RNA-binding proteins in bone pathophysiology.

Bone remodelling is a highly regulated process that maintains mineral homeostasis and preserves bone integrity. During this process, intricate communication among all bone cells is required. Indeed, adapt to changing functional situations in the bone, the resorption activity of osteoclasts is tightly balanced with the bone formation activity of osteoblasts. Recent studies have reported that RNA Binding Proteins (RBPs) are involved in bone cell activity regulation. RBPs are critical effectors of gene expression and essential regulators of cell fate decision, due to their ability to bind and regulate the activity of cellular RNAs. Thus, a better understanding of these regulation mechanisms at molecular and cellular levels could generate new knowledge on the pathophysiologic conditions of bone. In this Review, we provide an overview of the basic properties and functions of selected RBPs, focusing on their physiological and pathological roles in the bone.

Risk Factors for Bone Microarchitecture Impairments in Older Men with Type 2 Diabetes - The MrOS Study.

CONTEXT: Impaired bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), may contribute to bone fragility in type 2 diabetes (T2DM) but data on men are lacking. OBJECTIVE: To investigate the association between T2DM and HR-pQCT parameters in older men. METHODS: HR-pQCT scans were acquired on 1794 participants in the Osteoporotic Fractures in Men (MrOS) study. T2DM was ascertained by self-report or medication use. Linear regression models, adjusted for age, race, BMI, limb length, clinic site, and oral corticosteroid use, were used to compare HR-pQCT parameters by diabetes status. RESULTS: Among 1777 men, 290 had T2DM (mean age 84.4 years). T2DM men had smaller total cross-sectional area (Tt.AR) at the distal tibia (p=0.028) and diaphyseal tibia (p=0.025), and smaller cortical area at the distal (p= 0.009) and diaphyseal tibia (p= 0.023). Trabecular indices and cortical porosity were similar between T2DM and non-T2DM. Among men with T2DM, in a model including HbA1c, diabetes duration, and insulin use, diabetes duration ≥ 10 years, compared with <10 years, was significantly associated with higher cortical porosity but with higher trabecular thickness at the distal radius. Insulin use was significantly associated with lower cortical area and thickness at the distal radius and diaphyseal tibia and lower failure load at all three scan sites. Lower cortical area, cortical thickness, total BMD, cortical BMD, and failure load of the distal sites were associated with increased risk of incident non-vertebral fracture in T2DM. CONCLUSIONS: Older men with T2DM have smaller bone size compared to non-T2DM, which may contribute to diabetic skeletal fragility. Longer diabetes duration was associated with higher cortical porosity and insulin use with cortical bone deficits and lower failure load.

Immunohistochemistry analysis of autophagy-related proteins Beclin-1, p62/SQSTM1, and LC3B in breast carcinoma progression to bone metastasis.

Autophagy is a catabolic pathway involved both in tissue homeostasis and in cellular response to stress. The precise role of autophagy in cancer is still undefined and seems to depend on the tumor stage, appearing tumor-suppressive in physiological conditions and helpful to tumor progression in the established tumor. Here we analyzed by immunohistochemistry Beclin-1, p62, and LC3B, autophagic markers, in human specimens of normal breast, bone metastasis together with pair-matched invasive breast carcinoma of no special type (IBC-NST) as well as non-metastatic breast carcinoma, to disclose the possibility that they could be early prognostic indicators of the evolution of the disease toward the worst outcome. Different regions of metastatic carcinomas, i.e., areas adjacent to the tumor without signs of neoplastic growth, dysplastic lesions, and areas with invasive growth were considered. The pattern of autophagic parameters showed differences among the stages of breast carcinoma progression with a trend that indicated the activation of autophagic process in normal breast (Beclin-1 more elevated than p62), a pattern that was maintained in non-metastatic carcinoma. As the neoplasia proceeds with malignancy, the modification of the pattern of expression of autophagic markers (low ratio between Beclin-1 and p62) in areas of invasive growth of carcinomas suggested inhibition of the process. Of note, the parameters showed a different pattern in bone metastasis with respect to bone metastatic (bm)-IBC-NST, suggesting the reactivation of the autophagic process in the new growth site, helpful to the colonization. The course of autophagy markers during tumor progression could have a prognostic value towards bone metastasis and reveal different roles of the process in different phases of neoplastic growth. The understanding of the role of autophagy in bone metastasis could disclose new therapeutic targets to improve the conditions of patients.

