Perinatal outcome in anti-NMDAr encephalitis during pregnancy-a systematic review with individual patients' data analysis.

INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDAr) antibody encephalitis is an autoimmune disorder characterized by synaptic NMDAr current disruption and receptor hypofunction, often affecting women during pregnancy. Clinical manifestations associated with anti-NMDAr encephalitis can occur both in the mother and fetus. METHODS: We generated a systematic search of the literature to identify epidemiological, clinical, and serological data related to pregnant women with anti-NMDAr encephalitis and their children, analyzing the fetal outcomes. We examined the age and neurologic symptoms of the mothers, the presence of an underlying tumor, immunotherapies used during pregnancy, duration of the pregnancy, and type of delivery. RESULTS: Data from 41 patients were extrapolated from the included studies. Spontaneous interruption of pregnancy, premature birth, and cesarean section were reported in pregnant women with NMDAr encephalitis. Several fetal and neonatal symptoms (e.g., movement disorders, spina bifida, poor sucking, respiratory distress, cardiac arrhythmias, infections, icterus, hypoglycemia, and low birth weight) depending on the mother's serum anti-NR1 concentration were also reported. CONCLUSIONS: We characterized the outcomes of children born from mothers with anti-NMDAr encephalitis, analyzing the pivotal risk factors related to pregnancy and maternal disorder. Neuropsychiatric involvement seems strictly related to pathogenic NMDAr antibodies detected in maternal and/or neonatal serum. These findings clarify a complex condition to manage, outlining the risks associated with pregnant women with anti-NMDAr encephalitis and also providing a concrete guide for therapeutic strategies to prevent potential harm to the fetus and the child's neurodevelopment.

Natural IgG antibodies to ß amyloid are decreased in patients with Parkinson's disease.

Natural antibodies (nAbs) against aggregation-prone proteins have been found in healthy normal subjects. These proteins likely have a pathogenetic role in neurodegenerative diseases of ageing. They include the amyloid ß (Aß) protein which may play an important role in Alzheimer's dementia (AD), and α-synuclein, a major determinant of Parkinson's disease (PD). We measured nAbs to Aß in a group of Italian patients with AD, vascular dementia, non-demented PD patients and healthy elderly controls. We found that Aß antibody levels in AD were similar to age- and sex-matched controls, but contrary to our expectations, they were significantly reduced in PD. This may identify patients that could be more prone to amyloid aggregation.

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.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

Quantum Medicine: A Role of Extremely Low-Frequency Magnetic Fields in the Management of Chronic Pain.

Extremely low-frequency electromagnetic field (ELF-MF) therapy is a promising treatment for chronic pain, given its ability to interact with body homeostasis using water-mediated transmission mechanisms typical of quantum medicine. The present study aims to assess the effects of ELF-MF therapy on chronic pain in 49 patients suffering from various musculoskeletal disorders. The therapy was applied through a Quec Phisis setup generating the electromagnetic field as the ion cyclotronic resonance. Patients underwent eight therapy sessions of 45 min each performed every other day. The bioimpedance assessment was based on the comparison of the height-adjusted body resistance (R/h) and reactance (Xc/h) measured during the first and last sessions of eight-session treatment. Pain perception was quantified using the standard visual-analog scale. We found significant increases in both R/h and Xc/h parameters of body bioimpedance after electromagnetic therapy corresponding with reductions in pain perception. We conclude that the ELF-MF therapy can restore the body's state of health and thus seems a valid therapeutic approach for the treatment of musculoskeletal-derived pain.

Capacitive and Resistive Electric Transfer Therapy: A Comparison of Operating Methods in Non-specific Chronic Low Back Pain.

Capacitive and resistive electric transfer (TECAR) modes of therapy use radiant energy to generate endogenous heat and are used for musculoskeletal disorders for their analgesic, decontracting, and elasticizing properties. While the capacitive mode is supposed to interact with soft tissues, the resistive mode interacts more with hard tissues. This study aims to investigate whether the successive order of the two modes during their application could make a difference concerning the outcome. The study included 40 patients affected by chronic non-specific low back pain. Patients were assessed using algometry, before and immediately after the therapeutic intervention, and thermal imaging, before, immediately after, and then 30 and 60 min after the intervention. Each patient had two TECAR interventions on different days of a total of 20 min each, with a resistive followed by capacitive mode and conversely, capacitive followed by resistive mode. The capacitive mode alternated with the resistive mode by 10 min during either intervention. Results showed that the effects consisting of temporary increases in the superficial temperature of the lower back and pressure pain threshold were alike for both interventions. We conclude that TECAR therapy reduces low back pain regardless of the operative mode adopted, with only an insignificant advantage when starting the sequence from the resistive application.

