Lack of Immune Resilience Negatively Affects Physical Resilience: Results From the InCHIANTI Follow-Up Study.

There is consistent evidence that immune response declines with aging, with wide interindividual variability and a still unclear relationship with the development of frailty. To address this question, we assessed the role of immune resilience (capacity to restore immune functions), operationalized as the neutrophil-to-lymphocytes ratio (NL-ratio) and monocytes-to-lymphocytes ratio (ML-ratio), in the pathway that from robust status shifts to pre-frailty and frailty, and finally to death. The InCHIANTI study enrolled representative samples from the registry lists of 2 towns in Tuscany, Italy. Baseline data were collected in 1998, with follow-up visits every 3 years. The 1 453 participants enrolled were assessed and followed for lifestyle, clinical condition, physical performance, clinical, and physiological measures. For the purpose of this analysis, we used only 1 022 subjects aged 65 or older at baseline. Participants in the 3 highest deciles of distribution for NL-ratio (>2.44) were more likely to experience a transition from robust to pre-frail, and to overt frailty status. Moreover, NL-ratio (tenth decile > 3.53) and ML-ratio (tenth decile > 2.02) were both predictors of mortality. These results were independent of chronological age, sex, comorbidities, and chronic low-grade inflammation assessed by high sensitivity C-reactive protein measurement. The 2 leucocytes-derived ratios, NL-ratio and ML-ratio, represent markers of immune resilience and predict changes in physical resilience and mortality. These biomarkers are inexpensive because they are based on data routinely collected in clinical practice and can be used to assess the risk of frailty progression and mortality. Clinical Trials Registration Number: NCT01331512.

Neutrophil, lymphocyte count, and neutrophil to lymphocyte ratio predict multimorbidity and mortality-results from the Baltimore Longitudinal Study on Aging follow-up study.

Immunosenescence is the age-related changes in the immune system, namely, progressively higher levels of circulating inflammatory markers, characteristics changes of circulating immune subset cells and altered immune function. The neutrophil to lymphocyte ratio (NL ratio) has been identified as a prognostic indicator for neoplastic disease progression, in predicting chronic degenerative diseases, and as a potential indirect marker of healthy aging. This study aims to examine the longitudinal association of neutrophil, lymphocyte absolute count, and their ratio with longitudinal risk for multimorbidity and mortality. The Baltimore Longitudinal Study of Aging (BLSA) is an open observational cohort study of community-dwelling volunteers that are followed every 1-4 years depending on their age. The sample considered in the study consists of 1769 participants (5090 follow-ups) with completed data for physical examination, health history assessment, and donated a blood sample. The NL ratio increased with age and was associated with a higher risk of mortality, while a lower NL ratio was inversely correlated with multimorbidity. Neutrophils increased with aging and an increase in their absolute number predicted mortality risk. However, the absolute number of lymphocytes was associated with age only in a cross-sectional analysis. In conclusion, this study supports the importance of the NL ratio and absolute neutrophil count as markers of aging health status, and as significant predictors of all-cause mortality and multimorbidity in aging individuals. It remains to be demonstrated whether interventions contrasting these trends in circulating cells may result in improved health outcomes.

Muscle quality, physical performance, and comorbidity are predicted by circulating procollagen type III N-terminal peptide (P3NP): the InCHIANTI follow-up study.

Sarcopenia is characterized by skeletal muscle quantitative and qualitative alterations. A marker of collagen turnover, procollagen type III N-terminal peptide (P3NP), seems to be related to those conditions. This study aims to assess the predictive role of P3NP in muscle density and physical performance changes. In the InCHIANTI study, a representative sample from the registry lists of two towns in Tuscany, Italy, was recruited. Baseline data was collected in 1998, and follow-up visits were conducted every 3 years. Out of the 1453 participants enrolled at baseline, this study includes 1052 participants. According to P3NP median levels, population was clustered in two groups; 544 (51.7%) of the 1052 subjects included were classified in the low median levels (LM-P3NP); at the baseline, they were younger, had higher muscle density, and performed better at the Short Physical Performance Battery (SPPB), compared to the high-median group (HM-P3NP).LM-P3NP cases showed a lower risk to develop liver chronic diseases, CHF, myocardial infarction, and osteoarthritis. HM-P3NP levels were associated with a longitudinal reduction of muscle density, and this effect was potentiated by the interaction between P3NP and leptin. Moreover, variation in physical performance was inversely associated with high level of P3NP, and directly associated with high fat mass, and with the interaction between P3NP and muscle density. Our data indicate that P3NP is associated with the aging process, affecting body composition, physical performance, and clinical manifestations of chronic degenerative age-related diseases.

