Is the Pentagon-Copying Task More than a Cognitive Feature? Associations with Handgrip Strength, Gait Speed, and Frailty in Older Adults.

BACKGROUND: The pentagon copy is a sensitive item to the prediction of cognitive decline and dementia. Cognitive and physical/motor decline are able to accelerate the evolution of each other by representing a common pathway toward frailty. OBJECTIVES: The objective of the study was to investigate the association of the pentagon-copying task with physical and motor performances and with frailty, in a sample of older adults. METHOD: This observational, cross-sectional, and single-center study was conducted in a Geriatric Outpatients Clinic. Subjects aged ≥65 years were consecutively recruited, on a voluntary basis. Subjects with positive psychiatric history, with a severe neurocognitive disorder, with severe limitations on the upper limbs and/or reporting sensory deficits were excluded. The pentagon-copying task was scored from the Mini-Mental State Examination; the Qualitative Scoring Pentagon Test (QSPT) was also used. Handgrip strength was measured; a 46-item Frailty Index was calculated; in subjects with autonomous walking, a 4-meter gait speed was also measured. RESULTS: The study included 253 subjects (mean age 80.59 ± 6.89 years). Subjects making a wrong pentagon copy showed greater odds of exhibiting a strength deficit (OR = 3.57; p = 0.001) and of being frail (OR = 4.80; p < 0.001), and exhibited a slower gait. The QSTP score was significantly correlated with handgrip strength (r = 0.388) and gait speed (r = 0.188) and inversely correlated with frailty (r = -0.428); the QSTP score was significantly different between the quartiles of handgrip strength and frailty. CONCLUSIONS: The pentagon-copying task might also be confirmed as a quick screening tool of aging trajectories toward frailty by jointly evaluating cognitive and physical performances.

Is the relationship between erythropoiesis and renal function one of the secrets of extreme longevity?

BACKGROUND AND AIMS: Renal function and erythropoiesis could be impaired with advancing age. Neutrophil gelatinase-associated lipocalin (NGAL) as well as erythropoietin (EPO) levels are two useful biomarkers of the renal status. In advanced age, the relationships between NGAL, EPO and hemoglobin (Hb) levels remains unknown. The aim of the present study is to evaluate the relationship between renal function and erythropoiesis in a small cohort of centenarians. METHODS AND RESULTS: We observed thirty-one healthy centenarians with normal hemoglobin levels, a mild reduction in eGFR and no need of erythropoiesis support. We found a significant inverse association between NGAL and GFR, hemoglobin levels and EPO, confirming the key role of the renal function on erythropoiesis also in extreme longevity. A gender difference emerged, showing female participants with lower eGFR and Hb values more than males. CONCLUSIONS: Our findings suggested a new link between renal function, erythropoiesis and longevity in centenarians and these could have relevant implications in clinical practice. These findings could explain why very old subjects presenting a slight GFR reduction seemed not to be exposed to a significant risk of mortality.

Total Talar Prosthesis, Learning from Experience, Two Reports of Total Talar Prosthesis after Talar Extrusion and Literature Review.

Recently, total talar prosthesis has been proposed to substitute the talus during the management of complex talar lesions such as talar extrusion, comminuted talar fractures, or avascular necrosis. Herein, we report two cases of talar extrusion treated with total talar replacement after a high-intensity trauma. Both cases subsequently required revision surgery due to degenerative changes of the tibial plafond (arthrodesis in the first case, conversion to a total ankle prosthesis in the latter). We report and analyze the literature concerning total talar replacement to discuss strategies that could help improve prosthesis survival and reduce the incidence of osteoarthritis.

Emotion regulation strategies and difficulties in older adults: A systematic review.

OBJECTIVES: The purpose of this systematic review was to assess the types of emotion regulation (ER) strategies used and difficulties in emotion regulation experienced by older adults, within the theoretical frameworks proposed by Gross, and by Gratz and Roemer, respectively. METHODS: A systematic search was conducted using principal electronic scientific databases (PubMed, Scopus, and Web of Science). The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. RESULTS: The final number of articles included was 44. Older adults reported a higher use of adaptive ER strategies, as well as fewer difficulties in ER, compared with younger adults. Findings from this review also suggest that the use of maladaptive ER strategies can also expose older adults to psychological distress, and may affect their adaptation to negative disease-related outcomes more common in later life. CONCLUSIONS: Older adults generally showed a greater emotional control compared with younger subjects. Adaptive control strategies, rather than maladaptive control strategies, were correlated with more positive outcomes for psychological distress and adaptation to chronic diseases. CLINICAL IMPLICATIONS: Understanding the nature of ER processes in older adults may contribute to implement tailored interventions aimed at reinforcing adaptive ER processes.