Manual Therapy Approach to the Extraocular Muscles in Migraine Treatment: A Preliminary Study.

The oculomotor system plays an important role in the development of migraines. This is an observational study that aims to investigate the rehabilitative efficacy of muscle energy therapy (MET) in reducing migraine symptoms. MET was based on post-isometric relaxation and reciprocal inhibition, targeting the extraocular muscles. Patients diagnosed with chronic migraines and positive results in the Smooth Pursuit Eye Movement Test were enrolled in the study. The effects of treatment were assessed using the following questionnaires: Migraine Disability Assessment (MIDAS), Neck Disability Index (NDI), Pittsburg Sleep Quality Index (PSQI), Dizziness Handicap Inventory (DHI), and the neck range of motion (ROM). Additionally, rheological parameters of neck muscles were assessed. We reported beneficial effects of MET on the amelioration of the frequency of headaches, neck pain and dizziness-related disabilities and disordered sleep. However, benefits concerning the neck motion and rheological properties of oculomotor structures were unconvincing. In conclusion, the study showed advantageous effects of manual oculomotor therapy consisting of reductions in migraine-related painful symptomatology. The results diminish the role of ocular muscle mechanical properties in the genesis of migraine, shifting attention to the modulatory role of the neuromuscular ocular component, likely involving trigeminal innervation, which can be subject to migraine manual therapy.

Effectiveness of combined extracorporeal shock-wave therapy and hyaluronic acid injections for patients with shoulder pain due to rotator cuff tendinopathy: a person-centered approach with a focus on gender differences to treatment response.

BACKGROUND: Rotator cuff (RC) tendinopathy is a common shoulder pain condition. Extracorporeal shockwave therapy (ESWT) and hyaluronic acid peritendinous injection are viable treatment options for RC tendinopathy. The aim of this study is to evaluate the response in two different therapeutic rehabilitative approaches, the combined treatment ESWT plus hyaluronic acid injections (E + Hy) compared to ESWT alone (ESWT-al), in a cohort of patients with RC tendinopathy according to gender differences. METHODS: This is a retrospective longitudinal cohort study of patients with painful RC tendinopathy. Patients that had received a clinical evaluation, a shoulder ultra sound examination, as well as the Shoulder Pain and Disability Index (SPADI) questionnaire, and the Numerical Rating Scale (NRS) for pain at baseline, 1-month (T1) and 2-month follow-ups (T2) were included. RESULTS: Medical records of 53 patients were analyzed. In the comparison between baseline to T1 and similarly from baseline to T2, a statistically significant reduction has been reported in the NRS (p < 0.001) and in the SPADI (p < 0.001) in the entire study group. At T1, patients in the E + Hy compared to ESWT-al group, showed a slight but statistically significant reductions in both NRS and SPADI score, while these changes were more evident at T2 (p < 0.001). Interestingly, a gender dimorphism in NRS and in SPADI was found, with female patients that apparently responded better to the combined E + Hy compared to ESWT-al approach. CONCLUSION: This retrospective cohort study suggests that the combination of ESWT plus HyA injections seems to be more effective than ESWT alone in RC tendinopathy in both genders. Moreover, in ESWT alone treatment, male patients reported better outcomes compared to females. However, further randomized controlled trials should be structured to confirm and enforce these conclusions.

Effects of activity tracker-based counselling and live-web exercise on breast cancer survivors' sleep and waking time during Italy's COVID-19 lockdown.

The aim of the study was to compare the effects of weekly personal feedback, based on objectively measured physical activity, on daily sleep in breast cancer survivors (BCS) with those of an intervention that also included online supervised physical exercise sessions (OSPES). BCS benefiting from both personal feedback and OSPES (n = 24), from pre-lockdown (T0) to the first month (T1) of the national lockdown, experienced an increase in both total (p ≤ 0.001) and restorative (p ≤ 0.001) sleep time, inverting their trend from the first month of lockdown to its end (total sleeping time T1 vs. T2 0.01 ≤ p < .001, T1 vs. T3 p ≤ 0.001; restorative sleeping time T1 vs. T2 0.05 ≤ p < .01, T1 vs. T3 p ≤ 0.001). Supportive technology, together with the reception of weekly tailored advice and OSPES seems to improve both quality and quantity of sleep.