Association between the GLP1R A316T Mutation and Adolescent Idiopathic Scoliosis in French Canadian and Italian Cohorts.

Studies have revealed anthropometric discrepancies in girls with adolescent idiopathic scoliosis (AIS) compared to non-scoliotic subjects, such as a higher stature, lower weight, and lower body mass index. While the causes are still unknown, it was proposed that metabolic hormones could play a role in AIS pathophysiology. Our objectives were to evaluate the association of GLP1R A316T polymorphism in AIS susceptibility and to study its relationship with disease severity and progression. We performed a retrospective case-control association study with controls and AIS patients from an Italian and French Canadian cohort. The GLP1R rs10305492 polymorphism was genotyped in 1025 subjects (313 non-scoliotic controls and 712 AIS patients) using a validated TaqMan allelic discrimination assay. Associations were evaluated by odds ratio and 95% confidence intervals. In the AIS group, there was a higher frequency of the variant genotype A/G (4.2% vs. 1.3%, OR = 3.40, p = 0.016) and allele A (2.1% vs. 0.6%, OR = 3.35, p = 0.017) than controls. When the AIS group was stratified for severity (≤40° vs. >40°), progression of the disease (progressor vs. non-progressor), curve type, or body mass index, there was no statistically significant difference in the distribution of the polymorphism. Our results support that the GLP1R A316T polymorphism is associated with a higher risk of developing AIS, but without being associated with disease severity and progression.

Value of multidetector computed tomography angiography in severe non-variceal upper gastrointestinal bleeding: a retrospective study in a referral bleeding unit.

BACKGROUND: Non-variceal upper gastrointestinal bleeding is a common gastroenterological emergency associated with significant morbidity and mortality. Upper gastrointestinal endoscopy is currently recommended as the gold standard modality for both diagnosis and treatment. As historically played a limited role in the diagnosis of acute non-variceal upper gastrointestinal bleeding, multidetector-row computed tomography angiography is emerging as a promising tool in the diagnosis of non-variceal upper gastrointestinal bleeding, especially for severe cases. However, to date, evidence concerning the role of multidetector-row computed tomography angiography in the non-variceal upper gastrointestinal bleeding diagnosis is still lacking. AIM: The purpose of this study was to retrospectively investigate the diagnostic performance of emergent multidetector-row computed tomography angiography performed prior to any diagnostic modality or following urgent upper endoscopy to identify the status, the site, and the underlying etiology of severe non-variceal upper gastrointestinal bleeding. METHODS: Institutional databases were reviewed in order to identify severe acute non-variceal upper gastrointestinal bleeding patients who were admitted to our bleeding unit and were referred for emergent multidetector-row computed tomography angiography prior to any hemostatic treatment (< 3 h) or following (< 3 h) endoscopy, between December 2019 and October 2022. The study aim was to evaluate the diagnostic performance of multidetector-row computed tomography angiography to detect the status, the site, and the etiology of severe non-variceal upper gastrointestinal bleeding with endoscopy, digital subtraction angiography, surgery, pathology, or a combination of them as reference standards. RESULTS: A total of 68 patients (38 men, median age 69 years [range 25-96]) were enrolled. The overall multidetector-row computed tomography angiography sensitivity, specificity, and accuracy to diagnose bleeding status were 77.8% (95% CI: 65.5-87.3), 40% (95% CI: 5.3-85.3), and 75% (95% CI: 63.0-84.7), respectively. Finally, the overall multidetector-row computed tomography angiography sensitivity to identify the bleeding site and the bleeding etiology were 92.4% (95% CI: 83.2-97.5) and 79% (95% CI: 66.8-88.3), respectively. CONCLUSION: Although esophagogastroduodenoscopy is the mainstay in the diagnosis and treatment of most non-variceal upper gastrointestinal bleeding cases, multidetector-row computed tomography angiography seems to be a feasible and effective modality in detecting the site, the status, and the etiology of severe acute non-variceal upper gastrointestinal bleeding. It may play a crucial role in the management of selected cases of non-variceal upper gastrointestinal bleeding, especially those clinically severe and/or secondary to rare and extraordinary rare sources, effectively guiding timing and type of treatment. However, further large prospective studies are needed to clarify the role of multidetector-row computed tomography angiography in the diagnostic process of acute non-variceal upper gastrointestinal bleeding.

