Slowness in writing numbers in words and in digits among children with a specific learning disorder (SLD) and typically developing (TD).

INSTRUCTION: Children with a Specific Learning Disorder (SLD) write linguistic material more slowly than children with typically developing (TD). However, it is not known whether the same difficulties are present when they write numbers. The goal of the present study was to fill this gap and to compare TD's and SLD's speed in writing numbers both in words and in digits. METHODS: Therefore, we examined the ability to write numbers in words and digits (numerals) in a sample of sixth- to eighth-grade children diagnosed with SLD. We assessed 32 children with SLD (17 males and 15 females) and a control group of students with TD matched for sex, age, and grade with two writing speed tasks: writing numbers in words and in digits. The two tasks were administered both in normal condition (N) and in articulatory suppression condition (AS). RESULTS: We found that 6th to 8th graders with a SLD were slower than TD children when writing numbers, both in words and in digits, and their slowness was similar in the two cases. However, when the tasks were carried out under a condition of articulatory suppression, the SLD group exhibited a conspicuous impairment, only when writing numbers in words. A similar pattern of performance was observed also in the case of writing errors. CONCLUSION: We concluded that children with SLD have a general speed problem that may affect writing of different materials but also a specific problem related to the processing of phonological information during writing.

Copy Skills and Writing Abilities in Children With and Without Specific Learning Disabilities.

Copying a text quickly and accurately is important both in school and in daily life. However, this skill has never been systematically studied, either in children with typical development (TD) or in children with specific learning disabilities (SLD). The aim of this research was to study the features of a copy task and its relationship with other writing tasks. For this purpose, 674 children with TD and 65 children with SLD from Grades 6 through 8 in Italy were tested with a copy task and other writing assessment tasks, measuring three aspects of writing: handwriting speed, spelling, and expressive writing. Children with SLD performed worse on the copy task, both in terms of speed and accuracy, than children with TD. Copy speed was predicted by grade level and by all three major writing skills for children with TD but only by handwriting speed and spelling for children with SLD. Copy accuracy was predicted by gender and the three major writing skills for children with TD but only by spelling for children with SLD. These results suggest that children with SLD also have difficulty copying a text and benefit less than children with TD from their other writing skills.

Alarming Drop in Early Stage Colorectal Cancer Diagnoses After COVID-19 Outbreak: A Real-World Analysis from the Italian COVID-DELAY Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time. METHODS: All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. RESULTS: A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01). CONCLUSIONS: Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic-therapeutic pathways proper operation after March 2020.

The Role of Working Memory on Writing Processes.

Literature has extensively demonstrated the coordination role of working memory (WM) in complex tasks such as writing. However, previous studies mostly concentrated on the relation between passive WM (e.g., WM span) components and specific writing tasks (e.g., dictation). Here, we aimed to investigate the relationship between different writing skills and the performance on a WM updating task measuring the more active components of WM. From a pool of 160 Italian pupils (grades 3-5), we selected 46 children divided in two groups based on their WM updating performance. The first group consisted of 21 children with low WM updating performance (≤10th percentile), the second group consisted of 25 children with high WM updating performance (≥90th percentile). All children were tested on a battery of writing tasks to assess writing speed, orthographic skills, and competences in expressive writing. MANOVAs and a discriminant analysis were computed to assess group differences and the contribution of the different writing tests in correctly predicting group membership. The results revealed that children with high WM updating performance scored significantly higher than children with low WM updating performance on most of the writing tasks. These results highlight the relevant role of the active components of WM on writing processes. In addition, they suggest that the improvement of writing skills should rely not only on the training of the specific processes implied in this complex task, but also on the training of the cognitive processes that support them, such as active WM processes.

"Ecce Homo" by Antonello da Messina, from non-invasive investigations to data fusion and dissemination.

