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Broad evidence indicates that hypertensive response to exercise (HRE) is associated with future hypertension (aHT) at rest and cardiovascular morbidity and mortality. Nevertheless, a consensus on the definition of HRE is lacking and the comparability of the available data is difficult due to a wide variation of definitions used. This review aims to harmonize currently available definitions of HRE in normotensive and athletic populations and to propose a generally valid cut-off applicable in everyday clinical practice. A literature search on PubMed and Embase was conducted to assemble and analyze the most recent data. Various definitions of HRE were identified and linked with future cardiovascular diseases. Forty-one studies defined HRE at a peak systolic blood pressure (SBP) above or equal to 200 mmHg in men and 25 studies for 190 mmHg in women. Peak diastolic blood pressure (DBP) between 90 and 110 mmHg was reported in 14 studies, relative DBP increase in four. Eight studies defined HRE as SBP between 160 and 200 mmHg at 100 watts. 17 studies performed submaximal exercise testing, while two more looked at BP during recovery. A plethora of other definitions was identified. In athletes, total workload and average blood pressure during exercise were considerably higher. Based on the presented data, the most commonly used definition of HRE at peak exercise is 210/105 mmHg for men, 190/105 mmHg for women, and 220/210 mmHg for athletes. Furthermore, a uniform exercise testing protocol, a position statement by leading experts to unify the definition of HRE, and prospective studies are warranted to confirm these cut-offs and the associated morbidity and mortality.

Climate geoengineering might reduce the economic and ecological impacts of global warming. However, its governance is challenging: since climate preferences vary across countries, excessive climate geoengineering relative to the socially optimal level is a likely risk. Through a laboratory experiment on a public good-or-bad game, we study to what extent side payments can curb geoengineering efforts and restore efficiency. Although the availability of side payments is theoretically effective, its impact is modest in the experiment, especially in a multilateral setup. Replacing unstructured bilateral agreements with a structured framework improves outcomes.

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOEε4 allele.

We evaluated cardiac response to weight loss induced by a very-low-energy (VLE) diet similar to commercially available protein-sparing diets. Such diets have been implicated in sudden death, and whether organ and tissue responses to them are untoward is not known. Rapid weight loss was induced in rats with weights ranging from obese to normal, and cardiac mass and myocardial histomorphometry were assessed. Over 3 wk body weight dropped from 544 [+ or -] 12 to 417 [+ or -] 21 g (P < 0.001). Heart weight was less in the VLE group than in obese controls (1246 [+ or -] 115 vs 1625 [+ or -] 179 mg, P > 0.001), as were the weights of the left ventricle (805 [+ or -] 81 vs 1061 [+ or -] 134 mg, P < 0.001) and right ventricle (198 [+ or -] 27 vs 265 [+ or -] 40 mg, P < 0.002). Reduction in heart weight was commensurate with loss of body weight (r = 0.89). Myocyte cross-sectional area was reduced in the VLE group (452.6 [+ or -] 108.6 to 331.8 [+ or -] 41.5 [[micro]m.sup.2], P < 0.05), with no structural abnormalities. We conclude that weight loss in the weight range studied is accompanied by proportional reduction in cardiac mass and myocyte size. Myocardial regression is not accompanied by myocyte dropout or edema, and likely represents a simple adaptation to reduced body size. Am J Clin Nutr 1994;59:566-71.

Hepatic effects of very-low-energy diets (VLEDs) and refeeding were studied in dietary obese rats. Rats weighing 490-530 g (ages 72-119 d) were randomly assigned to control (C) and VLED groups. Control animals consumed a complete diet ad libitum whereas VLED animals consumed 20% of the energy intake of C animals for 7, 14, or 21 d, and some VLED animals were refed the C diet for 7 d. Hepatic weights, lipid, DNA, and total protein decreased in VLED animals. Observed hepatocytic lipid was high in C and progressively decreased in VLED rats. Hepatocytes from VLED rats lost cytoplasmic organelles, contained myelin figures, and became smaller. Decreased protein-DNA ratios and lipids in these same animals is consistent with atrophy. Other biochemical findings included reductions in blood urea nitrogen, albumin, triglycerides, total protein, and glucose, all of which are synthesized or metabolized by the liver. These observations suggest that attenuation of hepatic function is likely.