Effects of AIDiet intervention to improve diet quality, immuno-metabolic health in normal and overweight PCOS girls: a pilot study.

This study was conducted in two groups of girls with PCOS (polycystic ovary syndrome) categorized as slim (group N) and overweight-to-obese (group Ov/Ob). The study's primary outcome was to assess the impact of a 12-week anti-inflammatory diet (AIDiet) intervention, without energy deficit, on daily diet quality improvement, evaluated according to the KIDMED index. The secondary outcome was improving inflammatory, redox, hormonal, and metabolic statuses. In the study, which was completed by 13 girls from the Ov/Ob group and 19 girls from the N group, a significant improvement in the mean KIDMED score was obtained. Moreover, the intervention significantly improves concentration of total antioxidant capacity (TAC), fasting insulin, and the homeostatic model assessment for insulin resistance (HOMA-IR) index, in the Ov/Ob group, while both groups experienced a reduction in the concentration of interleukin (IL)-1 and IL-6, tumour necrosis factor (TNF-α), and androstenedione. The AIDiet intervention effectively improved the quality of the subjects' diets, which was associated with the improvement of hormonal and immuno-metabolic markers. However, these changes in normal-weight patients were observed regardless of body weight reduction. ClinicalTrials.gov Identifier NCT04738409.

Enhanced molecular release from elderly bone samples using collagenase I: insights into fatty acid metabolism alterations.

BACKGROUND: Bone is a metabolically active tissue containing different cell types acting as endocrine targets and effectors. Further, bone is a dynamic depot for calcium, phosphorous and other essential minerals. The tissue matrix is subjected to a constant turnover in response to mechanical/endocrine stimuli. Bone turnover demands high energy levels, making fatty acids a crucial source for the bone cells. However, the current understanding of bone cell metabolism is poor. This is partly due to bone matrix complexity and difficulty in small molecules extraction from bone samples. This study aimed to evaluate the effect of metabolite sequestering from a protein-dominated matrix to increase the quality and amount of metabolomics data in discovering small molecule patterns in pathological conditions. METHODS: Human bone samples were collected from 65 to 85 years old (the elderly age span) patients who underwent hip replacement surgery. Separated cortical and trabecular bone powders were treated with decalcifying, enzymatic (collagenase I and proteinase K) and solvent-based metabolite extraction protocols. The extracted mixtures were analyzed with the high-resolution mass spectrometry (HRMS). Data analysis was performed with XCMS and MetaboAnalystR packages. RESULTS: Fast enzymatic treatment of bone samples before solvent addition led to a significantly higher yield of metabolite extraction. Collagenase I and proteinase K rapid digestion showed more effectiveness in cortical and trabecular bone samples, with a significantly higher rate (2.2 folds) for collagenase I. Further analysis showed significant enrichment in pathways like de novo fatty acid biosynthesis, glycosphingolipid metabolism and fatty acid oxidation-peroxisome. CONCLUSION: This work presents a novel approach for bone sample preparation for HRMS metabolomics. The disruption of bone matrix conformation at the molecular level helps the molecular release into the extracting solvent and, therefore, can lead to higher quality results and trustable biomarker discovery. Our results showed ß-oxidation alteration in the aged bone sample. Future work covering more patients is worthy to identify the effective therapeutics to achieve healthy aging.