Changes in Cognitive and Functional Status and in Quality of Life of Older Outpatients during the COVID-19 Pandemic.

BACKGROUND: Older adults denoted one of the populations that mostly suffered from the consequences of the COVID-19 pandemic. The cost of confinement was paid in terms of social isolation, distance from relatives and friends, lack of social support, and limited access to the healthcare system, which had a negative impact on health of older adults with comorbidities and frailty. OBJECTIVES: The purpose of the present study was to report the consequences of the COVID-19 pandemic on cognitive performances, functional status, and health-related quality of life among frail outpatients, compared to pre-pandemic status. METHOD: The current sample was part of a larger sample of frail and pre-frail outpatients, who were first evaluated at the clinic between April and May 2019 and who underwent a first follow-up evaluation between April and May 2020. Those outpatients who have undergone the first follow-up evaluation were contacted between April and May 2021 and were asked to voluntarily participate in a second telephone-based evaluation. Cognitive performances (through Mini Mental State Examination - MMSE), functional independency in basic and instrumental daily activities, physical and mental components of health-related quality of life (SF-12 PCS and SF-12 MCS, respectively) were evaluated and compared to previous evaluations. RESULTS: Seventy one outpatients (mean age of 80.69 years) completed the present follow-up evaluation. Patients reported significantly lower cognitive performances (mean MMSE 19.37; p < 0.001), lower physical quality of life (mean score 31.69; p < 0.001), and lower mental quality of life (mean score 38.79; p < 0.001) compared to both pre-pandemic baseline and the first follow-up. Moreover, patients showed a significantly reduced independency in basic daily activities (mean score 3.8; p = 0.004), and a significantly reduced independency in managing telephone (p = 0.012) and medications (p = 0.035), compared to baseline. CONCLUSIONS: The COVID-19 pandemic has been a prolonged stressor over time, which has markedly affected health-related quality of life of outpatients, and it can be considered a stressor that might have contributed to the patients' greater cognitive and functional vulnerability.

Prevalence of hepatitis B and C viral infections in hospitalized patients with increased liver enzyme levels and with no known history of hepatic disease.

INTRODUCTION AND OBJECTIVES: Identification of asymptomatic hepatitis B virus (HBV) and hepatitis C virus (HCV) carriers is fundamental to reach the World Health Organization objective to eradicate viral hepatitis. The aim of this study was to evaluate the HBV and HCV prevalence among patients hospitalized for a non-liver-related disease but showing increased liver enzyme values. PATIENTS AND METHODS: All consecutive patients without history of hepatic disease but showing increased amino-transferase and/or gamma-glutamil-transpeptidase levels at admission to the Internal Medicine and Surgery divisions of the Messina University Hospital from 1st January to 31st December 2019 ("study group") were tested for HBV surface antigen (HBsAg) and anti-HCV antibody. Analogously, HBsAg and anti-HCV were tested for in all the individuals with normal liver enzyme values consecutively admitted from October 1st to December 31st, 2019 ("control group"). RESULTS: Of the 332 "study group" patients, 13 (3.9%) were anti-HCV positive versus 5/306 (1.6%) patients of the "control group" (p=0.008). HCV RNA was detected in 11/13 and in 0/5 anti-HCV patients of the "study group" and "control group", respectively (p=0.001). HBsAg was detected in 5 (1.5%) "study group" patients and in none of the "control group" (p=0.03). Prevalence of diabetes, arterial hypertension, and dyslipidaemia was comparable between the two groups, whereas 75/332 (22.3%) patients of the "study group" and 34/306 (11.1%) patients of the "control group" drank > 2 alcohol units/day (p < 0.001). CONCLUSION: Testing HBsAg and anti-HCV in subjects showing increased liver enzyme values may represent an efficacious tool to identify asymptomatic carriers of hepatitis virus infections.

From cognitive to motor impairment and from sarcopenia to cognitive impairment: a bidirectional pathway towards frailty and disability.

