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Objectives: The Montreal Cognitive Assessment (MoCA) is a cognitive screening test largely employed in vascular cognitive impairment, but there are no data about MoCA longitudinal changes in patients with cerebral small vessel disease (SVD). We aimed to describe changes in MoCA performance in patients with mild cognitive impairment (MCI) and SVD during a 2-year follow-up, and to evaluate their association with transition to major neurocognitive disorder (NCD). Materials and Methods: Within the prospective observational VMCI-Tuscany Study, patients with MCI and SVD underwent a comprehensive clinical, neuropsychological, and functional evaluation at baseline, and after 1 and 2 years. Results: Among the 138 patients (mean age 74.4 ± 6.9 years; males: 57%) who completed the study follow-up, 44 (32%) received a major NCD diagnosis. Baseline MoCA scores (mean±SD) were lower in major NCD patients (20.5 ± 5) than in reverter/stable MCI (22.2 ± 4.3), and the difference approached the statistical threshold of significance (p=.051). The total cohort presented a decrease in MoCA score (mean±SD) of -1.3 ± 4.2 points (-2.6 ± 4.7 in major NCD patients, -0.7 ± 3.9 in reverter/stable MCI). A multivariate logistic model on the predictors of transition from MCI to major NCD, showed MoCA approaching the statistical significance (OR=1.09, 95% CI=1.00–1.19, p=.049). Discussion: In our sample of MCI patients with SVD, longitudinal changes in MoCA performances were consistent with an expected more pronounced deterioration in patients who received a diagnosis of major NCD. MoCA sensitivity to change and predictive utility need to be further explored in VCI studies based on larger samples and longer follow-up periods.

Background/Objective: Growing evidence suggests a close relationship between motor and cognitive abilities, but possible common underlying mechanisms are not well-established. Atrial fibrillation (AF) is associated with reduced physical performance and increased risk of cognitive decline. The study aimed to assess in a cohort of elderly AF patients: (1) the association between motor and cognitive performances, and (2) the influence and potential mediating role of cerebral lesions burden.Design: Strat-AF is a prospective, observational study investigating biological markers for cerebral bleeding risk stratification in AF patients on oral anticoagulants. Baseline cross-sectional data are presented here.Setting: Thrombosis outpatient clinic (Careggi University Hospital).Participants: One-hundred and seventy patients (mean age 77.7 ± 6.8; females 35%).Measurements: Baseline protocol included: neuropsychological battery, motor assessment [Short Physical Performance Battery (SPPB), and walking speed], and brain magnetic resonance imaging (MRI) used for the visual assessment of white matter hyperintensities, lacunar and non-lacunar infarcts, cerebral microbleeds, and global cortical and medial temporal atrophies.Results: Mean Montreal Cognitive Assessment (MoCA) total score was 21.9 ± 3.9, SPPB total score 9.5 ± 2.2, and walking speed 0.9 ± 0.2. In univariate analyses, both SPPB and walking speed were significantly associated with MoCA (r = 0.359, r = 0.372, respectively), visual search (r = 0.361, r = 0.322), Stroop (r = −0.272, r = −0.263), short story (r = 0.263, r = 0.310), and semantic fluency (r = 0.311, r = 0.360). In multivariate models adjusted for demographics, heart failure, physical activity, and either stroke history (Model 1) or neuroimaging markers (Model 2), both SPPB and walking speed were confirmed significantly associated with MoCA (Model 1: β = 0.256, β = 0.236; Model 2: β = 0.276, β = 0.272, respectively), visual search (Model 1: β = 0.350, β = 0.313; Model 2: β = 0.344, β = 0.307), semantic fluency (Model 1: β = 0.223, β = 0.261), and short story (Model 2: β = 0.245, β = 0.273).Conclusions: In our cohort of elderly AF patients, a direct association between motor and cognitive functions consistently recurred using different evaluation of the performances, without an evident mediating role of cerebral lesions burden.

