Adipose Tissue Dysfunction in Obesity: Role of Mineralocorticoid Receptor

The mineralocorticoid receptor (MR) acts as an essential regulator of blood pressure, volume status, and electrolyte balance. However, in recent decades, a growing body of evidence has suggested that MR may also have a role in mediating pro-inflammatory, pro-oxidative, and pro-fibrotic changes in several target organs, including the adipose tissue. The finding that MR is overexpressed in the adipose tissue of patients with obesity has led to the hypothesis that this receptor can contribute to adipokine dysregulation and low-grade chronic inflammation, alterations that are linked to the development of obesity-related metabolic and cardiovascular complications. Moreover, several studies in animal models have investigated the role of MR antagonists (MRAs) in preventing the metabolic alterations observed in obesity. In the present review we will focus on the potential mechanisms by which MR activation can contribute to adipose tissue dysfunction in obesity and on the possible beneficial effects of MRAs in this setting.     

Individual and country-level factors associated with self-reported and accelerometer-based physical activity in old age: a cross-national analysis of European countries

This study aimed to investigate associations between individual-level (personality traits, quality of life) and country-level (gross domestic product per capita, number of policies and action plans for physical activity) factors with self-reported and accelerometer-based physical activity and cross-level interactions among European countries. Based on the Survey of Health, Ageing and Retirement in Europe (SHARE) from 2019–2020, self-reported physical activity (N = 46,617 from 27 countries) and accelerometer-based average acceleration and intensity gradient (N = 855 from 10 countries) were analyzed. Mixed-model regressions with two levels (individuals nested within countries) were used for analyses. Between countries differences accounted for relatively small portions of the variability in self-reported physical activity (intraclass correlation, ICC = 7.5%), average acceleration (ICC = 3.5%), and intensity gradient (ICC = 1.9%). There were more associations between individual- and country-level factors and self-reported physical activity than with accelerometer-based physical activity. The association between individual-level variables and accelerometer-based physical activity did not differ between countries. Cross-level interactions suggested that associations between some personality traits and self-reported physical activity were stronger in countries with lower GDP. Both individual- and country-level factors are related to participation in more intensive physical activities. Adults with less resilient personality traits living in countries with lower resources are at the highest risk for physical inactivity. Supplementary InformationThe online version contains supplementary material available at 10.1007/s10433-022-00737-8.     

Everything You Always Wanted to Know about Sarcopenia but Were Afraid to Ask: A Quick Guide for Radiation Oncologists (impAct oF saRcopeniA In raDiotherapy: The AFRAID Project)

Sarcopenia (SP) is a syndrome characterized by age-associated loss of skeletal muscle mass and function. SP worsens both acute and late radiation-induced toxicity, prognosis, and quality of life. Myosteatosis is a pathological infiltration of muscle tissue by adipose tissue which often precedes SP and has a proven correlation with prognosis in cancer patients. Sarcopenic obesity is considered a “hidden form” of SP (due to large fat mass) and is independently related to higher mortality and worse complications after surgery and systemic treatments with worse prognostic impact compared to SP alone. The evaluation of SP is commonly based on CT images at the level of the middle of the third lumbar vertebra. On this scan, all muscle structures are contoured and then the outlined surface area is calculated. Several studies reported a negative impact of SP on overall survival in patients undergoing RT for tumors of the head and neck, esophagus, rectum, pancreas, cervix, and lung. Furthermore, several appetite-reducing side effects of RT, along with more complex radiation-induced mechanisms, can lead to SP through, but not limited to, reduced nutrition. In particular, in pediatric patients, total body irradiation was associated with the onset of SP and other changes in body composition leading to an increased risk of cardiometabolic morbidity in surviving adults. Finally, some preliminary studies showed the possibility of effectively treating SP and preventing the worsening of SP during RT. Future studies should be able to provide information on how to prevent and manage SP before, during, or after RT, in both adult and pediatric patients.     

Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough

The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. The remaining individuals with CF harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although the clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, cell lines can be created by overexpression of mouse Bmi-1 and human TERT (hTERT). Using this approach, we developed 2 non-CF and 6 CF airway epithelial cell lines, 3 of which were homozygous for the W1282X PTC variant. The Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The 2 F508del-CFTR cell lines responded robustly to CFTR modulators, which was mirrored in the parent primary cells and in the cell donors’ clinical response. Cereblon E3 ligase modulators targeting eukaryotic release factor 3a (eRF3a) rescued W1282X-CFTR function to approximately 20% of WT levels and, when paired with G418, rescued G542X-CFTR function to approximately 50% of WT levels. Intriguingly, eRF3a degraders also diminished epithelial sodium channel (ENaC) function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirrored primary cell responses to CFTR modulators and illustrate a therapeutic approach to rescue CFTR nonsense mutations.     