Beyond Inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, Results From the InCHIANTI Study.

Aging is characterized by chronic low-level inflammation and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocyte ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow-up visits every 3 years. Out of the 1 453 participants enrolled at baseline, this study includes 1 179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and body mass index (BMI). Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocyte-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, interleukine-6 (IL-6), male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult.

Temporal trends, sex differences, and age-related disease influence in Neutrophil, Lymphocyte count and Neutrophil to Lymphocyte-ratio: results from InCHIANTI follow-up study.

BACKGROUND: Neutrophils and lymphocytes represent the larger percentage of all white blood cells, they vary with age, with a progressive increase of the ratio in the first years of life, and then tend to remain at similar levels in steady state condition during adult age. Neutrophils to lymphocytes-ratio (NL-ratio) was proposed as an effective and low-cost marker to monitor and predict the evolution of several clinical conditions. The main objective of the study is to analyze its temporal trend variation, over twenty years' follow-up, according to age, sex, and main clinical diagnosis, in a large representative Italian population. METHODS: The InCHIANTI study enrolled representative samples from the registry list of two towns in Tuscany, Italy. Baseline data were collected in 1998, and last follow-up visits were made in 2015-18. 1343 out of the 1453 participants enrolled were included, and consented to donate a blood sample. All subjects were assessed and followed for life-style, clinical condition, physical performance, and underwent an instrumental diagnostic session. RESULTS: The NL-ratio showed a statistically significant interaction between birth-cohort and time of the study (p-value = 0.005). A gender dimorphism was recognized in the neutrophils absolute count and in the NL-ratio. Moreover, in female participants only, those who reported CHF had lower neutrophil-count and NL-ratio; whereas an increase in creatinine clearance was directly associated with NL-ratio. In male subjects, an increase of BMI was inversely associated with both NL-ratio and neutrophils-count during the follow-up; a similar association but in the opposite direction was observed in female participants. CONCLUSION: NL-ratio is a more reliable predictor of healthy aging than absolute lymphocytes and/or neutrophils counts. It is associated with the changes induced by disease, lifestyle, and environmental challenges in the immune system. NL-ratio confirms the gender dimorphism in the occurrence of inflammation-driven diseases, thus providing additional evidence for the necessity of tailored sex-specific measures to prevent and treat such diseases.

Temporal trends, sex differences, and age-related disease influence in Neutrophil, Lymphocyte count and Neutrophil to Lymphocyte-ratio. Results from InCHIANTI follow-up study.

Background Neutrophils and lymphocytes represent the larger percentage of all white bloodcells, they vary with age, with a progressive increase of the ratio in the first years of life, and then tend to remain at similar levels in steady state condition during adult age. Neutrophils to lymphocytes-ratio (NL-ratio) was proposed as an effective and low-cost marker to monitor and predict the evolution of severalclinical conditions. The main objective of the study is to analyze its temporal trend variation, over twenty years' follow-up, according to age, sex, and main clinical diagnosis, in a large representative Italian population. Methods The InCHIANTI study enrolled representative samples from the registry list of two towns in Tuscany, Italy. Baseline data were collected in 1998, and last follow-up visits were made in 2015-18. 1343 out of the 1453 participants enrolled were included, and consented to donate a blood sample. All subjects were assessed and followed for life-style, clinical condition, physical performance, and underwent an instrumental diagnostic session. Results The NL-ratio showed a statistically significant interaction between birth-cohort and time of the study (p-value=0.005). A gender dimorphism was recognized in the neutrophils absolute count and in the NL-ratio. Moreover, in female participants only, those who reported CHF had lower neutrophil-count and NL-ratio; whereas an increase in creatinine clearance was directly associated with NL-ratio. In male subjects, an increase of BMI was inversely associated with both NL-ratio and neutrophils-count during the follow-up; a similar association but in the opposite direction was observed in female participants. Conclusion NL-ratio is a more reliable predictor of healthy aging than absolute lymphocytes and/or neutrophils counts. It is associated with the changes induced by disease, lifestyle, and environmental challenges in the immune system. NL-ratio confirms the gender dimorphism in the occurrence of inflammation-driven diseases, thus providing additional evidence for the necessity of tailored sex-specific measures to prevent and treat such diseases.

