabine and asparaginase were associated with a decreased percentage of positive tubules and a lower number of positive cells per tubule for the analyzed markers. Our results provide new evidences of the potential of chemotherapeutic agents previously considered to have low gonadotoxic effects such as cytarabine and asparaginase to trigger a severe testicular phenotype, hampering the potential success of future fertility restoration in experimental programs of fertility preservation in prepubertal boys.

Nasogastric tube utilization after esophagectomy: an unnecessary gesture? / Uso de sonda nasogástrica en pacientes sometidos a esofaguectomía: ¿Un gesto innecesario?

INTRODUCTION: Nasogastric decompressive tube utilization has been accepted as one of the basic perioperative care measures after esophageal resection surgery. However, with the development of multimodal rehabilitation programs and without clear evidence to support their use, the systematic indication of this measure may be controversial. MATERIAL AND METHODS: Retrospective, descriptive and comparative study of patients who had undergone Ivor-Lewis esophagectomy in our center -from January 2015 to December 2018- with placement (Group S), or without placement (Group N) of a decompressive tube in gastroplasty during postoperative period. Epidemiological variables and differences between groups in post-surgical morbidity and mortality, hospital stay, onset of oral tolerance and the need for nasogastric tube placement were evaluated. RESULTS: A total of 43 patients were included in this study, with a median age of 61 years, being 86% male. 46.5% were hypertensive, 25.5% had lung disease and 16.3% had diabetes mellitus. The median length of hospital stay was 9 days in group S versus 11.5 days in group N, with no differences in the onset of oral tolerance. Anastomotic dehiscence rate was 5% and 0% respectively. The overall mortality was 2.3% in the first 90 days, without differences between the groups. Placement of nasogastric tube during postoperative period was required only in 1 patient (4.3%) of the group N. CONCLUSIONS: Non-use of nasogastric tube during postoperative period of an Ivor-Lewis esophagectomy is a safe measure, as it is not associated with a higher rate of complications or hospital stay. This fact may be able to improve patients' comfort and postoperative recovery.

Neuropsychological assessment and cortisol levels in biofluids from early Alzheimer's disease patients.

Cortisol dysregulation is proposed as a factor in the development of Alzheimer's disease (AD). AD patients can show high cortisol levels in prodromal phases of AD, early enough that neuropsychological alterations exist but activities of daily living remain unimpaired. Nevertheless, it is unknown if biofluid cortisol levels can have some AD predictive power together with neuropsychological assessment in prodromal stages in comparison with other cognitive disorders. In this work, an analytical method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) was applied to determine the cortisol levels in different biofluids (urine, plasma, saliva, cerebrospinal fluid). Early AD patients and non-AD patients recruited at out-patient neurological unit were classified from the standard cerebrospinal fluid biomarkers levels (ß-amyloid, tau, phosphorylated tau), and studied with an extensive neuropsychological assessment including global, neuropsychological, functional and affective scales. We used a logistic regression model to discriminate between the AD and non-AD groups. Higher plasma cortisol levels were found in the AD group than in the non-AD group (p < 0.001). Regarding neuropsychological evaluation, delayed memory was used as representative of the neuropsychological status, and lower scores were obtained in the AD group (p < 0.001). The prediction model, including plasma cortisol levels and delayed memory scores, achieved an AUC of 0.93, as well as a sensitivity of 97% and a specificity of 69.4%. In conclusion, plasma cortisol levels and delayed memory scores were specifically impaired in early AD, allowing the development of a new diagnostic model which could be employed as a very satisfactory screening system.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients.

The characterization of the epigenetic changes within the obesity-related adipose tissue will provide new insights to understand this metabolic disorder, but adipose tissue is not easy to sample in population-based studies. We aimed to evaluate the capacity of circulating leukocytes to reflect the adipose tissue-specific DNA methylation status of obesity susceptibility. DNA samples isolated from subcutaneous adipose tissue and circulating leukocytes were hybridized in the Infinium HumanMethylation 450 BeadChip. Data were compared between samples from obese (n = 45) and non-obese (n = 8-10) patients by Wilcoxon-rank test, unadjusted for cell type distributions. A global hypomethylation of the differentially methylated CpG sites (DMCpGs) was observed in the obese subcutaneous adipose tissue and leukocytes. The overlap analysis yielded a number of genes mapped by the common DMCpGs that were identified to reflect the obesity state in the leukocytes. Specifically, the methylation levels of FGFRL1, NCAPH2, PNKD and SMAD3 exhibited excellent and statistically significant efficiencies in the discrimination of obesity from non-obesity status (AUC > 0.80; p < 0.05) and a great correlation between both tissues. Therefore, the current study provided new and valuable DNA methylation biomarkers of obesity-related adipose tissue pathogenesis through peripheral blood analysis, an easily accessible and minimally invasive biological material instead of adipose tissue.

Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects.

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process.