This article discusses the transformation that telecommunications companies (telcos) need to undergo in order to become more customer-centric and succeed in the digital age. It emphasizes the importance of persona-based customer segmentation, configurable product portfolios, and customer journey mapping. The article also highlights the role of AI-powered next-best-action engines, real-time triggers, and omnichannel customer experiences. Additionally, it discusses the need for an evolved operating model that clarifies the roles of marketing and channel teams, embraces product and channel agnosticism, embeds data scientists into business teams, builds cross-functional agile factories, and adopts an agile working mode. The article provides examples of telcos that have successfully implemented these changes and achieved improved customer satisfaction and business outcomes. [Extracted from the article]

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

IntroductionStructural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis.MethodsA total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation.ResultsAverage 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores.ConclusionOur results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.

This work presents a system based on an ensemble of Convolutional Neural Networks (CNNs) and descriptors for bioimage classification that has been validated on different datasets of color images. The proposed system represents a very simple yet effective way of boosting the performance of trained CNNs by composing multiple CNNs into an ensemble and combining scores by sum rule. Several types of ensembles are considered, with different CNN topologies along with different learning parameter sets. The proposed system not only exhibits strong discriminative power but also generalizes well over multiple datasets thanks to the combination of multiple descriptors based on different feature types, both learned and handcrafted. Separate classifiers are trained for each descriptor, and the entire set of classifiers is combined by sum rule. Results show that the proposed system obtains state-of-the-art performance across four different bioimage and medical datasets. The MATLAB code of the descriptors will be available at https://github.com/LorisNanni.

Almost no neurological disease exists without microglial activation. Microglia has exert a pivotal role in the maintenance of the central nervous system and its response to external and internal insults. Microglia have traditionally been classified as, in the healthy central nervous system, “resting”, with branched morphology system and, as a response to disease, “activated”, with amoeboid morphology; as a response to diseases but this distinction is now outmoded. The most devastating disease that hits the brain is cancer, in particular glioblastoma. Glioblastoma multiforme is the most aggressive glioma with high invasiveness and little chance of being surgically removed. During tumor onset, many brain alterations are present and microglia have a major role because the tumor itself changes microglia from the pro-inflammatory state to the anti-inflammatory and protects the tumor from an immune intervention. What are the determinants of these changes in the behavior of the microglia? In this review, we survey and discuss the role of sphingolipids in microglia activation in the progression of brain tumors, with a particular focus on glioblastoma.

BackgroundSemantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD.MethodsThis large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset).ResultsCSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628–3593) than in controls (577 (446–766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs=−0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs=−0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival.ConclusionCSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.

Background: Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in β-amyloid Precursor Protein (AβPP) processing. Usually, Alzheimer's disease (AD)-linked mutations in the PSEN-1 gene lead to the early onset and increase the production of the aggregation-prone peptide Aβ42. However, the PSEN-1 E318G variant has an unclear pathogenic role and is recently reported as a genetic risk factor for AD. In particular, E318G variant presence correlated with increased cerebrospinal fluid (CSF) levels of Total Tau (t-tau) and Phosphorylated Tau (p-tau). Objective: We describe a large Italian family, which we followed from January 2003 to January 2018, with the late-onset AD and the E318G variant, with the aim of assessing E318G-associated CSF or plasma biochemical changes in biomarkers of dementia. Method: CSF Aβ42, t-tau and p-tau, plasma Aβ42 and Aβ40 were assessed by ELISA tests, while CSF amyloid peptides profile was investigated by mass spectrometry. Results: We did not find any changes in CSF biochemical markers (Aβ42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma Aβ40 was increased at the same times. From 2003 to 2018, no asymptomatic E318G carrier developed AD. Conclusion: Our follow-up of this family may help elucidate E318G's role in AD and globally points to a null effect of this variant.