Radial or Focal Extracorporeal Shock Wave Therapy in Lateral Elbow Tendinopathy: A Real-Life Retrospective Study.

Lateral elbow tendinopathy (LET) is characterized by pain, poor muscle strength of the wrist ex-tensors, and disability. Among the conservative rehabilitative approaches, focal as well as radial extracorporeal shock wave therapy (ESWT), are considered effective in LET management. The objective of this study was to compare the safety and effectiveness of focal (fESWT) and radial (rESWT) in terms of LET symptoms and the strength of wrist extensors, taking into account potential gender differences. This is a retrospective longitudinal cohort study of patients with LET treated with ESWT that had received a clinical and functional evaluation, including visuo-analogic scale (VAS), muscle strength using an electronic dynamometer during Cozen's test, and the patient-rated tennis elbow evaluation (PRTEE) questionnaire. Follow-ups were carried out weekly in four visits after enrollment, and at 8 and 12 weeks. During the follow-ups, the VAS score decreased in both treatments, even if patients receiving fESWT reported early pain relief compared to those treated with rESWT (time for treatment p-value < 0.001). Additionally, peak muscle strength increased independently of the device used, and again more rapidly in the fESWT group (time for treatment p-value < 0.001). In the stratified analysis for sex and for the type of ESWT, rESWT appears to be less effective in female participants in terms of mean muscle strength and PRTEE scores, without differences according to the type of device used. The rESWT group reported a higher rate of minor adverse events (i.e., discomfort, p = 0.03) compared to fESWT. Our data suggest that both fESWT and rESWT might be effective in improving LET symptoms, even if the higher rate of painful procedures were reported in patients treated with rESWT.

Spinal Orthosis in Adolescent Idiopathic Scoliosis: An Overview of the Braces Provided by the National Health Service in Italy.

Adolescent idiopathic scoliosis (AIS) is a lateral, rotated curvature of the spine. It is a 3-dimensional deformity that arises in otherwise healthy children at or around puberty. AIS is the most common form of scoliosis in the pediatric population. The etiology is multifactorial, including genetic and environmental factors. The incidence is roughly equal between males and females, while there is a higher risk of progression in females. Guidelines for AIS treatment identify three levels of treatment: observation, physiotherapy scoliosis-specific exercises, and braces. In this paper, we carried out a review of the scientific literature about the indication and success rates of the braces provided for free by the National Health Service in Italy (SSN). Despite a general consensus on the efficacy of rigid bracing treatment and its use in AIS, an important heterogeneity about the treatment is present in the scientific literature, demonstrating a high degree of variability. The overall success rate of the braces provided by the SSN is high, suggesting an important therapeutic role in the treatment of AIS. Robust guidelines are needed to ensure uniform and effective treatments.

Urinary and Daily Assumption of Polyphenols and Hip-Fracture Risk: Results from the InCHIANTI Study.

A high polyphenol intake has been associated with higher bone-mineral density. In contrast, we recently demonstrated that the urinary levels of these micronutrients were associated with the long-term accelerated deterioration of the bone. To expand on the health consequences of these findings, we assessed the association between urinary level and dietary intake of polyphenols and the 9-year risk of hip fractures in the InCHIANTI study cohort. The InCHIANTI study enrolled representative samples from two towns in Tuscany, Italy. Baseline data were collected in 1998 and at follow-up visits in 2001, 2004, and 2007. Of the 1453 participants enrolled at baseline, we included 817 participants in this study who were 65 years or older at baseline, donated a 24 hour urine sample, and underwent a quantitative computerized tomography (pQCT) of the tibia. Fracture events were ascertained by self-report over 9 years of follow-up. Thirty-six hip fractures were reported over the 9-year follow-up. The participants who developed a hip fracture were slightly older, more frequently women, had a higher dietary intake of polyphenols, had higher 24-hour urinary polyphenols excretion, and had a lower fat area, muscle density, and cortical volumetric Bone Mineral Density (vBMD) in the pQCT of the tibia. In logistic regression analyses, the baseline urinary excretion of total polyphenols, expressed in mg as a gallic acid equivalent, was associated with a higher risk of developing a hip fracture. Dietary intake of polyphenols was not associated with a differential risk of fracture. In light of our findings, the recommendation of an increase in dietary polyphenols for osteoporosis prevention should be considered with caution.