Scientific investigations of artworks are crucial in terms of preservation since they provide a measurable evaluation of the materials and the state of conservation. This is the case of Antonello da Messina's painting "Ecce Homo": its delicate state of conservation, with the need for constant monitoring, required a broad and in-depth diagnostic campaign to support the restorers. The project was carried out entirely in situ using non-invasive cutting-edge techniques and proposes a multimodal and data-centric approach, integrating 3D and 2D methodologies. The surface irregularities and the support were analysed with a structured-light 3D scanner and X-ray tomography. The painting materials were investigated with X-ray fluorescence scanning (MA-XRF) and reflectance hyperspectral imaging (HSI). Primarily, the data were jointly used for a scientific scope and provided new knowledge of the painting in terms of materials and painting techniques. In addition, two web-based interactive platforms were developed: one to provide restorers and experts with a new perspective of the hidden geometries of the painting, and the other targeted at the general public for dissemination purposes. The results of the Ecce Homo scientific analysis were exhibited, using a touch-screen interface, and developed for different user levels, from adults to kids.

A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step?

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.

Instrumental and Non-Instrumental Evaluation of 4-Meter Walking Speed in Older Individuals.

BACKGROUND: Manual measurement of 4-meter gait speed by a stopwatch is the gold standard test for functional assessment in older adults. However, the accuracy of this technique may be biased by several factors, including intra- and inter-operator variability. Instrumental techniques of measurement using accelerometers may have a higher accuracy. Studies addressing the concordance between these two techniques are missing. The aim of the present community-based observational study was to compare manual and instrumental measurements of 4-meter gait speed in older individuals and to assess their relationship with other indicators of physical performance. METHODS: One-hundred seventy-two (69 men, 103 women) non-disabled community-dwellers aged ≥65 years were enrolled. They underwent a comprehensive geriatric assessment including physical function by Short Physical Performance Battery (SPPB), hand grip strength, and 6-minute walking test (6MWT). Timed usual walking speed on a 4-meter course was assessed by using both a stopwatch (4-meter manual measurement, 4-MM) and a tri-axial accelerometer (4-meter automatic measurement, 4-MA). Correlations between these performance measures were evaluated separately in men and women by partial correlation coefficients. RESULTS: In both genders, 4-MA was associated with 4-MM (men r = 0.62, p<0.001; women r = 0.73, p<0.001), handgrip strength (men r = 0.40, p = 0.005; women r = 0.29, p = 0.001) and 6MWT (men r = 0.50, p = 0.0004; women r = 0.22, p = 0.048). 4-MM was associated with handgrip strength and 6MWT in both men and women. Considering gait speed <0.6 m/s as diagnostic of dismobility syndrome, the two methods of assessment disagreed, with a different categorization of subjects, in 19% of men and 23% of women. The use of accelerometer resulted in 29 (13 M, 16 F) additional diagnoses of dismobility, compared with the 4-MM. CONCLUSIONS: In an older population, the concordance of gait speeds manually or instrumentally assessed is not optimal. The results suggest that manual measures might lead to misclassification of a substantial number of subjects. However, longitudinal studies using standardized and validated procedures aimed at the comparison of different techniques are needed before recommending the use of accelerometers in comprehensive geriatric assessment.

Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women.

BACKGROUND: In vitro evidence suggests anti-estrogenic properties for retinol and carotenoids, supporting a chemo-preventive role of these phytochemicals in estrogen-dependent cancers. During aging there are significant reductions in retinol and carotenoid concentrations, whereas estradiol levels decline during menopause and progressively increase from the age of 65. We aimed to investigate the hypothesis of a potential relationship between circulating levels of retinol, carotenoids, and estradiol (E2) in a cohort of late post-menopausal women. METHODS: We examined 512 women ≥ 65 years from the InCHIANTI study. Retinol, α-caroten, ß-caroten, ß-criptoxantin, lutein, zeaxanthin, and lycopene levels were assayed at enrollment (1998-2000) by High-Performance Liquid Chromatography. Estradiol and testosterone (T) levels were assessed by Radioimmunometry (RIA) and testosterone-to-estradiol ratio (T/E2), as a proxy of aromatase activity, was also calculated. General linear models adjusted for age (Model 1) and further adjusted for other confounders including Body Mass Index (BMI) BMI, smoking, intake of energy, lipids, and vitamin A; C-Reactive Protein, insulin, total cholesterol, liver function, and testosterone (Model 2) were used to investigate the relationship between retinol, carotenoids, and E2 levels. To address the independent relationship between carotenoids and E2 levels, factors significantly associated with E2 in Model 2 were also included in a fully adjusted Model 3. RESULTS: After adjustment for age, α-carotene (ß ± SE = -0.01 ± 0.004, p = 0.02) and ß-carotene (ß ± SE = -0.07 ± 0.02, p = 0.0007) were significantly and inversely associated with E2 levels. α-Carotene was also significantly and positively associated with T/E2 ratio (ß ± SE = 0.07 ± 0.03, p = 0.01). After adjustment for other confounders (Model 2), the inverse relationship between α-carotene (ß ± SE = -1.59 ± 0.61, p = 0.01), ß-carotene (ß ± SE = -0.29 ± 0.08, p = 0.0009), and E2 persisted whereas the relationship between α-carotene and T/E2 ratio was attenuated (ß ± SE = 0.22 ± 0.12, p = 0.07). In a fully adjusted model (Model 3), only ß-carotene (ß ± SE = -0.05 ± 0.02, p = 0.03) was significantly and inversely associated with E2 levels independent of α-carotene. No association was found between retinol, total non-pro-vitamin A carotenoids, lutein, zeaxanthin, and lycopene, and E2 levels. CONCLUSIONS: In older women, ß-carotene levels are independently and inversely associated with E2.