Most laboratory techniques are performed in biosafety cabinets (BSCs) to provide contamination control of the experiments. By using specifically directed airflow and high-efficiency particulate air (HEPA) filtration, potential contaminants are removed from the work area within the BSC. Aerosols may be created by common lab practices, such as centrifugation, pipetting, and opening tubes. HEPA filters are very effective at removing various-sized contaminants but do not prevent gases and vapors from penetrating through them. HEPA filters are not effective at all sizes of particles. Researchers have speculated that DNA may not be captured by HEPA filters, allowing for contamination of subsequent experiments by aerosolized DNA. Here we found that DNA is captured by a HEPA filter at the same efficiency as the filter is rated and discovered that DNA cannot be dislodged from a HEPA filter.

Many reliable and robust turbulence models are nowadays available for the Reynolds-Averaged Navier–Stokes (RANS) equations to accurately simulate a wide range of engineering flows. However, turbulence models are not suited to correctly described flows with low to moderate Reynolds numbers, which are characterized by strong transitional phenomena. Therefore, numerical models able to accurately predict transitional flows are mandatory to overcome the limits of turbulence models for the efficient design of many industrial applications. The only ways to describe transition are Direct Numerical Simulation (DNS), Large Eddy Simulation (LES), and transition models, where the computational cost of DNS and LES is still too high for their routine use in industry. A modified version of the k - ω ̃ and Spalart–Allmaras turbulence models is here proposed to predict transition due to the bypass and separation-induced modes. The modifications are based on the γ k - ω ̃ and the SA-BCM models and avoid complex formulations of transport equations ad-hoc defined for transition. Both the transition models are correlation-based algebraic models that rely only on local flow information and an intermittency function, which damps the turbulent production according to some transition onset requirements. The proposed transition models are implemented in a high-order discontinuous Galerkin (dG) solver and validated on benchmark cases from the ERCOFTAC suite to the Eppler 387 airfoil, with different transition mode, freestream Reynolds number and turbulent intensity, and pressure gradient. • Modification of traditional turbulence models to predict bypass and separation-induced transition. • Implementation of the γ k - ω ˜ and the SA-BCM transition models in a high-order solver. • Improvement of the transition models in comparison with literature. • Validation of the models on benchmark cases with different transition and flow conditions. [ABSTRACT FROM AUTHOR]

The present work describes an accurate tool based on numerical simulations and genetic algorithms, which is able to automatically choose the turbulator geometrical parameters with helical profile that optimize both the heat exchanged and the pressure losses with a low computation cost. In particular, the proposed methodology is assessed in the design of turbulators for the smoke-pipe of a steam boiler. The flue gases behavior is modeled with the compressible Reynolds-Averaged Navier–Stokes equations, coupled with transport equations for non-reacting chemical species. The optimization employs a surrogate-based optimization, where the single and multi objective genetic algorithm are applied to a response surface. Different objective functions from literature to drive the optimization process are compared, e.g, the heat exchange efficiency, the total entropy generation number, the merit function, and the net profit and total cost per unit transferred heat load. Even if these functions have been yet investigated in different works, showing pros and cons, it is still not clear from a practical point of view, which one should be used for a shape optimization process. The results suggest the use of a different objective function if the main goal is to maximize the heat exchanged and/or to minimize the pressure losses, with similar performance of the parameters based on the laws of thermodynamics or also on economic considerations. Furthermore, the results prove the higher fidelity of numerical simulations in the estimation of the Nusselt number and the friction factor in comparison with empirical correlations. The significance of the present work lies in the proof of the low computational cost and easy application of a shape optimization process for the design-of-things based on numerical simulations.

•22 « bitumen » samples from 15 timbers of sewn-boats from al-Balid (Oman), dated from the Middle Islamic period (10th-15th c.AD), were analyzed by geochemical techniques.•All samples contain bitumen originating from Iran.•Samples may be pure bitumen or bituminous mixtures in which grease or oil and resins (dammar and frankincense) were identified.