Ankle-Brachial Index and Arterial Stiffness, Modulate the Exertional Capacity of High-Frequency Training Athletes.

Ankle-brachial index and arterial stiffness are associated with leg function in the elderly and in patients with peripheral arterial disease. Little is known about the meaning of these parameters in young and trained subjects and how they are related to physical performance. The main objective was to evaluate the mediating role of arterial stiffness and ankle-brachial index in physical performance. In a cross-sectional, case-control study, 240 male athletes were consecutively enrolled from the Laboratory of Cardiology and Sports Medicine, "G. d'Annunzio" University (Italy). All the subjects underwent the examination protocol for the annual medical evaluation for sport participation. Soccer (football) players compared to runners showed a lower level of ankle-brachial index, higher arterial stiffness, and lower systolic and diastolic blood pressure. In the treadmill stress test, soccer players compared to runners showed a greater maximal aerobic capacity. Differences in cardiovascular performance between soccer players and runners were mediated by better arterial stiffness and low level of ankle-brachial index; the estimated effect was 0.11 ± 0.05 and 0.24 ± 0.06, respectively. Vigorous strength training drops blood pressure and increases arterial stiffness. Taken together, our findings would seem to suggest that ABI and CAVI could be used as markers for athletes' performance.

Combined ultrasound guided peritendinous hyaluronic acid (500-730 Kda) injection with extracorporeal shock waves therapy vs. extracorporeal shock waves therapy-only in the treatment of shoulder pain due to rotator cuff tendinopathy. A randomized clinical trial.

BACKGROUND: Rotator cuff tendinopathy (RCTe) is the most common cause of pain and shoulder dysfunction. Numerous clinical studies have demonstrated the therapeutic capacity of exogenous peritendinous hyaluronic acid (HA), and the effectiveness of extracorporeal shockwaves therapy (ESWT) in reducing pain. The aim of this study was to evaluate the added effects of HA treatment plus ESWT (E-g) or ESWT alone (SC-g), focusing on reduction of self-reported pain and disability of patients with RCTe. METHODS: Monocentric, randomized open-label clinical trial. Patients' selection, enrollment and interventions were conducted at the Chiparo Physical Medicine and Rehabilitation outpatient facility (Lecce, Italy). Patients with a diagnosis of RCTe, were randomly allocated to the E-g or to the SC-g. Participants were assessed for self-perceived pain, and for disability, at baseline, after 30 and 60 days. RESULTS: Forty adults (mean age 50.8±6.3; 23 woman, 17 men) were enrolled in the study, twenty for each group. During the study, both groups improved their perceived level of disability of the arm (-25.01±2.79; P<0.001), and for pain (-3.13±0.50; P<0.001). A multiplicative effect was demonstrated in the time × treatment interaction for disability (beta±SE beta: 7.40±1.77; P<0.001), and pain (beta±SE beta: 0.95±0.32; P<0.001). Moreover, more patients in the E-g reached the MCID in the outcomes-score compared to SC-g. Lastly, number needed to treat were calculated, for disability: NNT=2 (95% CI: 1-3), and for pain-score: NNT=1 (95% CI: 1-2). CONCLUSIONS: This study provides preliminary evidence that, compared to ESWT alone, the combining ESWT and peritendinous HA-injections, revert disability and reduces shoulder pain faster in patients with RCTe.

Markers of inflammation, vitamin E and peripheral nervous system function: the InCHIANTI study.