Cognitive and motor/physical functions may evolve at different speeds along the entire lifespan, and with different impact on aging processes, although running parallel along the same temporal continuum. The investigation of the shared association between cognitive and motor/physical functions has represented a challenging subject of debate in the last decades. However, the direction of this cognitive-motor link still needs to be furtherly clarified. A first approach suggests that pre-clinical cognitive decline, such as the MCI, may have a negative impact also on strength, walking speed and balance. Conversely, the presence of earlier motor dysfunction has been discussed as a potential predictor of further cognitive impairment, such in the Motoric Cognitive Risk syndrome, which is characterized by primary reduced gait speed in absence of cognitive deficits. Moreover, reduced handgrip strength has been discussed as a risk factor for the onset of further cognitive impairment. Recent studies have started to investigate the association between cognitive and motor/physical functions in a bidirectional way, suggesting instead both the predictive role of strength on the onset of further cognitive decline, as well as the predictive role of cognitive status on progressively higher risk to develop strength reduction. In conclusion, cognitive and motor/physical decline could often identify a common way, rather than parallel pathways. This integrated perspective should be addressed in the context of geriatric assessments, and it may also promote an increasingly multi-dimensional approach to frailty, together with a significant concern in the end of life stages such as disability and mortality.

Platelet-Rich Plasma Combined with Hyaluronic Acid versus Leucocyte and Platelet-Rich Plasma in the Conservative Treatment of Knee Osteoarthritis. A Retrospective Study.

Background and objectives: Knee osteoarthritis (KO) is one of the most common joint diseases, determining knee pain and reduction of mobility, with a negative effect on quality of life. Intra-articular injections of different formulations of platelet-rich plasma (PRP) are an increasingly common non-surgical treatment for KO. Recently, in order to combine the anti-inflammatory effect of platelet rich plasma and the viscosupplementation effect of hyaluronic acid, a formulation of PRP combined with hyaluronic acid (PRP + HA) has been proposed. The purpose of this study is to retrospectively compare the effectiveness of plasma with high concentration of platelets and leukocytes (L-PRP) with PRP + HA in patients with mild to moderate (Kellgren-Lawrence scale II-III grade) KO. Materials and Methods: Among the 51 patients included, 28 have been treated with L-PRP, while 23 with PRP + HA. A retrospective evaluation at baseline (T0), after 3 months (T1) and 1 year (T2) has been performed. The outcome analyzed are the Knee Society Score (KSS), the Visuo Analogic Scale (VAS) (at T0, T1, and T2) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) (T0 and T2). We evaluated change in mean scores within and between groups among different time points using repeated measures ANCOVA. Results: Although the two treatments have been both effective in reducing VAS, the group treated with PRP + HA showed a significantly lower KSS. Conclusions: Our results show that the use of both treatments may help to reduce pain in patients with mild to moderate KO. PRP + HA showed better results in improving knee mobility and function. These results should be considered only preliminary: Further research is needed to completely describe the clinical effectiveness of these formulations.

Luseogliflozin increases beta cell proliferation through humoral factors that activate an insulin receptor- and IGF-1 receptor-independent pathway.

AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice. METHODS: We treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets. RESULTS: SGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (ßIRKO) beta cells with serum from both luseogliflozin- and OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets. CONCLUSIONS/INTERPRETATION: These results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.

Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a non-cell-autonomous fashion.

FoxO proteins are major targets of insulin action, and FoxO1 mediates the effects of insulin on hepatic glucose metabolism. We reported previously that serpinB1 is a liver-secreted factor (hepatokine) that promotes adaptive ß-cell proliferation in response to insulin resistance in the liver-specific insulin receptor knockout (LIRKO) mouse. Here we report that FoxO1 plays a critical role in promoting serpinB1 expression in hepatic insulin resistance in a non-cell-autonomous manner. Mice lacking both the insulin receptor and FoxO1 (LIRFKO) exhibit reduced ß-cell mass compared with LIRKO mice because of attenuation of ß-cell proliferation. Although hepatic expression of serpinB1 mRNA and protein levels was increased in LIRKO mice, both the mRNA and protein levels returned to control levels in LIRFKO mice. Furthermore, liver-specific expression of constitutively active FoxO1 in transgenic mice induced an increase in hepatic serpinB1 mRNA and protein levels in refed mice. Conversely, serpinB1 mRNA and protein levels were reduced in mice lacking FoxO proteins in the liver. ChIP studies demonstrated that FoxO1 binds to three distinct sites located ∼9 kb upstream of the serpinb1 gene in primary mouse hepatocytes and that this binding is enhanced in hepatocytes from LIRKO mice. However, adenoviral expression of WT or constitutively active FoxO1 and insulin treatment are sufficient to regulate other FoxO1 target genes (IGFBP-1 and PEPCK) but not serpinB1 expression in mouse primary hepatocytes. These results indicate that liver FoxO1 promotes serpinB1 expression in hepatic insulin resistance and that non-cell-autonomous factors contribute to FoxO1-dependent effects on serpinB1 expression in the liver.