Syncope and related falls are one of the main causes and the predominant cause of hospitalization in elderly patients with dementia. However, the diagnostic protocol for syncope is difficult to apply to patients with dementia. Thus, we developed a “simplified” protocol to be used in a prospective, observational, and multicenter study in elderly patients with dementia and transient loss of consciousness suspected for syncope or unexplained falls. Here, we describe the protocol, its feasibility and the characteristics of the patients enrolled in the study. Patients aged ≥65 years with a diagnosis of dementia and one or more episodes of transient loss of consciousness during the previous 3 months, subsequently referred to a Geriatric Department in different regions of Italy, from February 2012 to May 2014, were enrolled. A simplified protocol was applied in all patients. Selected patients underwent a second-level evaluation. Three hundred and three patients were enrolled; 52.6 % presented with episodes suspected to be syncope, 44.5 % for unexplained fall and 2.9 % both. Vascular dementia had been previously diagnosed in 53.6 % of participants, Alzheimer’s disease in 23.5 % and mixed forms in 12.6 %. Patients presented with high comorbidity (CIRS score = 3.6 ± 2), severe functional impairment, (BADL lost = 3 ± 2), and polypharmacy (6 ± 3 drugs). Elderly patients with dementia enrolled for suspected syncope and unexplained falls have high comorbidity and disability. The clinical presentation is often atypical and the presence of unexplained falls is particularly frequent.

Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.

Highlights: [•] DG solution of the incompressible RANS and k–ω turbulence model eq. is presented. [•] The inviscid interface numerical fluxes is based on an exact Riemann solver. [•] Exact Riemann solver with a relaxed incompressibility constraint. [•] The formulation of the governing equations in a relative reference frame is discussed. [•] The method is validated by considering three testcases (steady and unsteady). [Copyright &y& Elsevier]

To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.

Normally, cell proliferation and death are carefully balanced in higher eukaryotes, but one of the most important regulatory mechanisms, apoptosis, is upset in many malignancies, including hepatocellular-derived ones. Therefore, reinforcing cell death often is mandatory in anticancer therapy. We previously reported that a combination of tumor necrosis factor-α (TNF) and cycloheximide (CHX) efficiently kill HTC cells, a rat hepatoma line, in an apoptosis-like mode. Death is actively mediated by the lysosomal compartment, although lysosomal ceramide was previously shown not to be directly implicated in this process. In the present study, we show that TNF/CHX increase lysosomal ceramide that is subsequently converted into sphingosine. Although ceramide accumulation does not significantly alter the acidic compartment, the sphingosine therein generated causes lysosomal membrane permeabilization (LMP) followed by relocation of lysosomal cathepsins to the cytoplasm. TNF/CHX-induced LMP is effectively abrogated by siRNAs targeting acid sphingomyelinase or acid ceramidase, which prevent both LMP and death induced by TNF/CHX. Taken together, our results demonstrate that lysosomal accumulation of ceramide is not detrimental per se, whereas its degradation product sphingosine, which has the capacity to induce LMP, appears responsible for the observed apoptotic-like death.

A new apparatus enhances the biosafety of containment (biosafety level 3 [BSL-3]) and provides experimental reproducibility for aerosol infection experiments with MDR and XDR Mycobacterium tuberculosis. The methods are generally applicable to the study of air-borne pathogens.

To determine whether TMEM106Bsingle nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106Bmodulates GRNexpression.

Background and aims:To describe the clinical and neuropsychological features of a large group of cognitively intact persons subjected to brain high-resolution magnetic resonance (MR), to compare them with the general population, and to set norms for medial temporal atrophy and white matter lesions. Methods:Participants in the Italian Brain Normative Archive (IBNA) study were 483 consecutive volunteers undergoing MR for reasons unrelated to cognition (migraine or headache, visual and balance or auditory disturbances, paresthesias, and others) and showing no brain damage. Manual tracing of hippocampal and amygdalar volumes and visual rating of white matter lesions were made. The whole study group was stratified by age (≤60 and 60+ yrs) and by the reason for MR prescription. Results:In the whole group, mean age and education were 52.4±13.7 and 9.8±4.2 years, respectively, and the prevalence of women was 63%. Clinical, neuropsychological and morphometric features were similar in the stratified subgroups. Neuropsychological features were those expected for age and education based on Italian normative values. Hippocampal and amygdalar volumes were not associated with age, except for the right amygdala (B −0.159, 95% CI −0.28 to −0.03, p=0.016). Conclusions:Persons in the IBNA study had clinical and neuropsychological features consistent with that of the general population. Their brain morphometric features may be used as normative references for patients with suspected neurodegenerative disorders.