Choroidal Changes in Blood Flow in Patients with Intermediate AMD after Oral Dietary Supplement Based on Astaxanthin, Bromelain, Vitamin D3, Folic Acid, Lutein, and Antioxidants.

Background and Objectives: The aim of this study was to investigate the impact of oral administration of the combination of astaxanthin (AXT), lutein, folic acid, vitamin D3, and bromelain with antioxidants on choroidal blood flow in patients with age-related intermediate macular degeneration (AMD). Materials and Methods: Patients affected by intermediate AMD and treated with daily oral nutritional supplement with AXT, bromelain, vitamin D3, folic acid, lutein, and antioxidants for a period of at least 6 months were included in this retrospective study. A control group homogenous for age and sex was also included in the analysis. All participants underwent a complete ophthalmologic examination, spectral domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCTA) evaluation. Outcome measures were choroidal thickness (CHT) and choriocapillary vessel density (CCVD) after six months of AXT assumption. Results: CCVD values showed statistically significant difference between cases and controls at baseline (p < 0.001) and in the cases during follow-up (p < 0.001). The CHT measurements showed statistically significant difference between cases and controls (p = 0.002) and in the cases during follow-up (p < 0.001). Conclusions: The combined use of structural OCT and OCTA allows for a detailed analysis in vivo of perfusion parameters of the choriocapillaris and choroid and evaluation of changes of choroidal blood flow after oral nutritional supplements that affect blood flow velocity.

Preexisting Bipolar Disorder Influences the Subsequent Phenotype of Parkinson's Disease.

BACKGROUND: Patients with bipolar spectrum disorders (BSDs) exhibit an increased risk of Parkinson's disease (PD). OBJECTIVE: The aim is to investigate whether a previous diagnosis of BSDs influences the phenotype of PD. METHODS: Of 2660 PD patients followed for at least 6 years (6-27), 250 (BSD-PD) had BSDs, 6-20 years before PD diagnosis; 48%-43% had a PD or BSD family history, and 34 carried glucocerebrosidase (GBA) and Parkin (PRKN) mutations. The cohort was split into a subset of 213 BSD-PD patients, compared with 426 matched PD patients without BSDs, and a subset of 34 BSD-PD and 79 PD patients carrying GBA or PRKN mutations. Carriers of mutations absent in BSD-PD patients and of synuclein triplication were excluded. Structured clinical interviews and mood disorder questionnaires assessed BSDs. Linear mixed models evaluated the assessment scales over time. Thirteen BSD-PD patients underwent subthalamic nucleus deep brain stimulation (STN-DBS) and were compared with 27 matched STN-DBS-treated PD patients. RESULTS: Compared to PD patients, BSD-PD showed (1) higher frequency of family history of PD (odds ratio [OR] 3.31; 2.32-4.71) and BSDs (OR 6.20; 4.11-9.35) 5); (2) higher incidence of impulse control disorders (hazard ratio [HR] 5.95, 3.89-9.09); (3) higher frequency of functional disorders occurring before PD therapy (HR, 5.67, 3.95-8.15); (4) earlier occurrence of delusions or mild dementia (HR, 7.70, 5.55-10.69; HR, 1.43, 1.16-1.75); and (5) earlier mortality (1.48; 1.11-1.97). Genetic BSD-PD subjects exhibited clinical features indistinguishable from nongenetic BSD-PD subjects. STN-DBS-treated BSD-PD patients showed no improvements in quality of life compared to the control group. CONCLUSIONS: BSDs as a prodrome to PD unfavorably shape their course and are associated with detrimental neuropsychiatric features and treatment outcomes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Low molecular weight heparin in COVID-19 patients prevents delirium and shortens hospitalization.

BACKGROUND: COVID-19 patients present with delirium during their hospitalization. AIMS: To assess the incidence of delirium in hospitalized COVID-19 patients and analyze the possible association with demographic, clinical, laboratory, and pharmacological factors. METHODS: COVID-19 patients were assessed for clinical signs of delirium and administered the assessment test for delirium and cognitive impairment (4AT) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scales. RESULTS: Out of the 56 patients of our cohort, 14 (25.0%) experienced delirium. The use of low molecular weight heparin (LMWH) (enoxaparin 1 mg/kg/daily) was less frequent in patients with delirium (p = 0.004) and was accompanied by lower C reactive protein (CRP) levels (p = 0.006). DISCUSSION: The use of LMWH was associated with absence of delirium, independently of comorbidities and age. CONCLUSIONS: The use of LMWH may help preventing the occurrence of delirium in COVID-19 patients, with possible reduction of length of stay in the hospital and sequelae.