Familial dilated cardiomyopathy (DCM) is mostly caused by mutations in genes encoding cytoskeletal and sarcomeric proteins. In the pediatric population, DCM is the predominant type of primitive myocardial disease. A severe form of DCM is associated with mutations in the DMD gene encoding dystrophin, which are the cause of Duchenne Muscular Dystrophy (DMD). DMD-associated cardiomyopathy is still poorly understood and orphan of a specific therapy. In the last 5 years, a rise of interest in disease models using human induced pluripotent stem cells (hiPSCs) has led to more than 50 original studies on DCM models. In this review paper, we provide a comprehensive overview on the advances in DMD cardiomyopathy disease modeling and highlight the most remarkable findings obtained from cardiomyocytes differentiated from hiPSCs of DMD patients. We will also describe how hiPSCs based studies have contributed to the identification of specific myocardial disease mechanisms that may be relevant in the pathogenesis of DCM, representing novel potential therapeutic targets.

Abstract Genetic testing for hypertrophic cardiomyopathy (HCM) is an established clinical technique, supported by 30 years of research into its genetic etiology. Although pathogenic variants are often detected in patients and used to identify at‐risk relatives, the effectiveness of genetic testing has been hampered by ambiguous genetic associations (yielding uncertain and potentially false‐positive results), difficulties in classifying variants, and uncertainty about genotype‐negative patients. Recent case‐control studies on rare variation, improved data sharing, and meta‐analysis of case cohorts contributed to new insights into the genetic basis of HCM. In particular, although research into new genes and mechanisms remains essential, reassessment of Mendelian genetic associations in HCM argues that current clinical genetic testing should be limited to a small number of validated disease genes that yield informative and interpretable results. Accurate and consistent variant interpretation has benefited from new standardized variant interpretation guidelines and innovative approaches to improve classification. Most cases lacking a pathogenic variant are now believed to indicate non‐Mendelian HCM, with more benign prognosis and minimal risk to relatives. Here, we discuss recent advances in the genetics of HCM and their application to clinical genetic testing together with practical issues regarding implementation. Although this review focuses on HCM, many of the issues discussed are also relevant to other inherited cardiac diseases.

In previous studies of septal heart muscle from HCM patients with hypertrophic obstructive cardiomyopathy (HOCM, LVOT gradient 50–120 mmHg) we found that the level of phosphorylation of troponin I (TnI) and myosin binding protein C (MyBP-C) was extremely low yet samples from hearts with HCM or DCM mutations that did not have pressure overload were similar to donor heart controls. We therefore investigated heart muscle samples taken from patients undergoing valve replacement for aortic stenosis, since they have pressure overload that is unrelated to inherited cardiomyopathy. Thirteen muscle samples from septum and from free wall were analyzed (LVOT gradients 30–100 mmHg) The levels of TnI and MyBP-C phosphorylation were determined in muscle myofibrils by separating phosphospecies using phosphate affinity SDS-PAGE and detecting with TnI and MyBP-C specific antibodies. TnI was predominantly monophosphorylated and total phosphorylation was 0.85 ± 0.03 molsPi/mol TnI. This phosphorylation level was significantly different (p < 0.0001) from both donor heart TnI (1.6 ± 0.06 molsPi/mol TnI) and HOCM heart TnI (0.19 ± 0.04 molsPi/mol TnI). MyBP-C is phosphorylated at up to four sites. In donor heart the 4P and 3P species predominate but in the pressure overload samples the 4P species was much reduced and 3P and 1P species predominated. Total phosphorylation was 2.0 ± 0.2 molsPi/mol MyBP-C (n = 8) compared with 3.4 ± 0.07 (n = 21) in donor heart and 1.1 ± 0.1 (n = 10) in HOCM heart. We conclude that pressure overload may be associated with substantial dephosphorylation of troponin I and MyBP-C.

