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A letter to the editor is presented regarding the article "Plasma oxidative stress biomarkers, nitric oxide and heat shock protein 70 in trained elite soccer players" that was published in "European Journal of Applied Physiology."

Background: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments., Objective: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD)., Method: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups., Result: LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes., Conclusion: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders., (© 2024. The Author(s).)

Background: Medial temporal lobe atrophy has been linked to decline in neuropsychological measures of explicit memory function. While the hippocampus has long been identified as a critical structure in learning and memory processes, less is known about contributions of the amygdala to these functions. We sought to investigate the relationship between amygdala volume and memory functioning in a clinical sample of older adults with and without cognitive impairment., Methods: A serial clinical sample of older adults that underwent neuropsychological assessment at an outpatient neurology clinic was selected for retrospective chart review. Patients were included in the study if they completed a comprehensive neuropsychological assessment within six months of a structural magnetic resonance imaging scan. Regional brain volumes were quantified using Neuroreader® software. Associations between bilateral hippocampal and amygdala volumes and memory scores, derived from immediate and delayed recall conditions of a verbal story learning task and a visual design reconstruction task, were examined using mixed-effects general linear models, controlling for total intracranial volume, scanner model, age, sex and education. Partial correlation coefficients, adjusted for these covariates, were calculated to estimate the strength of the association between volumes and memory scores., Results: A total of 68 (39 F, 29 M) participants were included in the analyses, with a mean (SD) adjusted age of 80.1 (6.0) and educational level of 15.9 (2.5) years. Controlling for age, sex, education, and total intracranial volume, greater amygdala volumes were associated with better verbal and visual memory performance, with effect sizes comparable to hippocampal volume. No significant lateralized effects were observed. Partial correlation coefficients ranged from 0.47 to 0.33 (p<.001)., Conclusion: These findings contribute to a growing body of knowledge identifying the amygdala as a target for further research in memory functioning. This highlights the importance of considering the broader functioning of the limbic system in which multiple subcortical structures contribute to memory processes and decline in older adults., Competing Interests: Declaration of Competing Interest The authors involved with this work have no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real-world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real-world settings., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

This work highlights the role of the clinical laboratory, in the early detection of the use of substances prohibited for doping. This is because most people who practice sports today are non-professional athletes and amateurs, in particular young kids. These persons are not subjected to anti-doping controls but are at risk for their health. Endocrinologists and laboratory tests, by detecting evidence of such usage can help protect their health. Anti-doping testing require specific instruments for qualitative and quantitative chemistry, to meet regulations of official competitions but are impossible to be used in every person because of high cost. A particular role the clinical laboratory can acquire in the future is through its molecular biology sections, when genetic doping will probably be a reality and quantitative chemistry will be unable to detect it. A brief history of doping is provided to understand the reasons of its spread. Although doping has great resonance nowadays, it is not a recent problem. It was common among ancient Greek wrestlers and Romans, who used mixtures of herbs and stimulants. Ancient Greece started the Olympic Games and winners assumed great esteem, akin to demi-god status. Therefore, any attempt to improve athletic performance was a norm, also because the damage caused by the substances used was not known at that time. The use became so widespread that soldiers also used drugs to better combat during recent wars, and doping was practiced by athletes, actors and musicians in attempts to obtain better performance results. Today, doping has been refined so as not to be discovered and there is a continuous race between those who promote new substances and those who, like the World Anti-Doping Agency (WADA), were created to defend the health of athletes and comply with regulations of competitions. The clinical laboratory plays a fundamental role in identifying the use of prohibited substances, especially in competitions not classified as official, which are the majority and involve thousands of amateurs. In this paper a series of laboratory tests are proposed in this perspective, at low cost without the need of qualitative/quantitative chemical analyses required by the sport jurisdictions. Finally, a glance into genetic doping illustrates a likely future and imminent practice.

