7p22.2 Microduplication: A Pathogenic CNV?

Partial duplication of the short arm of chromosome 7 is a rare chromosome rearrangement. The phenotype spectrum associated with this rearrangement is extremely variable even if in the last decade the use of high-resolution microarray technology for the investigation of patients carrying this rearrangement allowed for the identification of the 7p22.1 sub-band causative of this phenotype and to recognize the corresponding 7p22.1 microduplication syndrome. We report two unrelated patients that carry a microduplication involving the 7.22.2 sub-band. Unlike 7p22.1 microduplication carriers, both patients only show a neurodevelopmental disorder without malformations. We better characterized the clinical pictures of these two patients providing insight into the clinical phenotype associated with the microduplication of the 7p22.2 sub-band and support for a possible role of this sub-band in the 7p22 microduplication syndrome.

Unveiling the Burden of Interactions Among Clinical Risk Factors for 1-Year Mortality in Hospitalized Older Patients.

Background: Hospitalized older patients are particularly exposed to adverse health outcomes. Objective: In this study, we aimed at investigating the prognostic interactions between disability in basic activities of daily living (BADL), cognitive impairment, low handgrip strength, anticholinergic cognitive burden (ACB), and depression on 1-year mortality. Setting and Subjects: Our series consisted of 503 older patients discharged from acute care hospitals. Methods: Disability in at least one BADL, ACB, depression, cognitive impairment, and low handgrip strength was considered in the analysis. One-year mortality was investigated by Cox regression analysis and prognostic interactions among study variables were assessed by survival tree analysis. Results: Basic activities of daily living disability, ACB, cognitive impairment, and low handgrip strength were significantly associated with 1-year mortality. Survival tree analysis showed that patients with BADL disability and high ACB carried the highest risk of poor survival [hazard ratio (HR): 16.48 (2.63-74.72)], followed by patients with BADL disability and low ACB (HR: 8.43, 95% CI: 1.85-38.87). Patients with cognitive impairment and no BADL disability were characterized by a lower but still significant risk of mortality (HR: 6.61, 95% CI: 1.51-28.97) and those with high ACB scores and good cognitive and functional performance (HR: 5.28, 95% CI: 1.13-24.55). Conclusion: Basic activities of daily living dependency, cognitive impairment, and ACB score were the three main predictors of 1-year mortality among patients discharged from acute care hospitals; the interaction between BADL dependency and ACB score was found to significantly affect survival. Early identification of such high-risk patients may help tailor targeted interventions to counteract their detrimental effects on prognosis.

Design and methodology of the chronic kidney disease as a dysmetabolic determinant of disability among older people (CKD-3D) study: a multicenter cohort observational study.

BACKGROUND: Chronic kidney disease (CKD) is a common condition in older people and represents a global health issue since it increases the risk of associated comorbidities and all-cause mortality. Furthermore, older people with reduced renal function might be at higher risk for developing functional limitation and disability. Moreover, the current creatinine-based measures of renal function are influenced by several factors in older population. The aims of the CKD-3D project are to perform an observational study to expand the knowledge about CKD-disability relationship and to investigate the use of novel biomarkers of kidney function. METHODS: An observational, multicenter, prospective cohort study will be conducted in 75 + old patients consecutively admitted to acute care wards of geriatric medicine at participating hospitals. The study planned to enroll 440 patients undergoing clinical and laboratory evaluations at baseline and after 12 months. Face-to-face follow-up at 6 months and telephone follow-up at 3 and 9 months will be carried out. Comprehensive Geriatric Assessment (CGA) and the measurement of Cystatin C, Beta-Trace Protein and Beta2-Microglobulin levels will be included. DISCUSSION: This study will provide useful information to prevent CKD-related disability by collecting real-life data over 1-year period. The combined approach of CGA and the investigation of innovative existing biomarkers will make it possible to develop new recommendations and guidelines for a patient-centered approach. It is believed that such a study may lead to an improvement of knowledge on CKD in elderly patients and may also have implications in daily clinical practice and in decision-making process.

Cognitive Impairment, Chronic Kidney Disease, and 1-Year Mortality in Older Patients Discharged from Acute Care Hospital.

The prognostic interaction between chronic kidney disease (CKD) and cognitive impairment is still to be elucidated. We investigated the potential interaction of overall cognitive impairment or defective constructional praxis and CKD in predicting 1-year mortality among 646 older patients discharged from hospital. The estimated glomerular filtration rate (eGFR) was calculated using the Berlin Initiative Study (BIS) equation. Cognitive impairment was assessed by the Mini Mental State Exam (MMSE) and defective constructional praxis was ascertained by the inherent MMSE item. The study outcome was 1-year mortality. Statistical analysis was carried out using Cox regression. After adjusting for potential confounders, the co-occurrence of eGFR <30 and overall cognitive impairment (Hazard Ratio (HR) = 3.12, 95% Confidence Interval (CI) = 1.26-7.77) and defective constructional praxis (HR = 2.50, 95% CI = 1.08-5.77) were associated with the outcome. No significant prognostic interaction of eGFR < 30 with either overall cognitive impairment (HR = 1.99, 95% CI = 0.38-10.3) or constructional apraxia (HR = 1.68, 95% CI = 0.33-8.50) was detectable, while only cognitive deficits were found significantly associated with the outcome in the interaction models (HR = 3.12, 95% CI = 1.45-6.71 for overall cognitive impairment and HR = 2.16, 95% CI = 1.05-4.45 for constructional apraxia). Overall cognitive impairment and defective constructional praxis may be associated with increased risk of 1-year mortality among older hospitalized patients with severe CKD. However, no significant prognostic interaction between CKD and cognitive impairment could be observed.