Plasma microRNA signature associated with skeletal muscle wasting in post-menopausal osteoporotic women.

BACKGROUND: Skeletal muscle mass wasting almost invariably accompanies bone loss in elderly, and the coexistence of these two conditions depends on the tight endocrine crosstalk existing between the two organs, other than the biomechanical coupling. Since the current diagnostics limitation in this field, and given the progressive population aging, more effective tools are needed. The aim of this study was to identify circulating microRNAs (miRNAs) as potential biomarkers for muscle mass wasting in post-menopausal osteoporotic women. METHODS: One hundred seventy-nine miRNAs were assayed by quantitative real-time polymerase chain reaction in plasma samples from 28 otherwise healthy post-menopausal osteoporotic women (73.4 ± 6.6 years old). The cohort was divided in tertiles based on appendicular skeletal muscle mass index (ASMMI) to better highlight the differences on skeletal muscle mass (first tertile: n = 9, ASMMI = 4.88 ± 0.40 kg·m-2; second tertile: n = 10, ASMMI = 5.73 ± 0.23 kg·m-2; third tertile: n = 9, ASMMI = 6.40 ± 0.22 kg·m-2). Receiver operating characteristic (ROC) curves were calculated to estimate the diagnostic potential of miRNAs. miRNAs displaying a statistically significant fold change ≥ ±1.5 and area under the curve (AUC) > 0.800 (P < 0.05) between the first and third tertiles were considered. A linear regression model was applied to estimate the association between miRNA expression and ASMMI in the whole population, adjusting for body mass index, age, total fat (measured by total-body dual-energy X-ray absorptiometry [DXA]) and bone mineral density (measured by femur DXA). Circulating levels of adipo-myokines were evaluated by bead-based immunofluorescent assays and enzyme-linked immunosorbent assays. RESULTS: Five miRNAs (hsa-miR-221-3p, hsa-miR-374b-5p, hsa-miR-146a-5p, hsa-miR-126-5p and hsa-miR-425-5p) resulted down-regulated and two miRNAs (hsa-miR-145-5p and hsa-miR-25-3p) were up-regulated in the first tertile (relative-low ASMMI) compared with the third tertile (relative-high ASMMI) (fold change ≥ ±1.5; P-value < 0.05). All the corresponding ROC curves had AUC > 0.8 (P < 0.05). Two signatures hsa-miR-126-5p, hsa-miR-146a-5p and hsa-miR-425-5p; and hsa-miR-126-5p, hsa-miR-146a-5p, hsa-miR-145-5p and hsa-miR-25-3p showed the highest AUC, 0.914 (sensitivity = 77.78%; specificity = 100.00%) and 0.901 (sensitivity = 88.89%; specificity = 100.00%), respectively. CONCLUSIONS: In this study, we identified, for the first time, two miRNA signatures, hsa-miR-126-5p, hsa-miR-146a-5p and hsa-miR-425-5p; and hsa-miR-126-5p, hsa-miR-146a-5p, hsa-miR-145-5p and hsa-miR-25-3p, specifically associated with muscle mass wasting in post-menopausal osteoporotic women.

Murine Myoblasts Exposed to SYUIQ-5 Acquire Senescence Phenotype and Differentiate into Sarcopenic-Like Myotubes, an In Vitro Study.