INSULIN-LIKE GROWTH FACTOR-1 AND ANEMIA IN OLDER SUBJECTS: THE INCHIANTI STUDY.

OBJECTIVE: Recent studies indicate a role for the age-related decline of anabolic hormones, especially testosterone, in the onset of "anemia of aging." Some of testosterone's erythropoietic activities are mediated by insulin-like growth factor (IGF)-1, which also seems to have independent erythropoietic effects. However, the associations among IGF-1, anemia, and hemoglobin (Hb) have not been adequately investigated in older populations. METHODS: We used data from a representative sample of 953 subjects ≥65 years who participated in the InCHIANTI (Invecchiare in Chianti) Study and were not on growth hormone (GH) or erythropoietin therapy and were not diagnosed with hematologic malignancies or other cancers. Anemia was defined according to the World Health Organization (WHO) criteria by Hb level ≤13 g/dL in males and ≤12 g/dL in females. Backward multiple regression analyses including age, IGF binding protein (IGFBP)-3, testosterone, comorbidities, inflammatory markers, and anemia-related measures were used to address the relationship between IGF-1 and Hb and between IGF-1 and anemia in both sexes. RESULTS: We found that 46/410 (11.2%) males and 71/543 (13.0%) females were defined as anemic. After adjustment for age, anemic males (100 ± 54 vs. 130 ± 56, P<.001) and females (89.1 ± 48 vs. 110 ± 52, P = .001) exhibited lower IGF-1 levels than their nonanemic counterparts. IGF-1 levels were independently and negatively associated with anemia in males (ß ± SE = -0.0005 ± 0.0002, P = .04) but not in females (ß ± SE = -0.0002 ± 0.0002, P = .40). In both males (ß ± SE = 0.002 ± 0.001, P = .03) and females (ß ± SE = 0.002 ± 0.0009, P = .03), IGF-1 levels were independently and positively associated with Hb levels. CONCLUSION: In older males but not in females, IGF-1 levels are negatively associated with anemia. IGF-1 levels are independent and positive determinants of Hb concentration in both sexes.

DHEA and cognitive function in the elderly.

The adrenal prohormone dehydroepiandrosterone (DHEA) and its sulphate conjugate (DHEAS) steadily decrease with age by 10% per decade reaching a nadir after the age of 80. Both DHEA and DHEAS (DHEA/S) exert many biological activities in different tissues and organs. In particular, DHEA and DHEAS are produced de novo in the brain, hence their classification as neurosteroids. In humans, the brain-to-plasma ratios for DHEA and DHEAS are 4-6.5 and 8.5, respectively, indicating a specific neuroendocrine role for these hormones. DHEA/S stimulates neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion. Together with antioxidant, anti-inflammatory and anti-glucocorticoid properties, it has been hypothesized a neuroprotective effect for DHEA/S. We conducted an accurate research of the literature using PubMed. In the period of time between 1994 and 2013, we selected the observational human studies testing the relationship between DHEA/S and cognitive function in both sexes. The studies are presented according to the cross-sectional and longitudinal design and to the positive or neutral effects on different domains of cognitive function. We also analysed the Clinical Trials, available in the literature, having cognitive domains as the main or secondary outcome. Although the cross-sectional evidence of a positive association between DHEA/S and cognitive function, longitudinal studies and RCTs using DHEA oral treatment (50mg/day) in normal or demented adult-older subjects, have produced conflicting and inconsistent results. In summary, the current data do not provide clear evidence for the usefulness of DHEA treatment to improve cognitive function in adult-older subjects. This article is part of a Special Issue entitled 'Essential role of DHEA'.