How, When, and Where Do Human ß-Cells Regenerate?

PURPOSE OF REVIEW: Pancreatic ß-cells play a critical role in whole-body glucose homeostasis by regulating the release of insulin in response to minute by minute alterations in metabolic demand. As such, ß-cells are staunchly resilient but there are circumstances where they can become functionally compromised or physically lost due to pathophysiological changes which culminate in overt hyperglycemia and diabetes. RECENT FINDINGS: In humans, ß-cell mass appears to be largely defined in the postnatal period and this early replicative and generative phase is followed by a refractory state which persists throughout life. Despite this, efforts to identify physiological and pharmacological factors which might re-initiate ß-cell replication (or cause the replenishment of ß-cells by neogenesis or transdifferentiation) are beginning to bear fruit. Controlled manipulation of ß-cell mass in humans still represents a holy grail for therapeutic intervention in diabetes, but progress is being made which may lead to ultimate success.

Frailty modifications and prognostic impact in older patients admitted in acute care.

BACKGROUND: Frailty is a predictor of adverse outcomes in older subjects. AIMS: The aims of this study are to (1) measure the frailty status and its changes occurring during the hospital stay, (2) determine the relationships among frailty and adverse outcomes. METHODS: Frailty was assessed using a 46-item Frailty Index (FI) in 156 patients admitted to an Acute Geriatric Medicine Unit. The FI was calculated within 24 h from the hospital admission (aFI) and at his/her discharge (dFI). Patients were followed up to 12 months after the hospital discharge. RESULTS: A statistically significant difference was reported between the aFI (0.31, IQR 0.19-0.44) and the dFI (0.29, IQR 0.19-0.40; p = 0.04). The aFI was directly associated with the risk of in-hospital death (OR = 5.9; 95% CI 2.0-17.5; p = 0.001), 1 year mortality (OR = 5.5, 95% CI 2.4-12.7, p < 0.001) and re-hospitalization (OR = 6.3, 95% CI 2.2-17.9, p = 0.03). CONCLUSION: Frailty is a strong predictor of negative endpoints in hospitalized older persons. DISCUSSION: Frailty assessment from routinely collected clinical data may provide important insights about the biological status of the individual and promote the personalization of care.

Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus.

Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552(∗)] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552(∗) alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3ß phosphorylation that is observed after wild-type APPL1 transfection. These findings-linking APPL1 mutations to familial forms of diabetes-reaffirm the critical role of APPL1 in glucose homeostasis.

Relationship between blood pressure and frailty in older hypertensive outpatients.

BACKGROUND: The benefits and risks of treating hypertension in old and frail patients are debated. AIM: The aim of the present study is to measure the frailty status in older patients with hypertension and determine the relationships existing between blood pressure (BP) values and frailty. METHODS: Frailty was retrospectively assessed by using the frailty index (FI) in 56 hypertensive old outpatients. Patients with an FI > 0.25 were classified as frail. RESULTS: Forty-five out of 56 (80%) had a FI > 0.25. A statistically significant inverse correlation was found between FI and systolic BP (r = -0.319, p = 0.016), orthostatic systolic BP (r = -0.408, p = 0.002), orthostatic diastolic BP (r = -0.299, p = 0.025), and orthostatic pulse pressure (r = -0.297, p = 0.026). DISCUSSION: Frailer subjects appear as over-treated according to current European guidelines. CONCLUSIONS: FI can play an important role in the clinical setting by supporting the identification of subjects at risk and allowing an improved provision of adapted and personalized care.

Denosumab Inhibition of RANKL and Insulin Resistance in Postmenopausal Women with Osteoporosis.