Erratum: Multi-Tissue DNA Methylation Remodeling at Mitochondrial Quality Control Genes According to Diet in Rat Aging Models.

The Nutrients Editorial Office would like to update the error in the original published version [...].

Hand Grip Strength May Affect the Association Between Anticholinergic Burden and Mortality Among Older Patients Discharged from Hospital.

BACKGROUND AND OBJECTIVE: The relationship between anticholinergic burden and mortality is unclear, and the impact of anticholinergic burden on prognosis may vary in the presence of other conditions common in old age. We aimed to investigate the role of hand grip strength as a potential effect modifier in the association between anticholinergic burden and 1-year mortality in older patients discharged from hospital. METHODS: Our series consisted of 620 older patients consecutively admitted to seven geriatric and internal medicine acute care wards in the context of a prospective multicenter observational study. Overall anticholinergic burden was assessed by Anticholinergic Cognitive Burden (ACB) score. Hand grip strength was assessed by the use of a North Coast medical hand dynamometer and categorized by using sex-specific cut-offs (women < 15 kg, men < 20 kg). The study outcome was 1-year mortality. Statistical analysis was performed by Cox regression analysis. RESULTS: After adjusting for potential confounders, the co-occurrence of an ACB score of 2 or more and low hand grip strength was significantly associated with mortality (hazard ratio [HR] = 2.30, 95% confidence interval [CI] 1.07-6.01). Stratified analysis confirmed that an ACB score of 2 or more was associated with mortality among patients with low (HR = 2.15, 95% CI 1.08-5.02), but not normal hand grip strength (HR = 0.88, 95% CI 0.13-3.52). The association was confirmed among patients with low hand grip strength after adjusting for the ACB score at the 3-month follow-up (HR = 2.20; 95% CI 1.09-4.87), as well as when considering the ACB score as a continuous variable (HR = 1.24, 95% CI 1.03-1.48). CONCLUSIONS: The ACB score at discharge may predict mortality among older patients discharged from an acute care hospital with low hand grip strength. Hospital physicians should be aware that prescribing anticholinergic medications in such a vulnerable population may have negative prognostic implications.

Multi-Tissue DNA Methylation Remodeling at Mitochondrial Quality Control Genes According to Diet in Rat Aging Models.

An adequate mitochondrial quality control system ensures the maintenance of a healthy mitochondrial pool so as to slow down the progressive accumulation of damage affecting mitochondrial function during aging and diseases. The amount and quality of nutrients availability were demonstrated to induce a process of bioenergetics adaptation by influencing the above system via epigenetic modifications. Here, we analyzed DNA samples from differently-aged rats fed a standard or low-calorie diet to evaluate tissue-specific changes in DNA methylation of CpG sites falling within Polg, Polg2, Tfam, Fis1, and Opa1 genes. We found significant changes according to age and tissue type and the administration of the low-calorie diet is responsible for a prevalent increase in DNA methylation levels. Particularly, this increase was more appreciable when this diet was administered during adulthood and at old age. Regression analysis demonstrated that DNA methylation patterns of the analyzed genes were negatively correlated with their expression levels. Data we obtained provide the first evidence about changes in DNA methylation patterns of genes involved in the mitochondrial biogenesis in response to specific diets and demonstrated that epigenetic modifications are involved in the modulation of mitochondrial dynamics driven by age and nutrition.

Individual DNA Methylation Profile is Correlated with Age and can be Targeted to Modulate Healthy Aging and Longevity.

Patterns of DNA methylation, the best characterized epigenetic modification, are modulated by aging. In humans, different studies at both site-specific and genome-wide levels have reported that modifications of DNA methylation are associated with the chronological aging process but also with the quality of aging (or biological aging), providing new perspectives for establishing powerful biomarkers of aging. In this article, the role of DNA methylation in aging and longevity has been reviewed by analysing literature data about DNA methylation variations occurring during the lifetime in response to environmental factors and genetic background, and their association with the aging process and, in particular, with the quality of aging. Special attention has been devoted to the relationship between nuclear DNA methylation patterns, mitochondrial DNA epigenetic modifications, and longevity. Mitochondrial DNA has recently been reported to modulate global DNA methylation levels of the nuclear genome during the lifetime, and, in spite of the previous belief, it has been found to be the target of methylation modifications. Analysis of DNA methylation profiles across lifetime shows that a remodeling of the methylome occurs with age and/or with age-related decline. Thus, it can be an excellent biomarker of aging and of the individual decline and frailty status. The knowledge about the mechanisms underlying these modifications is crucial since it might allow the opportunity for targeted treatment to modulate the rate of aging and longevity.