The Role of the Multiple Hormonal Dysregulation in the Onset of "Anemia of Aging": Focus on Testosterone, IGF-1, and Thyroid Hormones.

Anemia is a multifactorial condition whose prevalence increases in both sexes after the fifth decade of life. It is a highly represented phenomenon in older adults and in one-third of cases is "unexplained." Ageing process is also characterized by a "multiple hormonal dysregulation" with disruption in gonadal, adrenal, and somatotropic axes. Experimental studies suggest that anabolic hormones such as testosterone, IGF-1, and thyroid hormones are able to increase erythroid mass, erythropoietin synthesis, and iron bioavailability, underlining a potential role of multiple hormonal changes in the anemia of aging. Epidemiological data more consistently support an association between lower testosterone and anemia in adult-older individuals. Low IGF-1 has been especially associated with anemia in the pediatric population and in a wide range of disorders. There is also evidence of an association between thyroid hormones and abnormalities in hematological parameters under overt thyroid and euthyroid conditions, with limited data on subclinical statuses. Although RCTs have shown beneficial effects, stronger for testosterone and the GH-IGF-1 axis and less evident for thyroid hormones, in improving different hematological parameters, there is no clear evidence for the usefulness of hormonal treatment in improving anemia in older subjects. Thus, more clinical and research efforts are needed to investigate the hormonal contribution to anemia in the older individuals.

Identification and treatment of older persons with sarcopenia.

In the last decades, sarcopenia in older persons has been operationalized by the assessment of lean body mass, muscle strength and/or physical performance. Several definitions of sarcopenia, using different parameters and cut-offs, have been proposed. However, which is the best definition to describe and to assess this condition is still matter of debate. Hand grip strength has been suggested as better predictor of incident mobility impairment and mortality, than skeletal muscle mass. In the light of the current knowledge, we sought to propose an operative approach for identifying and treating sarcopenic older persons according to main categories of sarcopenia: the age-related or primary sarcopenia and disease-related or secondary sarcopenia. We suggest that a quantitative assessment of grip strength alone might be sufficient to identify patients with primary sarcopenia. When chronic diseases accompany the ageing process, the combined assessment of muscle strength plus a balance test could be more appropriate. The identification of tests and pathological relevant cut-offs that facilitates the entry of sarcopenia into the clinical practice, could step forward researchers and physicians. This could be important for planning multidisciplinary models to maximize the maintenance of locomotive abilities especially in older persons affected by chronic diseases such as Parkinson's disease.

Effects of transdermal testosterone treatment on inflammatory markers in elderly males.

OBJECTIVE: During the male aging process, testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these 2 phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T. METHODS: A total of 108 healthy males >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University and randomized to 60-cm2 T or a placebo patch for 36 months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of the inhibitory effect of T on inflammation. We evaluated 70 males (42 in the T group) who had banked specimens from multiple time points available for assays of T, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, soluble TNF-α receptor-1 (TNFR1), interleukin-6 (IL-6), and soluble IL-6 receptors (sIL6r and sgp130). RESULTS: The mean age ± SD at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months did not induce significant decreases in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-α (P = .03) and sgp130 (P = .01). Significant differences in estimated means of TNFR1 (but not other inflammatory markers), with lower levels in the T group, were observed at the 36-month time point. In T-treated subjects we found an almost significant treatment x time interaction term TNFR1 (P = .02) independent of total body fat content as assessed by dual energy X-ray absorptiometry (DXA). No serious adverse effect was observed. CONCLUSIONS: Transdermal T treatment of older males for 36 months is not associated with significant changes in inflammatory markers.