The tumor necrosis factor-related cytokine receptor activator of nuclear factor kappa B ligand (RANKL) has been proposed as predictor of incident type 2 diabetes mellitus, and experimental blockade of RANKL resulted in a marked improvement of glucose tolerance. Denosumab is a fully human monoclonal antibody that binds to RANKL and prevents osteoclast formation, function and survival, leading to fracture risk reduction. The aim of our study was to investigate glucometabolic parameters, insulin resistance, and lipid profile in non-diabetic women receiving denosumab. Forty-eight women with postmenopausal osteoporosis were enrolled and treated with a subcutaneous dose (60 mg) of denosumab. At baseline and after 4, 12, ad 24 weeks, insulin resistance was computed by homeostasis model assessment of insulin resistance (HOMA-IR) and total cholesterol, triglycerides and HDL cholesterol were also measured. At baseline and after 24 weeks, bone turn-over markers were also evaluated. After denosumab administration, with the exception of a slight reduction of insulin and HOMA-IR values after 4 weeks (p < 0.05), neither fasting plasma glucose nor insulin and insulin resistance were significantly changed. Lipid parameters remained unchanged at each time-points of this study. A reduction of C-telopeptide of type 1 collagen (-63%, p < 0.0001) and osteocalcin (-45%, p < 0.0001), as bone resorption and formation markers, respectively, were observed after 24 weeks. Baseline levels of bone biomarkers were not predictive of HOMA-IR, and changes of osteocalcin were not associated to markers of glucose control. In osteoporotic otherwise healthy postmenopausal women, denosumab was not associated with relevant modification of insulin resistance and lipid profile.

Effects of strontium ranelate on bone mass and bone turnover in women with thalassemia major-related osteoporosis.

Subjects affected by thalassemia major (TM) often have reduced bone mass and increased fracture risk. Strontium ranelate (SrR) is an effective treatment for postmenopausal and male osteoporosis. To date, no data exist on the use of SrR in the treatment of TM-related osteoporosis. Our aim was to evaluate the effects of SrR on bone mineral density (BMD), bone turnover markers and inhibitors of Wnt signaling (sclerostin and DKK-1). Twenty-four TM osteoporotic women were randomized to receive daily SrR 2 g or placebo in addition to calcium carbonate (1,000 mg) and vitamin D (800 IU). BMD at the lumbar spine and femoral neck, bone turnover markers (C-terminal telopeptide of procollagen type I [CTX], bone-specific alkaline phosphatase [BSAP]) and insulin-like growth factor-1 (IGF-1), sclerostin and DKK-1 were assessed at baseline and after 24 months. Back pain was measured by visual analog scale (VAS) every 6 months. After 24 months, TM women treated with SrR had increased their spine BMD values in comparison to baseline (p < 0.05). Moreover, they also exhibited a reduction of CTX and sclerostin levels (but not DKK-1) and exhibited an increase of BSAP and IGF-1 (p < 0.05); however, no significant changes were observed in the placebo group. In the SrR group, a reduction of back pain was observed after 18 months in comparison to baseline (p < 0.05) and after 24 months in comparison to placebo (p < 0.05). Our study reports for the first time the effects of SrR in the treatment of TM-related osteoporosis. SrR treatment improved BMD and normalized bone turnover markers, as well as lowering sclerostin serum levels.

Calcifediol improves lipid profile in osteopenicatorvastatin-treated postmenopausal women.

BACKGROUND: Low vitamin D serum levels have been associated with unfavourable lipid profile and poorer response to atorvastatin. Aims of this study were to test the effects of 25-hydroxyvitamin D3 (calcifediol) compared to parental vitamin D3 (cholecalciferol) supplementation on modifications of plasma 25(OH)D levels and lipid profile. MATERIALS AND METHODS: Fifty-seven postmenopausal women (aged 59.03 ± 6.73 years) who were at low risk of fracture and with basal plasma 25(OH)D < 30 ng/mL were included if they were on atorvastatin treatment prescribed as appropriate. Recruited women were randomized to receive oral calcifediol or cholecalciferol, both at a dose of 140 µg according to a weekly regimen. RESULTS: At baseline, 25(OH)D was negatively associated with BMI (r = -0.37; P = 0.004), total cholesterol (r = -0.31; P = 0.01) and LDL-C (r = -0.32; P = 0.02). After 24 weeks, 25(OH)D increased significantly in both groups (P < 0.001), although higher levels were obtained with calcifediol as compared with cholecalciferol (P < 0.001). Only in the calcifediol group, a significant reduction of LDL-C (P = 0.01) and an increase of HDL-C (P = 0.02) were obtained, even after adjustment for age, and baseline BMI, 25(OH)D and lipid levels (P < 0.05). The percentage changes in 25(OH)D levels were associated with the variations of LDL-C (r = -0.44; P = 0.01) and HDL-C levels (r = 0.30; P = 0.10). CONCLUSION: Calcifediol administration in osteopenic and dyslipidemic postmenopausal women with low 25(OH)D improves lipid profile when added to an ongoing atorvastatin treatment.