Baker's Cyst with Knee Osteoarthritis: Clinical and Therapeutic Implications.

OBJECTIVE: Several symptoms are common to knee osteoarthritis and Baker's cyst. To what extent each condition contributes to the patient's discomfort is still a matter of debate. The aim of the present study was twofold: first, to compare the burden of symptoms in patients with isolated knee osteoarthritis and patients with knee osteoarthritis associated with Baker's cyst; second, to assess the outcomes after conservative treatments. SUBJECT AND METHODS: Patients suffering from monolateral idiopathic knee osteoarthritis were enrolled. Demographic, anthropometric and clinical data (KOOS scale) were collected. Ultrasound evaluation was performed according to standard protocols. On the basis of the clinical presentation different therapeutic options were used (fluid withdrawal, hyaluronic acid and/or steroids injections). RESULTS: One-hundred and thirty patients were included in the study (97 with isolated knee osteoarthritis, 33 with knee osteoarthritis and Baker's cyst). In basal conditions, lower scores in KOOS sub-scales were observed in patients with knee osteoarthritis associated with Baker's cyst and in patients with effusion compared with patients without effusion. At 3 months after therapy significant higher scores were observed in both groups. At 6 months the scores were unchanged in the patients without Baker's cyst, but worsened in those with Baker's cyst. CONCLUSIONS: The study shows that Baker's cysts associated with knee osteoarthritis contribute to the burden of symptoms. The conservative treatment of both conditions allows significant improvements, but in the medium term (6 months) the efficacy of the therapy declines in patients with knee osteoarthritis associated with Baker's cyst.

Walking training and cortisol to DHEA-S ratio in postmenopause: An intervention study.

The literature indicates that the plasma cortisol-to-dehydroepiandrosterone-sulfate (DHEA-S) ratio is a marker of health status after menopause, when a decline in both estrogen and DHEA-S and an increase in cortisol occur. An increase in the cortisol-to-DHEA-S ratio has been positively correlated with metabolic syndrome, all-cause mortality, cancer, and other diseases. The aim of this study was to investigate the effects of a walking program on the plasma cortisol-to-DHEA-S ratio in postmenopausal women. Fifty-one postmenopausal women participated in a 13-week supervised walking program, in the metropolitan area of Pescara (Italy), from June to September 2013. Participants were evaluated in April-May and September-October of the same year. The linear mixed model showed that the variation of the log10Cortisol-to-log10DHEA-S ratio was associated with the volume of exercise (p = .03). Participants having lower adherence to the walking program did not have a significantly modified log10Cortisol or log10DHEA-S, while those having the highest adherence had a significant reduction in log10Cortisol (p = .016) and a nearly significant increase in log10DHEA-S (p = .084). Walking training appeared to reduce the plasma log10Cortisol-to-log10DHEA-S ratio, although a minimum level of training was necessary to achieve this significant reduction.

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.

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.

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.

Increased variance in germline allele-specific expression of APC associates with colorectal cancer.

BACKGROUND & AIMS: Germline variations in allele-specific expression (ASE) are associated with highly penetrant familial cancers, but their role in common sporadic cancers is unclear. ASE of adenomatous polyposis coli (APC) is associated with pathogenesis of familial adenomatous polyposis. We investigated whether moderate variations in ASE of APC contribute to common forms of colorectal cancer (CRC). METHODS: Denaturing high-performance liquid chromatography was used to analyze germline ASE of APC in blood samples from patients with CRC (cases, n = 53) and controls (n = 68). Means, medians, and variances of ASE were compared. Variants in the APC gene region also were analyzed. RESULTS: The distribution of ASE differed significantly between groups; cases had significantly larger amounts of variance than controls (P = .0004). Risk for CRC increased proportionally with the degree of deviation from the mean. The odds ratio for individuals with levels of ASE that deviated more than 1 standard deviation from the mean was 3.97 (95% confidence interval, 1.71-9.24; P = .001); for those with levels greater than 1.645 standard deviations, the odds ratio was 13.46 (95% confidence interval, 1.76-609.40; P = .005). Sequence analysis revealed that a patient with a high level of ASE who did not have a family history of CRC carried a nonsense mutation in APC (p.Arg216X). Genotype analysis of APC associated multiple single-nucleotide polymorphisms with ASE values and/or variance among cases, but not controls. Cis variants, therefore, might account for some of the variance in ASE of APC. CONCLUSIONS: Patients with CRC have a larger variance in germline levels of ASE in APC than controls; large distances from the mean ASE were associated with risk for common forms of CRC.