Relationship between vitamin D and inflammatory markers in older individuals.

In older persons, vitamin D insufficiency and a subclinical chronic inflammatory status frequently coexist. Vitamin D has immune-modulatory and in vitro anti-inflammatory properties. However, there is inconclusive evidence about the anti-inflammatory role of vitamin D in older subjects. Thus, we investigated the hypothesis of an inverse relationship between 25-hydroxyvitamin D (25(OH)D) and inflammatory markers in a population-based study of older individuals. After excluding participants with high-sensitivity C-reactive protein (hsCRP) ≥ 10 mg/dl and those who were on chronic anti-inflammatory treatment, we evaluated 867 older adults ≥65 years from the InCHIANTI Study. Participants had complete data on serum concentrations of 25(OH)D, hsCRP, tumor necrosis factor (TNF)-α, soluble TNF-α receptors 1 and 2, interleukin (IL)-1ß, IL-1 receptor antagonist, IL-10, IL-18, IL-6, and soluble IL-6 receptors (sIL6r and sgp130). Two general linear models were fit (model 1-adjusted for age, sex, and parathyroid hormone (PTH); model 2-including covariates of model 1 plus dietary and smoking habits, physical activity, ADL disability, season, osteoporosis, depressive status, and comorbidities). The mean age was 75.1 ± 17.1 years ± SD. In model 1, log(25OH-D) was significantly and inversely associated with log(IL-6) (ß ± SE = -0.11 ± 0.03, p = <0.0001) and log (hsCRP) (ß ± SE = -0.04 ± 0.02, p = 0.04) and positively associated with log(sIL6r) (ß ± SE = 0.11 ± 0.04, p = 0.003) but not with other inflammatory markers. In model 2, log (25OH-D) remained negatively associated with log (IL-6) (ß ± SE = -0.10 ± 0.03, p = 0.0001) and positively associated with log(sIL6r) (ß ± SE = 0.11 ± 0.03, p = 0.004) but not with log(hsCRP) (ß ± SE = -0.01 ± 0.03, p = 0.07). 25(OH)D is independently and inversely associated with IL-6 and positively with sIL6r, suggesting a potential anti-inflammatory role for vitamin D in older individuals.

Vitamin D and endothelial vasodilation in older individuals: data from the PIVUS study.

CONTEXT: Vitamin D plays a role in a wide range of extraskeletal processes, including vascular function. Endothelial dysfunction is a predictor of cardiovascular disease, especially in older subjects. However, the relationship between vitamin D levels and indexes of endothelial vasodilation has never been fully addressed in older individuals. OBJECTIVE: The objective of this study was to examine the association between vitamin D and endothelial function in a large community-based sample of older subjects. METHODS: This cross-sectional study involved 852 community-dwelling men and women aged 70 years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), with complete data on vascular function and 25-hydroxyvitamin D. We evaluated endothelium-dependent vasodilation by an invasive forearm technique with acetylcholine, endothelium-independent vasodilation by sodium nitroprussiate, flow-mediated vasodilation, and the pulse wave analysis (reflectance index). Vitamin D levels were measured by chemiluminescence. We used multivariate regression models adjusted for body mass index (model 1) and for multiple confounders (high-sensitivity C-reactive protein, insulin, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, smoking, sex hormones, season of blood collection, hypertension, diabetes, cardiovascular medications and diseases, statin usage, plasma calcium and calcium intake, PTH, physical exercise, liver and kidney function tests, albumin; model 2). RESULTS: In women, but not in men, vitamin D levels were positively associated with endothelium-independent vasodilation in both model 1 (ß ± SE = 1.41 ± 0.54; P = .001), and model 2 (ß ± SE = 2.01 ± 0.68; P = .003).We found no significant relationship between vitamin D levels and endothelium-dependent vasodilation, flow-mediated vasodilation, and reflectance index in both sexes. CONCLUSIONS: In older women, but not in men, vitamin D is positively and independently associated with EIDV.

The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men.