Paraaortic sentinel lymph node detection in intermediate and high-risk endometrial cancer by transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR)

ObjectiveWe aimed to evaluate the accuracy of sentinel lymph node (SLN) mapping with transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR) to detect lymph node (LN) metastases, in patients with intermediate and high-risk endometrial cancer (EC), focusing on its performance to detect paraaortic involvement.MethodsProspective study including women with preoperative intermediate or high-risk EC, according to ESMO-ESGO-ESTRO consensus, who underwent SLN mapping using the TUMIR approach. SLNs were preoperatively localized by planar and single photon emission computed tomography/computed tomography images, and intraoperatively by gamma-probe. Immediately after SLN excision, all women underwent systematic pelvic and paraaortic lymphadenectomy by laparoscopy.ResultsThe study included 102 patients. The intraoperative SLN detection rate was 79.4% (81/102). Pelvic and paraaortic drainage was observed in 92.6% (75/81) and 45.7% (37/81) women, respectively, being exclusively paraaortic in 7.4% (6/81). After systematic lymphadenectomy, LN metastases were identified in 19.6% (20/102) patients, with 45.0% (9/20) showing paraaortic involvement, which was exclusive in 15.0% (3/20). The overall sensitivity and negative predictive value (NPV) of SLNs by the TUMIR approach to detect lymphatic involvement were 87.5% and 97.0%, respectively; and 83.3% and 96.9%, for paraaortic metastases. After applying the MSKCC SLN mapping algorithm, the sensitivity and NPV were 93.8% and 98.5%, respectively.ConclusionThe TUMIR method provides valuable information of endometrial drainage in patients at higher risk of paraaortic LN involvement. The TUMIR approach showed a detection rate of paraaortic SLNs greater than 45% and a high sensitivity and NPV for paraaortic metastases in women with intermediate and high-risk EC.     

Influence of perinatal inflammation on the neurodevelopmental outcome of premature infants

Objective: To evaluate the influence of perinatal inflammation on neurodevelopmental outcome of premature infants.

Study design: From a retrospective cohort study of women with preterm labor with intact membranes or preterm prelabor rupture of membranes (PPROM) with an amniocentesis to rule out intra-amniotic inflammation (IAI) and microbial invasion of the amniotic cavity (MIAC), we evaluated neurodevelopmental outcome of their infants born between 24.0 and 34.0 weeks gestation. Women with clinical chorioamnionitis at admission were excluded. Neurodevelopmental outcome was screened with the Ages & Stages Questionnaire (ASQ)-3. We analyzed the relationship between an altered ASQ-3 and antenatal, intra-partum and post-partum factors related to perinatal inflammation.

Result: Among 98 infants evaluated, 22% had an abnormal score. Amniotic fluid interleukin-6 levels and early-onset sepsis (EOS) were independent factors of an altered ASQ-3 with delivery <26.0 weeks being the strongest predictor.

Conclusions: In premature infants, the presence of IAI, delivery <26.0 weeks and EOS were found to be independent factors of an altered ASQ-3.     

Protection against severe COVID-19 after second booster dose of adapted bivalent (original/Omicron BA.4-5) mRNA vaccine in persons ≥ 60 years,by time since infection,Italy, 12 September to 11 December 2022

Effectiveness against severe COVID-19 of a second booster dose of the bivalent (original/BA.4–5) mRNA vaccine 7–90 days post-administration, relative to a first booster dose of an mRNA vaccine received ≥ 120 days earlier, was ca 60% both in persons ≥ 60 years never infected and in those infected > 6 months before. Relative effectiveness in those infected 4–6 months earlier indicated no significant additional protection (10%; 95% CI: −44 to 44). A second booster vaccination 6 months after the latest infection may be warranted.     

Hyperspectral evaluation of vasculature in induced peritonitis mouse models

Imaging of blood vessel structure in combination with functional information about blood oxygenation can be important in characterizing many different health conditions in which the growth of new vessels contributes to the overall condition. In this paper, we present a method for extracting comprehensive maps of the vasculature from hyperspectral images that include tissue and vascular oxygenation. We also show results from a preclinical study of peritonitis in mice. First, we analyze hyperspectral images using Beer-Lambert exponential attenuation law to obtain maps of hemoglobin species throughout the sample. We then use an automatic segmentation algorithm to extract blood vessels from the hemoglobin map and combine them into a vascular structure-oxygenation map. We apply this methodology to a series of hyperspectral images of the abdominal wall of mice with and without induced peritonitis. Peritonitis is an inflammation of peritoneum that leads, if untreated, to complications such as peritoneal sclerosis and even death. Characteristic inflammatory response can also be accompanied by changes in vasculature, such as neoangiogenesis. We demonstrate a potential application of the proposed segmentation and processing method by introducing an abnormal tissue fraction metric that quantifies the amount of tissue that deviates from the average values of healthy controls. It is shown that the proposed metric successfully discriminates between healthy control subjects and model subjects with induced peritonitis and has a high statistical significance.