Hypertrophic cardiomyopathy (HCM) is the most frequent genetic cardiac disease with a prevalence of 1:500 to 1:200. While most patients show obstructive HCM and a relatively stable clinical phenotype (stage II), a small group of patients progresses to end-stage HCM (stage IV) within a relatively brief period. Previous research has shown sex-differences in stage II HCM with more diastolic dysfunction in female than in male patients. Moreover, female patients more often show progression to heart failure. Here we investigated if differences in functional and structural properties of the heart may underlie sex-differences in disease progression from stage II to stage IV HCM. Cardiac tissue from stage II and IV patients was obtained during myectomy (n = 54) and heart transplantation (n = 10), respectively. Isometric force was measured in membrane-permeabilized cardiomyocytes to define active and passive myofilament force development. Titin isoform composition was assessed using gel electrophoresis, and the amount of fibrosis and capillary density were determined with histology. In accordance with disease stage-dependent adverse cardiac remodeling end-stage patients showed a thinner interventricular septal wall and larger left ventricular and atrial diameters compared to stage II patients. Cardiomyocyte contractile properties and fibrosis were comparable between stage II and IV, while capillary density was significantly lower in stage IV compared to stage II. Women showed more adverse cellular remodeling compared to men at stage II, evident from more compliant titin, more fibrosis and lower capillary density. However, the disease stage-dependent reduction in capillary density was largest in men. In conclusion, the more severe cellular remodeling in female compared to male stage II patients suggests a more advanced disease stage at the time of myectomy in women. Changes in cardiomyocyte contractile properties do not explain the progression of stage II to stage IV, while reduced capillary density may underlie disease progression to end-stage heart failure.

To understand how pathology-induced changes in contractile protein isoforms modulate cardiac muscle function, it is necessary to quantify the temporal-mechanical properties of contractions that occur under various conditions. Pathological responses are much easier to study in animal model systems than in humans, but extrapolation between species presents numerous challenges. Employing computational approaches can help elucidate relationships that are difficult to test experimentally by translating the observations from rats and mice, as model organisms, to the human heart. Here, we use the spatially explicit MUSICO platform to model twitch contractions from rodent and human trabeculae collected in a single laboratory. This approach allowed us to identify the variations in kinetic characteristics of α- and β-myosin isoforms across species and to quantify their effect on cardiac muscle contractile responses. The simulations showed how the twitch transient varied with the ratio of the two myosin isoforms. Particularly, the rate of tension rise was proportional to the fraction of α-myosin present, while the β-isoform dominated the rate of relaxation unless α-myosin was >50%. Moreover, both the myosin isoform and the Ca2+ transient contributed to the twitch tension transient, allowing two levels of regulation of twitch contraction.

User-friendly devices for detecting low gliadin content in commercial foods are of extreme importance for people with gluten diseases. With this concern, the present work proposes a rapid and sensitive optical nanostructured microarrays platform for the detection of gliadin using specific anti-gliadin IgG antibodies immobilized on annealed gold nanostructures (AuNPs) obtained after the high annealing process (550 °C) of gold thin films evaporated on commercial glass coverslips. Localized Surface Plasmon Resonance (LSPR) immunosensing of gliadin in the range of 0.1 ppm to 1000 ppm is successfully achieved. In addition, the biofunctionalization protocol was used for gluten screening in five food complex products.

Aims: The DSM-5 introduced the term “major neurocognitive disorders” (NCDs) to replace the previous term “dementia.” However, psychometric and functional definitions of NCDs are missing. We aimed to apply the DSM-5 criteria for diagnosing the transition to NCD to patients with mild cognitive impairment (MCI) and small vessel disease (SVD), and to define clinically significant thresholds for this transition. Methods: The functional and cognitive features of the NCD criteria were evaluated as change from baseline and operationalized according to hierarchically ordered psychometric rules. Results: According to the applied criteria, out of 138 patients, 44 were diagnosed with major NCD (21 with significant cognitive worsening in ≥1 additional cognitive domain), 84 remained stable, and 10 reverted to normal. Single-domain MCI patients were the most likely to revert to normal, and none progressed to major NCD. The amnestic multiple-domain MCI patients had the highest rate of progression to NCD. Conclusion: We provide rules for the DSM-5 criteria for major NCD based on cognitive and functional changes over time, and define psychometric thresholds for clinically significant worsening to be used in longitudinal studies. According to these operationalized criteria, one-third of the MCI patients with SVD progressed to major NCD after 2 years, but only within the multiple-domain subtypes.