Prognosis and Interplay of Cognitive Impairment and Sarcopenia in Older Adults Discharged from Acute Care Hospitals.

Sarcopenia and cognitive impairment are associated with an increased risk of negative outcomes, but their prognostic interplay has not been investigated so far. We aimed to investigate the prognostic interaction of sarcopenia and cognitive impairment concerning 12-month mortality among older patients discharged from acute care wards in Italy. Our series consisted of 624 patients (age = 80.1 ± 7.0 years, 56.1% women) enrolled in a prospective observational study. Sarcopenia was defined following the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Cognitive impairment was defined as age- and education-adjusted Mini-Mental State Examination (MMSE) score < 24 or recorded diagnosis of dementia. The study outcome was all-cause mortality during 12-month follow-up. The combination of sarcopenia and cognitive ability was tested against participants with intact cognitive ability and without sarcopenia. Overall, 159 patients (25.5%) were identified as having sarcopenia, and 323 (51.8%) were cognitively impaired. During the follow-up, 79 patients (12.7%) died. After adjusting for potential confounders, the combination of sarcopenia and cognitive impairment has been found associated with increased mortality (HR = 2.12, 95% CI = 1.05-4.13). Such association was also confirmed after excluding patients with dementia (HR = 2.13, 95% CI = 1.06-4.17), underweight (HR = 2.18, 95% CI = 1.03-3.91), high comorbidity burden (HR = 2.63, 95% CI = 1.09-6.32), and severe disability (HR = 2.88, 95% CI = 1.10-5.73). The co-occurrence of sarcopenia and cognitive impairment may predict 1-year mortality in older patients discharged from acute care hospitals.

Epigenetic signature: implications for mitochondrial quality control in human aging.

Maintenance of functional mitochondria is essential to prevent damage leading to aging and diseases. What is more, the research of biomarkers of aging is focusing on better predicting functional capability along the lifetime beyond chronological age. Aim of this study was to identify novel CpG sites the methylation of which might be correlated to the chronological and biological age. We performed methylation analyses of the CpG sites in candidate genes involved in mitochondrial biogenesis, mitophagy, fusion, and fission, all key quality control mechanisms to ensure maintenance of healthy mitochondria and homeostasis during aging, using DNA samples from two independent datasets composed by 381 and 468 differently-aged individuals, respectively. Twelve potential CpG predictors resulted associated with aging in the discovery dataset. Of these, two sites located within RAB32 and RHOT2 genes were replicated in the second dataset. What is more, individuals exhibiting methylation levels of the RAB32 CpG site higher than 10% were observed more prone to disability than people with lower levels.These results seem to provide the first evidence that epigenetic modifications of genes involved in mitochondrial quality control occur over time according to the aging decline, and may then represent potential biomarkers of both chronological and biological age.

Aging and nutrition induce tissue-specific changes on global DNA methylation status in rats.

A number of epigenetic studies have demonstrated that DNA methylation patterns exhibit a tissue specificity, but not much has been done to highlight the extent of this phenomenon. Moreover, it is unknown how external factors modulate the plasticity of the tissue specific epigenetic profile. We examined global DNA methylation profiles in tissues from rats of different age, fed with standard or low-calorie diet, and evaluated their association with aging and nutrition. Tissue-specific variations occur during aging with hyper-methylation taking place in all tissues except for liver. The expression of enzymes involved in methylation reactions (DNMTs and TETs) was consistent with the methylation patterns. Nutrition affects global DNA methylation status throughout lifespan. Interestingly, the differences among different tissues are magnified in 96 weeks old rats fed with low calorie diet. Moreover, the low-calorie diet appears to affect the offspring's epigenetic status more strongly if administered during the maternal pre-gestational period than the gestational and lactation time. Therefore, we propose that changes in the global DNA methylation status may represent an epigenetic mechanism by which age and nutrition intersect each other and, in turn, influence the aging plasticity.

Mitochondrial genome and epigenome: two sides of the same coin.

The involvement of mitochondrial content, structure and function as well as of the mitochondrial genome (mtDNA) in cell biology, by participating in the main processes occurring in the cells, has been a topic of intense interest for many years. More specifically, the progressive accumulation of variations in mtDNA of post-mitotic tissues represents a major contributing factor to both physiological and pathological phenotypes. Recently, an epigenetic overlay on mtDNA genetics is emerging, as demonstrated by the implication of the mitochondrial genome in the regulation of the intracellular epigenetic landscape being itself object of epigenetic modifications. Indeed, in vitro and population studies strongly suggest that, similarly to nuclear DNA, also mtDNA is subject to methylation and hydroxymethylation. It follows that the mitochondrial-nucleus cross talk and mitochondrial retrograde signaling in cellular properties require a concerted functional cooperation between genetic and epigenetic changes. The present paper aims to review the current advances in mitochondrial epigenetics studies and the increasing indication of mtDNA methylation status as an attractive biomarker for peculiar pathological phenotypes and environmental exposure.