The musculoskeletal system is one of the most affected organs by aging that correlates well with an accumulation of senescent cells as for other multiple age-related pathologies. The molecular mechanisms underpinning muscle impairment because of senescent cells are still elusive. The availability of in vitro model of skeletal muscle senescence is limited and restricted to a small panel of phenotypic features of these senescent cells in vivo. Here, we developed a new in vitro model of senescent C2C12 mouse myoblasts that, when subjected to differentiation, the resulting myotubes showed sarcopenic features. To induce senescence, we used SYUIQ-5, a quindoline derivative molecule inhibitor of telomerase activity, leading to the expression of several senescent hallmarks in treated myoblasts. They had increased levels of p21 protein accordingly with the observed cell cycle arrest. Furthermore, they had enhanced SA-ßgalactosidase enzyme activity and phosphorylation of p53 and histone H2AX. SYUIQ-5 senescent myoblasts had impaired differentiation potential and the resulting myotubes showed increased levels of ATROGIN-1 and MURF1, ubiquitin ligases components responsible for protein degradation, and decreased mitochondria content, typical features of sarcopenic muscles. Myotubes differentiated from senescent myoblasts cultures release increased levels of MYOSTATIN that could affect skeletal muscle cell growth. Overall, our data suggest that a greater burden of senescent muscle cells could contribute to sarcopenia. This study presents a well-defined in vitro model of muscle cell senescence useful for deeper investigation in the aging research field to discover new putative therapeutic targets and senescence biomarkers associated with the aged musculoskeletal system.

Downhill running increases markers of muscle damage and impairs the maximal voluntary force production as well as the late phase of the rate of voluntary force development.

PURPOSE: To examined the time-course of the early and late phase of the rate of voluntary force development (RVFD) and muscle damage markers after downhill running. METHODS: Ten recreational runners performed a 30-min downhill run at 10 km h-1 and -20% (-11.3°) on a motorized treadmill. At baseline and each day up to 4 days RVFD, knee extensors maximum voluntary isometric force (MVIC), serum creatine kinase (CK) concentration, quadriceps swelling, and soreness were assessed. The early (0-50 ms) and late (100-200 ms) phase of the RVFD, as well as the force developed at 50 and 200 ms, were also determined. RESULTS: MVIC showed moderate decrements (p < 0.05) and recovered after 4 days (p > 0.05). Force at 50 ms and the early phase were not impaired (p > 0.05). Conversely, force at 200 ms and the late phase showed moderate decrements (p < 0.05) and recovered after 3 and 4 days, respectively (p > 0.05). CK concentration, quadriceps swelling, and soreness increased (p < 0.05) were overall fully resolved after 4 days (p > 0.05). CONCLUSION: Downhill running affected the knee extensors RVFD late but not early phase. The RVFD late phase may be used as an additional marker of muscle damage in trail running.

Low circulating levels of miR-17 and miR-126-3p are associated with increased mortality risk in geriatric hospitalized patients affected by cardiovascular multimorbidity.

MultiMorbidity (MM), defined as the co-occurrence of two or more chronic conditions, is associated with poorer health outcomes, such as recurrent hospital readmission and mortality. As a group of conditions, cardiovascular disease (CVD) exemplifies several challenges of MM, and the identification of prognostic minimally invasive biomarkers to stratify mortality risk in patients affected by cardiovascular MM is a huge challenge. Circulating miRNAs associated to inflammaging and endothelial dysfunction, such as miR-17, miR-21-5p, and miR-126-3p, are expected to have prognostic relevance. We analyzed a composite profile of circulating biomarkers, including miR-17, miR-21-5p, and miR-126-3p, and routine laboratory biomarkers in a sample of 246 hospitalized geriatric patients selected for cardiovascular MM from the Report-AGE INRCA database and BioGER INRCA biobank, to evaluate the association with all-cause mortality during 31 days and 12 and 24 months follow-up. Circulating levels of miR-17, miR-126-3p, and some blood parameters, including neutrophil to lymphocyte ratio (NLR) and eGFR, were significantly associated with mortality in these patients. Overall, our results suggest that in a cohort of geriatric hospitalized patients affected by cardiovascular MM, lower circulating miR-17 and miR-126-3p levels could contribute to identify patients at higher risk of short- and medium-term mortality.

Seasonal changes in free 25-(OH)D and vitamin D metabolite ratios and their relationship with psychophysical stress markers in male professional football players.