Quantitative relations between the sensory overall quality (OQJ) of commercial single grape variety Pinot Gris and Pinot Noir wines, defined using specific sensory attributes, and the most influencing chemical components were investigated in commercial wines from different international origins. Multiple factor analysis (MFA) was applied to achieve a comprehensive map of the quality of the samples while multivariate regression models were applied to each varietal wine to determine the sensory attributes influencing OQJ the most and to understand how the combinations of the volatile compounds influenced the olfactory sensory attributes. For Pinot Gris wine, OQJ was positively correlated with sensory attributes, like "floral" aroma, "stone-fruit" flavor, "yellow" color, "caramelized" aroma, and "tropical fruit" aroma according to an Italian panel. For Pinot Noir wine, "licorice" aroma, "cloves" aroma, "fresh wood" aroma, "red fruit" flavor, "cherry" aroma, and "spicy" flavor were positively correlated with OQJ by the same panel. Important predictors for the wine quality of Pinot Gris could be characterized, but not for Pinot Noir. Additionally, sensory tests were also carried out by different panel compositions (German and Italian). Both the German and the Italian panels preferred (based on OQJ) a Pinot Gris wine from New Zealand (Gisborne), but for different perceived characteristics (fruity and aromatic notes by the Italian panel and acidity by the German panel). For Pinot Noir, different panel compositions influenced the OQJ of the wines, as the wines from Chile (with more spicy, red fruit and woody notes) were preferred by the Italian panel, while the German panels preferred the wines from Argentina (with light, subtle woody and red fruit notes). The profile of cyclic and non-cyclic proanthocyanidins was also evaluated in the two varietal wines. No clear effect of the origin was observed, but the wines from Italy (Sicily/Puglia) were separated from the rest and were characterized by percentage ratio chemical indexes (%C-4) and (%C-5) for both varieties. [ABSTRACT FROM AUTHOR]

A multivariate regression approach based on sensory data and chemical compositions has been applied to study the correlation between the sensory and chemical properties of Pinot Blanc wines from South Tyrol. The sensory properties were identified by descriptive analysis and the chemical profile was obtained by HS-SPME-GC/MS and HPLC. The profiles of the most influencing (positively or negatively) chemical components have been presented for each sensory descriptor. Partial Least Square Regression (PLS) and Principal Component Regression (PCR) models have been tested and applied. Visual (clarity, yellow colour), gustatory (sweetness, sourness, saltiness, bitterness, astringency, and warmness) and olfactory (overall intensity, floral, apple, pear, tropical fruit, dried fruit, fresh vegetative, spicy, cleanness, and off-odours) descriptors have been correlated with the volatile and phenolic profiles, respectively. Each olfactory descriptor was correlated via a PCR model to the volatile compounds, whereas a comprehensive PLS2 regression model was built for the correlation between visual/gustatory descriptors and the phenolic fingerprint. “Apple” was the olfactory descriptor best modelled by PCR, with an adjusted R2 of 0.72, with only 20% of the validation samples falling out of the confidence interval (α = 95%). A PLS2 with 6 factors was chosen as the best model for gustatory and visual descriptors related to the phenolic compounds. Finally, the overall quality judgment could be explained by a combination of the calibrated sensory descriptors through a PLS model. This allowed the identification of sensory descriptors such as “olfactory intensity”, “warmness”, “apple”, “saltiness”, “astringency”, “cleanness”, “clarity” and “pear”, which relevantly contributed to the overall quality of Pinot Blanc wines from South Tyrol, obtained with two different winemaking processes and aged in bottle for 18 months.