Nowadays, thanks to ever-increasing computational resources, a viable path to a robust and fast design strategy for both thermal machines and turbomachinery is the coupling of Computational Fluid Dynamics (CFD) and shape optimization algorithms. In general, numerical optimization approaches require less time than the trial-and-error procedure traditionally employed, where the designer produces only a tentative initial geometry. This work assesses the capability of a shape optimization algorithm to enhance the design of a steam boiler mixing channel to guarantee negligible NOxproduction, avoid combustion instabilities especially at lower thermal powers, due to a bad mixing quality of the mixture, and thermal deformation on the burner surface mesh, due to a non uniform distribution of the flame. In particular, the effect of the mixing quality, flow uniformity and the pressure losses at the outlet section of the mixing channel are investigated. The shape optimization approach is here based on a Surrogate Based Optimization (SBO) with the Multi Objective Genetic Algorithm (MOGA), where response surfaces based on the Kriging meta-model are adopted to decrease the computational cost of the proposed approach.

Serum copper not bound to ceruloplasmin (“free”) appears slightly elevated in patients with Alzheimer disease (AD). We explored whether a deregulation of the free copper pool can predict AD clinical worsening.

Mutations in the progranulin gene (PGRN) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles leading to a 50% loss of progranulin transcript.

Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin‐like growth factor binding protein (IGFBP)‐3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP‐3 plays a role in promoting angiogenesis. IGFBP‐3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up‐regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)‐2 and ‐9. IGFBP‐3 even induced membrane‐type 1 MMP (MT1‐MMP), which regulates MMP‐2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP‐3‐induced network formation and inhibited VEGF, MT1‐MMP but not IGF‐I up‐regulation. IGF‐I activated SphK, leading to sphingosine‐1‐phosphate (S1P) formation. The IGF‐I effect on SphK activity was blocked by specific inhibitors of IGF‐IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF‐I signaling prevented the IGFBP‐3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF‐I up‐regulation. Finally, IGFBP‐3 dose‐dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo. Thus, IGFBP‐3 positively regulates angiogenesis through involvement of IGF‐IR signaling and subsequent SphK/S1P activation.

Estrogens are known to be protective in age-associated cognitive changes in humans and in neurodegeneration in animal models. The aim of this study was to evaluate the potential effects of estrogen therapy (ET) on human gray matter volume in vivo.

We compared mortality rates league tables for six cardiac surgery centres developed using an administrative database (integrated with information on patients' EuroSCORE) with those drawn from a specialised clinical database. Data from 4017 patients undergoing cardiac surgery over the period January 1st-December 31st 2003, and identified both databases were used. Case mix adjusted in-hospital mortality rates were estimated relying on information provided by each database, and league tables were drawn from both. The correlation between the two league tables was assessed through the Spearman correlation coefficient. League tables drawn from the two sources identified the same 'best' and 'worst' centres and the Spearman correlation coefficient confirmed a high level of agreement between the two rankings (r=0.89; P<0.02). Use of the logistic EuroSCORE instead of the additive one did not change the results. An administrative and a clinical specialised database provided similar league tables. However, this finding by no means implies that clinical databases should be abandoned. While administrative data allow a more efficient performance assessment, clinical databases may more properly satisfy the legitimate demand of surgical staff of being directly involved in quality monitoring, rather than being mere passive objects of external assessment.

Relationships between the apolipoprotein E ε4 allele and electroencephalographic (EEG) rhythmicity have been demonstrated in Alzheimer's disease (AD) patients but not in the preclinical stage prodromic to it, namely, mild cognitive impairment (MCI). The present multicentric EEG study tested the hypothesis that presence of ε4 affects sources of resting EEG rhythms in both MCI and AD subjects. We enrolled 89 MCI subjects (34.8% with ε4) and 103 AD patients (50.4% with ε4). Resting eyes‐closed EEG data were recorded for all subjects. EEG rhythms of interest were delta (2—4Hz), theta (4–8Hz), alpha 1 (8–10.5Hz), alpha 2 (10.5–13Hz), beta 1 (13–20Hz), and beta 2 (20–30Hz). EEG cortical sources were estimated by low‐resolution brain electromagnetic tomography. Results showed that amplitude of alpha 1 and 2 sources in occipital, temporal, and limbic areas was lower in subjects carrying the ε4 allele than in those not carrying the ε4 allele (p< 0.01). This was true for both MCI and AD. For the first time to our knowledge, a relationship was shown between ApoE genotype and global neurophysiological phenotype (ie, cortical alpha rhythmicity) in a preclinical AD condition, MCI, in addition to clinically manifest AD. Such a demonstration motivates future genotype–EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects. Ann Neurol 2005