The role of nutritional status as key factor of successful aging is very well recognized. Among the different mechanisms by which nutrients may exert their beneficial effects is the modulation of the hormonal anabolic milieu, which is significantly reduced with aging. Undernutrition and anabolic hormonal deficiency frequently coexist in older individuals determining an increased risk of mobility impairment and other adverse outcomes. Mineral assessment has received attention as an important determinant of physical performance. In particular, there is evidence that magnesium exerts a positive influence on anabolic hormonal status, including Testosterone, in men. In this review we summarize data from observational and intervention studies about the role of magnesium in Testosterone bioactivity and the potential underlying mechanisms of this relationship in male subjects. If larger studies will confirm these pivotal data, the combination of hormonal and mineral replacements might be adopted to prevent or delay the onset of disability in the elderly.

Multiple hormonal dysregulation as determinant of low physical performance and mobility in older persons.

Mobility-disability is a common condition in older individuals. Many factors, including the age-related hormonal dysregulation, may concur to the development of disability in the elderly. In fact, during the aging process it is observed an imbalance between anabolic hormones that decrease (testosterone, dehydroepiandrosterone sulphate (DHEAS), estradiol, insulin like growth factor-1 (IGF-1) and Vitamin D) and catabolic hormones (cortisol, thyroid hormones) that increase. We start this review focusing on the mechanisms by which anabolic and catabolic hormones may affect physical performance and mobility. To address the role of the hormonal dysregulation to mobility-disability, we start to discuss the contribution of the single hormonal derangement. The studies used in this review were selected according to the period of time of publication, ranging from 2002 to 2013, and the age of the participants (≥65 years). We devoted particular attention to the effects of anabolic hormones (DHEAS, testosterone, estradiol, Vitamin D and IGF-1) on both skeletal muscle mass and strength, as well as other objective indicators of physical performance. We also analyzed the reasons beyond the inconclusive data coming from RCTs using sex hormones, thyroid hormones, and vitamin D (dosage, duration of treatment, baseline hormonal values and reached hormonal levels). We finally hypothesized that the parallel decline of anabolic hormones has a higher impact than a single hormonal derangement on adverse mobility outcomes in older population. Given the multifactorial origin of low mobility, we underlined the need of future synergistic optional treatments (micronutrients and exercise) to improve the effectiveness of hormonal treatment and to safely ameliorate the anabolic hormonal status and mobility in older individuals.

Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals.

Proton pump inhibitors (PPIs) are highly effective in the treatment of upper gastrointestinal acid-related conditions and are fast becoming one of the most frequently prescribed treatments in adult or older persons. Recent data show that long-term use of PPIs in older subjects is associated with important undesirable effects, including a higher risk of osteoporotic fractures. The mechanisms of this association are unclear and the relationship between the use of PPIs and parameters of bone mass and geometry has never been fully explored. This study investigates the relationship between the chronic use of PPIs and the parameters of bone mass (cortical and trabecular bone mineral density - vBMDc and vBMDt) and bone geometry (cortical and trabecular cross sectional area - tCSA and cCSA) in older individuals. The study population consisted of 1038 subjects (452 men and 586 women) 65years or older, selected from the InCHIANTI study, with complete information on computerized tomography performed at tibial level (pQCT) and on medications. Participants were classified as PPI users and nonusers based on self-report of PPI use over the last 15days, with PPI users (36 subjects, 14 men and 22 women) making up 3.4% of the study population (mean age 75.7±7.4years). The relationship between use of PPIs and pQCT bone parameters was tested by multivariate linear regression analysis adjusted for age, sex and several clinical factors and/or statistically confounding variables identified by partial correlation coefficient and Spearman partial rank order correlation coefficients, as appropriate (age, sex, BMI, caloric intake, IGF-1, IL-6, calcium, estradiol, bioavailable testosterone, vitamin D, parathyroid hormone, cross-sectional muscle area, and level of physical activity). PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5±54.8 vs. 207.9±59.4, p=0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc, tCSA and cCSA between PPI users and nonusers. In community dwelling older persons, the use of PPIs is inversely associated with vBMDt, an early marker of the osteoporotic process. These findings suggest that PPI use might increase the risk of fractures in older subjects through its detrimental effects on trabecular bone.

IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty.

The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects.

Insulin-like growth factor-1 bioactivity plays a prosurvival role in older participants.

The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second-third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population.