Redox regulation of m6A methyltransferase METTL3 in ß-cells controls the innate immune response in type 1 diabetes.

Type 1 diabetes (T1D) is characterized by the destruction of pancreatic ß-cells. Several observations have renewed the interest in ß-cell RNA sensors and editors. Here, we report that N6-methyladenosine (m6A) is an adaptive ß-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m6A writer methyltransferase 3 (METTL3) levels increase drastically in ß-cells at T1D onset but rapidly decline with disease progression. m6A sequencing revealed the m6A hypermethylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-ßH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in ß-cells delayed diabetes progression in the non-obese diabetic mouse model of T1D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human ß-cells. Collectively, we report that m6A regulates the innate immune response at the ß-cell level during the onset of T1D in humans.

Fracture risk assessment in postmenopausal women referred to an Italian center for osteoporosis: a single day experience in Messina.

Osteoporosis is a major cause of fragility fractures and these are responsible of large social burden; nevertheless, osteoporosis often remains an underdiagnosed disease. FRAX is a new and simple validate fracture risk assessment tool helping physicians to select patients at high risk of future fragility fractures. To promote early diagnosis of osteoporosis, we evaluated fracture risk by FRAX and performed phalangeal quantitative ultrasound (QUS) measurements in a population of postmenopausal women referring to our center during the World Osteoporosis Day on 20th October 2011. Eighty post-menopausal women (age 60.8±8.6) were screened and the risk of major osteoporotic and hip fractures over ten years was calculated by considering multiple clinical risk factors (CRFs). The median risk of major osteoporotic fracture (%) was 4.9 (3.5-8.6) in women younger than 55 years, 7.3 (5.4-11) in women aged between 55 and 65 years and 17.5 (11-27) in women older than 65 years; the median risk of hip fracture (%) was 0.6 (0.3-1.3), 1.5 (0.9-2.5) and 7.2 (3.1-14) respectively. QUS measurements, were lower in the older women and when multiple CRFs coexisted, and were found to correlate with fracture risk, especially with hip fracture risk (p<0.05). Within one month from the screening, 75% (44/59) of the women over 55 years came back and received a diagnosis of osteoporosis/osteopenia by dual x-ray absorptiometry (DXA); a positive association between DXA and QUS measurements was observed (p<0.0001). Adequate treatment of these subjects could reduce fracture rates, improve the quality of life, and reduce the social costs of osteoporosis.

Efficacy and Safety of Biological Therapies and JAK Inhibitors in Older Patients with Inflammatory Bowel Disease.

With the introduction of more and more monoclonal antibodies selectively targeting various mediators of the immune system, together with Janus-Kinase (JAK)-inhibitors with variable affinities towards different JAK subtypes, the available therapeutic options for the treatment of inflammatory bowel diseases (IBD) have undergone an acceleration in the last five years. On the other hand, the prevalence of IBD patients over 65-years-old is steadily increasing, and, with this, there is a large population of patients that presents more comorbidities, polypharmacy, and, more frequently, frailty compared to younger patients, exposing them to potentially major risks for adverse events deriving from newer therapies, e.g., infections, cardiovascular risks, and malignancies. Unfortunately, pivotal trials for the commercialization of new therapies rarely include older IBD patients, and those with serious comorbidities are virtually excluded. In the present review, we focus on existing literature from pivotal trials and real-world studies, analyzing data on efficacy/effectiveness and safety of newer therapies in older IBD patients with special emphasis on comorbidities and frailty, two distinct but intercorrelated aspects of the older population since age by itself seems to be of minor importance.