Background and aims:Substantial evidence supports the hypothesis that impairment of mitochondrial function and increased oxidative damage are involved in the pathogenesis of several neurodegenerative disorders including Alzheimer’s disease (AD). Manganese Superoxide dismutase (MnSOD) plays a major role in protecting the mitochondrion from oxidative damage due to Superoxide radicals and other excited oxygen species. Recent studies have indicated that MnSOD mRNA levels are significantly increased in the lymphocytes of AD patients, supporting the role of oxidative alterations in the pathogenetic mechanism underlying this neurodegeneration. A potentially functional amino acid polymorphism (Ala-9Val) has been described in the signal sequence of enzymes associated with decreased defense capacity against oxidative stress. The object of this study was to investigate the association between this polymorphism of the MnSOD gene and AD in the Italian population. Methods:The Ala-9Val polymorphism was genotyped by PCR amplification and SSCP analysis in 227 AD patients and 198 healthy controls. Results:No significant differences in genotype or allele frequencies between cases and controls, even after stratification for APOE carrier status, were observed. Conclusions:Our data suggest that the Ala-9Val polymorphism in the MnSOD gene is not associated with genetic susceptibility in AD patients.

Resveratrol, a natural product with a stilbene structure, exerts profound proapoptotic activity in human cancer cells, by triggering the accumulation of ceramide, a bioactive sphingolipid. We studied the biological effects of seven methoxylated and/or naphthalene-based resveratrol analogues and compared these compounds with resveratrol with the objective to identify an analogue with higher ceramide-mediated proapoptotic activity relative to resveratrol. Here we show that the compound with three hydroxyls and a naphthalene ring is the most effective in triggering apoptosis coupled to the induction of endogenous ceramide in human cancer cells.

Most individuals with constitutional deletions of chromosome 18q have developmental delays, dysmyelination of the brain, and growth failure due to growth hormone deficiency. We monitored the effects of growth hormone treatment by evaluating 23 individuals for changes in growth, nonverbal intelligence quotient (nIQ), and quantitative brain MRI changes. Over an average of 37 months, the treated group of 13 children had an average nIQ increase of 17 points, an increase in height standard deviation score of 1.7, and significant change in T1 relaxation times in the caudate and frontal white matter. Cognitive changes of this magnitude are clinically significant and are anticipated to have an effect on the long‐term outcomes for the treated individuals. © 2005 Wiley‐Liss, Inc.

The clinical interest in HER-2/neu is related to trastuzumab, a drug used to treat patients with invasive breast carcinoma overexpressing the HER-2/neu protein. It is very important to correctly identify those patients who may benefit from trastuzumab by accurate assessment of the HER-2/neu status. Of the various methods available, the Dako Herceptest for immunohistochemical assay is considered the most reliable to reach this goal. The aim of this study was to investigate within a group of Italian laboratories the reproducibility of the results of HER-2/neu assessment by means of the Dako scoring system on slides stained with the Herceptest kit. This study was also conceived as the continuation of one of our previous studies, which was similar in its aims but different in the classification criteria adopted. Our results show that, whereas the intra-observer reproducibility was generally satisfactory, the interobserver reproducibility was not. Moreover, our findings confirm that the two extreme classes (0 and 3+) are more easy to identify than the other two and that the Herceptest does not allow to discriminate optimally between scoring classes 2+ and 3+. These findings are relevant in clinical practice where the treatment choice is based on categories defined by this assay, suggesting the need of adopting educational programs and/or new reference materials to improve the assay performance.