Introduction: Novel markers of vitamin D status are currently being investigated, including free 25-(OH)D (25-(OH)DF) and the vitamin D metabolite ratio (24,25-(OH)2D3:25-(OH)D3; VMR). The VMR may provide additional functional information on vitamin D metabolism in athletes. Therefore, the main objective of the current study was to evaluate 25-(OH)DF, bioavailable 25-(OH)D (25-(OH)DB), VMR, and psychophysical stress markers during different training periods over a half-season. The second aim was to assess the association between vitamin D binding protein (VDBP), total and free 25-(OH)D, VMRs, and psychophysical stress markers in professional football players. Moreover, we examined the relationship between 25-(OH)D3 and vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3) to determine if training loads in different training periods influenced the vitamin D metabolome. Methods: Twenty professional football players were tested at six different time points across half a year (V1-June; V2-July; V3-August; V4-October; V5-December; V6-January). Results: Analyses indicated a significant seasonal rhythm for VDBP, and total 25-(OH)D (25-(OH)DT), 25-(OH)DB, 24,25-(OH)2D3, 3-epi-25-(OH)D3, 25-(OH)D3:24,25-(OH)2D3, and 24,25-(OH)2D3:25-(OH)D3 VMRs throughout the training period. No correlation was detected between 25-(OH)DT, 25-(OH)DB, 25-(OH)DF, vitamin D metabolites, VMRs, VDBP, and ferritin, liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]), creatine kinase (CK), cortisol, testosterone, and testosterone-to-cortisol ratio (T/C) in each period (V1-V6). However, there was a strong statistically significant correlation between 25-(OH)D3 and 24,25-(OH)D3 in each training period. Conclusion: In conclusion, a seasonal rhythm was present for VDBP, 25-(OH)DT, 25-(OH)DB, vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3), and VMRs (25-(OH)D3:24,25-(OH)2D3, 25-(OH)D3:3-epi-25-(OH)D3). However, no rhythm was detected for 25-(OH)DF and markers of psychophysical stress (ferritin, liver enzymes, CK, testosterone, cortisol, and T/C ratio). Moreover, the relationships between free and total 25-(OH)D with psychophysical stress markers did not demonstrate the superiority of free over total measurements. Furthermore, training loads in different training periods did not affect resting vitamin D metabolite concentrations in football players.

Definition of malnutrition from routinely-collected data for orthopedic surgery research: the global leadership initiative on malnutrition (GLIM) tool and others.

The correct identification of malnourished patients in the context of hip, knee, or spine surgery research would enhance the quality of analytical studies investigating the prediction potential of preoperative nutritional disorders on postoperative recovery. However, accurate malnutrition screening and diagnostic assessment rely on parameters that were not routinely collected in routine practice until a few years ago. The authors of this article present substitute literature-based equations that can be built up using historical routinely collected data to classify patients that had been at risk of malnutrition or malnourished. For what concerns the risk screening, several methods are available to identify patients at risk of over- or undernutrition, encompassing the BWd (body weight difference from the ideal weight), GNRI (geriatric nutritional risk index), INA (instant nutritional assessment), LxA (combination of lymphocyte count and albumin), PMA (protein malnutrition with acute inflammation), PMAC (protein malnutrition with acute and chronic inflammation), IDM (iron deficit malnutrition), and VBD (vitamin B deficit malnutrition). Conversely, the GLIM (global leadership initiative on malnutrition) criteria can be used to assess malnutrition and diagnose subclasses of undernutrition. Rational use of these tools can facilitate the conduction of efficient prospective studies in the future, as well as bespoke retrospective cohort studies and database research.

Evaluating safety risks of whole-body cryotherapy/cryostimulation (WBC): a scoping review from an international consortium.