Introduction: Three tiny bones compose the human ossicular chain: malleus, incus and stapes. Also known as auditory ossicles, they are united by joints in the middle ear cavity of the petrous part of the temporal bone. Completely developed two years after birth, the ossicular chain is involved in the physiological process of hearing, by which sound waves from the environment are converted into electrochemical impulses. In the last 500 years, most studies have focused on the morphogenesis, morphological variability and clinical pathology of the ossicular chain, whilst only a few studies have added relevant knowledge to anthropology and forensic science. The auditory ossicles and the enclosing petrous bone are some of the hardest in the human skeleton. This is reflected in a relative resistance to fire and in the possibility of preservation and fossilization in millions of years. Materials and Methods: The literature and four present-day forensic cases were included in studying the postmortem loss of the auditory ossicles in skeletal or decomposing remains. Results indicate that it can be ascribed to their destruction or physical displacement, by either macro-micro-faunal action and/or any other natural or artificial disturbance. Discussion: Physical displacement is closely connected to the depositional environment of the skeletal remains, such as burial, entombment (sarcophagus, coffin, vault...), submersion or exposure to natural elements. Auditory ossicles can be recovered in situ, or very close to their anatomical location, when the skeletal material has been involved in an archaeological excavation. In the case of accessible or disturbed remains, scavengers may remove the tiny ossicles and/or they can slip out of the middle ear cavity following skull movements. Entombment offers effective protection against the displacement of the auditory ossicles, whereas aquatic submersion and aquatic movement almost invariably displace them. Conclusion: the preservation of the human auditory ossicles should be critically considered in the comprehensive context of any forensic investigation on human remains since it can assist the reconstruction of their taphonomic history. Taphonomic histories of remains can add crucial information to forensic investigations (e.g., the Post Mortem Interval, PMI). The aim of this study, limited by scarce relevant literature, is to discuss the potential role of the ossicular chain, detected by postmortem imaging techniques, as a taphonomical indicator in decomposing and/or skeletonized bodies. [ABSTRACT FROM AUTHOR]

PURPOSE:We aimed to perform intraindividual comparison of computed tomography (CT) parameters, image quality, and radiation exposure between standard CT angiography (CTA) and high-pitch dual source (DS)-CTA, in subjects undergoing serial CTA of thoracoabdominal aorta.METHODS:Eighteen subjects with thoracoabdominal CTA by standard technique and high-pitch DS-CTA technique within 6 months of each other were retrieved for intraindividual comparison of image quality in thoracic and abdominal aorta. Quantitative analysis was performed by comparison of mean aortic attenuation, noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). Qualitative analysis was performed by visual assessment of motion artifacts and diagnostic confidence. Radiation exposure was quantified by effective dose. Image quality was apportioned to radiation exposure by means of figure of merit.RESULTS:Mean aortic attenuation and noise were higher in high-pitch DS-CTA of thoracoabdominal aorta, whereas SNR and CNR were similar in thoracic aorta and significantly lower in high-pitch DS-CTA of abdominal aorta (P = 0.024 and P = 0.016). High-pitch DS-CTA was significantly better in the first segment of thoracic aorta. Effective dose was reduced by 72% in high-pitch DS-CTA.CONCLUSION:High-pitch DS-CTA without electrocardiography-gating is an effective technique for imaging aorta with very low radiation exposure and with significant reduction of motion artifacts in ascending aorta; however, the overall quality of high-pitch DS-CTA in abdominal aorta is lower than standard CTA.