ABSTRACTThe apicomplexan parasite Toxoplasma gondiiis a leading opportunistic pathogen associated with AIDS and congenital birth defects. Due to the need for identifying new parasite-specific treatments, the possibility of targeting sphingolipid biosynthesis in the parasite was investigated. Aureobasidin A, an inhibitor of the enzyme synthesizing the sphingolipid inositol phosphorylceramide, which is present in fungi, plants, and some protozoa but absent in mammalian cells, was found to block in vitro T. gondiireplication without affecting host cell metabolism. Aureobasidin A treatment did not induce tachyzoite to bradyzoite stage conversion in T. gondiibut resulted in a loss of intracellular structures and vacuolization within the parasite. In addition, aureobasidin A inhibited sphingolipid synthesis in T. gondii. Sphingolipid biosynthetic pathways may therefore be considered targets for the development of anti-T. gondiiagents.

Introduction:β-Blockers have been shown to be effective in the treatment of both arterial hypertension and heart failure. However, slow titration of β-blockers over several weeks and rigorous supervision are essential to minimise antiadrenergic adverse effects in patients with heart failure. α1-Blockers are well tolerated and effectively lower blood pressure by reducing peripheral resistance.

Cancer develops from overlapping events that tend to deregulate the metabolism and unbalance the homeostasis of cells. Sphingolipids, major components of biological membranes, are also mediators of intracellular signalling. Their metabolism can be influenced by diverse stimuli and the accumulation or deficiency of intermediates may trigger proliferation and/or impair the ability of damaged cells to undergo apoptosis. Many sphingolipid-regulated functions are implicated in tumour initiation, promotion, progression and responsiveness to chemotherapy. In this review, evidence of the alteration of sphingolipids metabolism and signalling will be discussed in breast cancer prevention and therapy.

Genetic factors are involved in the aetiology of dementias. Three genes have been identified which, when mutated, cause Familial Alzheimer disease (FAD): the presenilin-1 (PS1), the presenilin-2 (PS2) and the amyloid precursor protein (APP) genes. Together, these mutations are responsible for 30-50andamp;#x25; of the cases with autosomal dominant Alzheimer disease (AD), and for about 5andamp;#x25; of all AD cases. While over 130 mutations have been identified in PS1, mutations in PS2 and APP are rarer, since only 10 and 22 mutations, respectively, have been found in these FAD genes. Instead, mutations in the MAPT gene were associated with Familial Frontotemporal dementia (FFTD) linked to chromosome 17 (FTDP-17). Frontotemporal dementia (FTD) can occur in a sporadic form, but in 30-50andamp;#x25; of cases there is a positive family history of dementia. In this study, we determined the spectrum of mutations and the relative contribution of the above mentioned four genes in our Italian clinical series of patients with a positive family history of dementia.

The Howard Hughes Medical Institute sponsored a workshop on laboratory chemical hoods on June 8, 9, and 10, 1998, that brought together 24 experts in the field of laboratory chemical hoods to critically assess the information known about hood performance. Workshop participants developed 31 consensus statements that reflect their collective views on the body of knowledge or lack thereof, for laboratory chemical hoods. The consensus statements fall into four broad categories: (1) hood selection, use, and operation; (2) hood and laboratory design issues; (3) ventilation system design issues; and (4) hood performance testing. The consensus statements include 26 statements on what is known and unknown about the performance of laboratory chemical hoods, 2 statements of definition, and 3 statements that reflect the participants' agreement not to agree. The brief commentary that follows each consensus statement provides guidance and recommendations.

We describe an Italian pedigree with hereditary dementia associated with a novel T122R mutation in the presenilin‐2 gene (PSEN2). The clinical history, symptom presentation, and structural neuroimaging were consistent with an atypical form of dementia. Disease expression varied within family members. One in a pair of mutated monozygotic twins had evident signs of disease, whereas the other did not, even if her functional neuroimaging investigations, cerebrospinal fluid levels of Aβ1‐42, and Tau protein were able to provide markers for future disease development. These observations suggest the importance of still unknown biological and perhaps environmental factors in the disease determination.