BACKGROUND: Aging of the peripheral nervous system is associated with several morphologic and functional changes, including a decrease of the nerve conduction velocity. There is evidence that these changes contribute to age-related-decline in muscle strength, sensory discrimination, and autonomic responses. The aim of this study was to characterize the decline in nerve conduction velocity in the peripheral nervous system over the aging process and to identify factors that, independent of age, affect nerve conduction velocity. METHODS: We measured motor nerve conduction velocity of the right superficial peroneal nerve using a standard neurophysiologic technique in a population-based sample of subjects aged between 20 and 103 years old enrolled in the InCHIANTI study. RESULTS: Average conduction velocities in the peripheral nerve decreased linearly with age in both sexes. We found that diabetes, cognitive impairment, uric acid, sIL-6R and alpha-tocopherol were significant predictors of nerve conduction velocity independently of the potential confounding effect of age, sex, sex x age interaction term, height, lymphocytes, neutrophils number, alpha1 and alpha2-globulin serum protein. CONCLUSIONS: Our findings are consistent with the hypothesis that inflammation and inadequate antioxidant defenses are associated with accelerated decline of nerve conduction velocity over the aging process.

IL-4 in vitro production is upregulated in Alzheimer's disease patients treated with acetylcholinesterase inhibitors.

Cytokines appear to be involved in the pathogenesis of Alzheimer's Disease (AD). Their modulation by treatment has been investigated only in a few studies. The aim of our study was to evaluate the effect of acetylcholinesterase inhibitors (AChEI) on Interleukin-4 (IL-4) production in AD patients. IL-4 levels were measured by ELISA on peripheral blood mononuclear cell cultures in the presence or absence of Concanavalin A or Phytohaemagglutinin. Linear regression analysis shows that patients who have been treated, have higher levels of IL-4 independently from age, gender and comorbidity. The increased production of IL-4 in AChEI treated patients might represent an additional mechanism through which AChEI act on AD progression.

Serum IL-1beta levels in health and disease: a population-based study. 'The InCHIANTI study'.

Interleukin-1 plays a role in normal homeostasis and in the inflammatory response which is deemed to be responsible for the development of major chronic diseases that are highly prevalent in the elderly. Aim of this study is to evaluate the factors influencing the serum levels of Interleukin-1 beta, in a large and representative population. Data were from the InCHIANTI project, a study of factors contributing to the decline of mobility in late life, which sampled people living in two sites in the surroundings of Florence. Blood samples were obtained from 1,292 participants and frozen aliquots were stored at -80 degrees C. The serum levels of several cytokines were measured by enzyme linked immunosorbent assay using an ultrasensitive commercial kit. Interleukin-1 beta serum levels were associated with congestive heart failure (p > 0.001) and angina (p = 0.02), with Ca2+ serum levels (p = 0.02), and with a history of dyslipidemia (p = 0.05). We found no association between serum IL-1beta level and age, sex, consumption of cardioactive drugs and serum levels of IL-1Ra, IL-6, sIL-6R, IL-10 and TNF-alpha. Our data could lend support to the hypothesis that IL-1beta is mainly involved in the functional alterations of cardiomyocytes under conditions marked by mononuclear cell infiltration and by downregulation of calcium.

Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer's disease patients.

Cognitive functions display a progressive impairment with ageing, and this is thought to be due to the accumulation of neuronal loss or acute and/or repeated microvascular accidents. Chronic damage to the brain cortex lead to decreasing ability of elderly subjects to cope with daily events and ultimately result in loss of self-sufficiency. Since proinflammatory cytokines have been implicated both in cerebrovascular injury due to atherosclerosis and in Alzheimer's disease (AD), we investigated 70 elderly subjects with neurocognitive and functional impairment. Diagnosis was established in 54, the others were included in the "mixed" group. Sera were collected and stored at -70 degrees C until measurement of IL-1beta and TNF-alpha, performed by commercial ELISA kits. Data obtained were analysed with respect to other socio-demographic, psychoneurological and clinical variables. The results show that serum TNF-alpha was lower in mild-moderate AD compared to severe AD and dementias due to vascular disease, as well as the TNF-alpha/IL-1beta ratio. Both cytokines showed a significant relationship with age. Our study suggests that proinflammatory cytokines serum profiles seem to discriminate between mild-moderate AD and vascular or mixed forms of dementia. Furthermore, it offers new evidence of a strong implication of inflammatory mechanisms in atherosclerosis, more than in less severe AD.