Myofibril based mechanical studies allow evaluation of sarcomeric protein function. We describe a novel method of obtaining myofibrils from primary cardiomyocyte culture. Adult rat ventricular myocytes (ARVMs) were obtained by enzymatic digestion and maintained in serum free condition. ARVMs were homogenized in relaxing solution (pCa 9.0) with 20% sucrose, and myofibril suspension was made. Myofibrils were Ca2+-activated and relaxed at 15°C. Results from ARVM myofibrils were compared to myofibrils obtained from ventricular tissue skinned with Triton X-100. At maximal Ca2+-activation (pCa 4.5) myofibril mechanical parameters from ARVMs were 6.8 ± 0.9 mN/mm2 (resting tension), 146.8 ± 13.8 mN/mm2 (maximal active tension, P0), 5.4 ± 0.22 s−1 (rate of force activation), 53.4 ± 4.4 ms (linear relaxation duration), 0.69 ± 0.36 s−1 (linear relaxation rate), and 10.8 ± 1.3 s−1 (exponential relaxation rate). Force-pCa curves were constructed from Triton skinned tissue, ARVM culture day 1, and ARVM culture day 3 myofibrils, and pCa50 were 5.79 ± 0.01, 5.69 ± 0.01, and 5.71 ± 0.01, respectively. Mechanical parameters from myofibrils isolated from ARVMs treated with phenylephrine were compared to myofibrils isolated from time-matched non-treated ARVMs. Phenylephrine treatment did not change the kinetics of activation or relaxation but decreased the pCa50 to 5.56 ± 0.03 (vehicle treated control: 5.67 ± 0.03). For determination of protein expression and post-translational modifications, myofibril slurry was re-suspended and resolved for immunoblotting and protein staining. Troponin I phosphorylation was significantly increased at serine 23/24 in phenylephrine treated group. Myofibrils obtained from ARVMs are a viable method to study myofibril mechanics. Phenylephrine treatment led to significant decrease in Ca2+-sensitivity that is due to increased phosphorylation of TnI at serine 23/24. This culture based approach to obtaining myofibrils will allow pharmacological and genetic manipulation of the cardiomyocytes to correlate biochemical and biophysical properties.

Patients with cerebral small vessel disease (SVD) frequently show decline in cognitive performance. However, neuroimaging in SVD patients discloses a wide range of brain lesions and alterations so that it is often difficult to understand which of these changes are the most relevant for cognitive decline. It has also become evident that visually-rated alterations do not fully explain the neuroimaging correlates of cognitive decline in SVD. Fractal dimension (FD), a unitless feature of structural complexity that can be computed from high-resolution T1-weighted images, has been recently applied to the neuroimaging evaluation of the human brain. Indeed, white matter (WM) and cortical gray matter (GM) exhibit an inherent structural complexity that can be measured through the FD.In our study, we included 64 patients (mean age ± standard deviation, 74.6 ± 6.9, education 7.9 ± 4.2 years, 53% males) with SVD and mild cognitive impairment (MCI), and a control group of 24 healthy subjects (mean age ± standard deviation, 72.3 ± 4.4 years, 50% males). With the aim of assessing whether the FD values of cerebral WM (WM FD) and cortical GM (GM FD) could be valuable structural predictors of cognitive performance in patients with SVD and MCI, we employed a machine learning strategy based on LASSO (least absolute shrinkage and selection operator) regression applied on a set of standard and advanced neuroimaging features in a nested cross-validation (CV) loop. This approach was aimed at 1) choosing the best predictive models, able to reliably predict the individual neuropsychological scores sensitive to attention and executive dysfunctions (prominent features of subcortical vascular cognitive impairment) and 2) identifying a features ranking according to their importance in the model through the assessment of the out-of-sample error.For each neuropsychological test, using 1000 repetitions of LASSO regression and 5000 random permutations, we found that the statistically significant models were those for the Montreal Cognitive Assessment scores (p-value = .039), Symbol Digit Modalities Test scores (p-value = .039), and Trail Making Test Part A scores (p-value = .025). Significant prediction of these scores was obtained using different sets of neuroimaging features in which the WM FD was the most frequently selected feature.In conclusion, we showed that a machine learning approach could be useful in SVD research field using standard and advanced neuroimaging features. Our study results raise the possibility that FD may represent a consistent feature in predicting cognitive decline in SVD that can complement standard imaging. Keywords: Fractal dimension, LASSO regression, Machine learning, Mild cognitive impairment, Small vessel disease, White matter