Over the two last decades, whole-body cryotherapy/cryostimulation (WBC) has emerged as an exciting non-pharmacological treatment influencing inflammatory events at a cellular and physiological level, which can result in improved sleep quality, faster neuromuscular recovery after high-intensity exercise, and chronic pain relief for patients suffering different types of diseases (fibromyalgia, rheumatism, arthritis). Some evidence even suggests that WBC has benefits on mental health (depression, anxiety disorders) and cognitive functions in both adults and older adults, due to increased circulating BDNF levels. Recently, some safety concerns have been expressed by influential public health authorities (e.g., FDA, INSERM) based on reports from patients who developed adverse events upon or following WBC treatment. However, part of the data used to support these claims involved individuals whose entire body (except head) was exposed to extreme cold vaporized liquid nitrogen while standing in a narrow bathtub. Such a procedure is known as partial-body cryotherapy (PBC), and is often erroneously mistaken to be whole-body cryotherapy. Although having similarities in terms of naming and pursued aims, these two approaches are fundamentally different. The present article reviews the available literature on the main safety concerns associated with the use of true whole-body cryotherapy. English- and French-language reports of empirical studies including case reports, case series, and randomized controlled trials (RCTs) were identified through searches of PubMed, Scopus, Cochrane, and Web of Science electronic databases. Five case reports and two RCTs were included for a total of 16 documented adverse events (AEs). A critical in-depth evaluation of these AEs (type, severity, context of onset, participant's medical background, follow-up) is proposed and used to illustrate that WBC-related safety risks are within acceptable limits and can be proactively prevented by adhering to existing recommendations, contraindications, and commonsense guidelines.

Nordic Walking training in BungyPump form improves cognitive functions and physical performance and induces changes in amino acids and kynurenine profiles in older adults.

Introduction: Although impacts of physical activity on cognitive functions have been intensively investigated, they are still far from being completely understood. The aim of this study was to evaluate the effect of 12 weeks of the Nordic Walking training with BungyPump resistance poles (NW-RSA) on the amino acid and kynurenine profiles as well as selected myokine/exerkine concentrations, which may modify the interface between physical and cognitive functions. Methods: A group of 32 older adults participated in the study. Before and after the intervention, body composition, cognitive functions, and physical performance were assessed. Blood samples were taken before and 1 h after the first and last sessions of the NW-RSA training, to determine circulating levels of exercise-induced proteins, i.e., brain-derived neurotrophic factor (BDNF), irisin, kynurenine (KYN), metabolites, and amino acids. Results: The NW-RSA training induced a significant improvement in cognitive functions and physical performance as well as a reduction in fat mass (p = 0.05). Changes were accompanied by a decline in resting serum BDNF (p = 0.02) and a slight reduction in irisin concentration (p = 0.08). Still, changes in irisin concentration immediately after the NW-RSA intervention depended on shifts in kynurenine-irisin dropped as kynurenine increased. The kynurenine-to-tryptophan and phenylalanine-to-tyrosine ratios decreased significantly, suggesting their possible involvement in the amelioration of cognitive functions. No changes of glucose homeostasis or lipid profile were found. Shifts in the concentrations of selected amino acids might have covered the increased energy demand in response to the NW-RSA training and contributed to an improvement of physical performance. Conclusion: Regular Nordic Walking training with additional resistance (BungyPump) improved cognitive functions and physical performance. These positive effects were associated with a reduced BDNF concentration and kynurenine-to-tryptophan ratio as well as changes in the amino acid profile.

Rare causes of acute non-variceal upper gastrointestinal bleeding: A comprehensive review.

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality. Gastroenterologists and other involved clinicians are generally assisted by international guidelines in its management. However, NVUGIB due to peptic ulcer disease only is mainly addressed by current guidelines, with upper gastrointestinal endoscopy being recommended as the gold standard modality for both diagnosis and treatment. Conversely, the management of rare and extraordinary rare causes of NVUGIB is not covered by current guidelines. Given they are frequently life-threatening conditions, all the involved clinicians, that is emergency physicians, diagnostic and interventional radiologists, surgeons, in addition obviously to gastroenterologists, should be aware of and familiar with their management. Indeed, they typically require a prompt diagnosis and treatment, engaging a dedicated, patient-tailored, multidisciplinary team approach. The aim of our review was to extensively summarize the current evidence with regard to the management of rare and extraordinary rare causes of NVUGIB.