Congenital disorder of glycosylation Ia (CDG-Ia) is an autosomal recessive disease, characterized by the impaired biosynthesis of the N-linked oligosaccharide chains of proteins due to a deficiency of phosphomannomutase (PMM), the enzyme converting mannose-6-phosphate into mannose-1-phosphate. We investigated the consequences of the altered N-linked glycoprotein (GP) biosynthesis on the quantity and quality of glycosphingolipids (GSLs) in fibroblasts of CDG-Ia patients. First, we found that CDG-Ia fibroblasts contain an increased amount of total GSLs when compared with normal fibroblasts. Further, we assessed by metabolic labeling of CDG-Ia fibroblasts with radioactive sugar precursors, including galactose and N-acetylmannosamine, that a diminished biosynthesis of cellular GPs is antagonized by an increased biosynthesis of GSLs. An increased GSL biosynthesis was also observed by means of radiolabeled lipid precursors including sphingosine and lactosylceramide. Notably, also the degradation of GLSs is slowed down in CDG-Ia fibroblasts. Finally, when we labeled normal human fibroblasts and CHO cells with radioactive galactose in the presence and absence of deoxymannojirimycin (dMM), an inhibitor of N-glycan processing, we found that this cellular model mimics what occurs in CDG-Ia fibroblasts. Since an inverse relationship between GP expression and GSL content does exist, we assume that increased glycosphingolipid biosynthesis is secondary to protein hypoglycosylation. Altogether, our data suggest that the cell metabolic machinery may be able to partially re-equilibrate protein hypoglycosylation with increased biosynthesis of glycosphingolipids, possibly to preserve the overall physico-chemical equilibrium of the outer layer of the plasma membrane.

AbstractCeramide has been suggested as an important mediator of apoptosis. In HT-29 colorectal cancer cells increased ceramide levels, induced by exogenous Nacetylsphingosine (NAS, also known as C2-ceramide) or by 1-phenyl-2-(decanoylamino)-3-morpholino-1- propanol (PDMP), inhibited the transport and processing of cathepsin D (CD), a lysosomal protease implicated in apoptosis of tumour cells. C2-dihydroceramide (DHC2), an inactive analogue of NAS, had no effect on CD transport and maturation. The treatment with either NAS or PDMP was revealed to be cytotoxic for HT-29 cells and led to cell death with classical features of apoptosis. Morphological signs of apoptosis and DNA fragmentation became apparent only between 24 and 48 h of incubation and poly(ADP ribose)polymerase cleavage, a hallmark of caspase 3 activity, occurred no earlier than 8 h from incubation. Secretion of proCD was almost abolished and the formation of doublechain mature CD was reduced and delayed by NAS, whereas PDMP largely inhibited the lysosomal targeting and maturation of proCD. NAS and PDMPinduced alteration of proCD transport and maturation were apparent already 2 h after incubation with the drugs, which is much earlier than when classical biochemical and morphological evidence of apoptosis could be detected. These data indicate that alteration of CD (and possibly of other glycoproteins) transport along the secretory pathway due to increased levels of cellassociated ceramide is an early event in cells undergoing apoptosis.

Mutations in gene encoding presenilin 1 (PS1) are responsible for the majority of familial Alzheimer's disease (FAD) cases. We studied PS1 localization in HEK293 cells and in primary neurons obtained from rat cortex and hippocampus. We first demonstrated that PS1-CTF, but neither PS1-FL nor PS1-NTF, is released into the medium as a soluble and membrane-associated form. After induction of apoptosis with staurosporine (Sts), we observed a dramatic increase in the level of PS1-CTF in the medium, both in HEK293 and in primary neurons. Immunocytochemical analysis suggested that the release of PS1-CTF might occur via membrane shedding. Aβ1–42treatment reduced PS1-CTF extracellular levels. This decrease was strongly associated to an impaired secretion of sAPP fragments, thus suggesting a role of PS1-CTF in the control of trafficking and generation of APP fragments.

A correlation between a 5-nucleotide deletion polymorphism in the A2Mgene and an enhanced risk of developing Alzheimer’s disease (AD) was reported. We studied this polymorphism in sporadic AD patients and patients with frontotemporal dementia (FTD) by using an electrophoretical separation of PCR products on a Metaphor gel. Our results did not show any significant difference between A2M-2allelic frequency (p = 0.89) or genotype frequency (p = 0.97) in the two different clinical series and in control subjects. The frequencies were not significantly different after stratification by APOE Ε4status.