Objective: This retrospective study aimed at ascertaining the clinical usefulness of nebulized myo-inositol in the management of patients affected by bronchiectasis., Patients and Methods: 19 patients, aged between 63 and 73 years old, with bronchiectasis, were treated for 15 days with nebulized myo-inositol or placebo. Lung functionality [forced expiratory volume in the 1st second (FEV1)], solid content of expectorate, and surfactant tension were analyzed., Results: All patients treated with nebulized myo-inositol had a significant decrease in the percentage of solid content in the expectorate (T0 7.9±2.8% vs. T1 5.2±2.7%; p<0.001) and surfactant tension (T0 81.5±6.9 mN/m vs. T1 77.4±7.2 mN/m; p<0.001). Among treated patients, these variations correlated with FEV1 (rs=- 0.79; p<0.01) and forced expiratory flow at 25-75% of FVC (FEF25-75%) (rs=-0.81; p<0.01) scores. Also, variation of surfactant tension correlated with FEV1 (rs= -0.74; p<0.05) score., Conclusions: Nebulized myo-inositol increases lung functionality and mucus clearance in patients affected by bronchiectasis.

This review summarises the long period in which man has approached nature to understand its powers, and has tried to control it through physical and chemical, and also magical, practices. From the attempt to manage nature to the development of primordial drugs and medical practices and later to achieve modern biomedical science, laboratory practices always played a pivotal role. Over the years and centuries, the laboratory has acquired more and more importance in the improvement of health.In addition to the well-known importance of laboratory medicine in the early diagnosis and appropriateness, the discoveries of the last 50 years have also given the Laboratory a decisive role in regenerative and personalised medicine.This paper examines the evolution of the laboratory and is not meant to be a treatise on the history of medicine. The goal is to highlight the moments of the transition from magic and alchemy to laboratory science.-------------------------------Roberto Verna is President of the World Association of Societies of Pathology and Laboratory Medicine and President of the Academy for Health and Clinical Research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Myo-inositol is a natural polyol, the most abundant among the nine possible structural isomers available in living organisms. Inositol confers some distinctive traits that allow for a striking distinction between prokaryotes and eukaryotes, the basic clusters into which organisms are partitioned. Inositol cooperates in numerous biological functions where the polyol participates or by furnishing the fundamental backbone of several related derived metabolites, mostly obtained through the sequential addition of phosphate groups (inositol phosphates, phosphoinositides, and pyrophosphates). Overall myo-inositol and its phosphate metabolites display an entangled network, which is involved in the core of the biochemical processes governing critical transitions inside cells. Noticeably, experimental data have shown that myo-inositol and its most relevant epimer D-chiro-inositol are both necessary to permit a faithful transduction of insulin and of other molecular factors. This improves the complete breakdown of glucose through the citric acid cycle, especially in glucose-greedy tissues, such as the ovary. In particular, while D-chiro-inositol promotes androgen synthesis in the theca layer and down-regulates aromatase and estrogen expression in granulosa cells, myo-inositol strengthens aromatase and FSH receptor expression. Inositol effects on glucose metabolism and steroid hormone synthesis represent an intriguing area of investigation, as recent results have demonstrated that inositol-related metabolites dramatically modulate the expression of several genes. Conversely, treatments including myo-inositol and its isomers have proven to be effective in the management and symptomatic relief of a number of diseases associated with the endocrine function of the ovary, namely polycystic ovarian syndrome.

Background: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI)., Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry., Methods: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance., Results: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes., Conclusion: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Background: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer's disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis., Objective: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet., Methods: A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted., Results: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks., Conclusions: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.

The currently accepted theory on the influence of DNA mutations on carcinogenesis (the Somatic Mutation Theory, SMT) is facing an increasing number of controversial results that undermine the explanatory power of mutated genes considered as "causative" factors. Intriguing results have demonstrated that several critical genes may act differently, as oncogenes or tumor suppressors, while phenotypic reversion of cancerous cells/tissues can be achieved by modifying the microenvironment, the mutations they are carrying notwithstanding. Furthermore, a high burden of mutations has been identified in many non-cancerous tissues without any apparent pathological consequence. All things considered, a relevant body of unexplained inconsistencies calls for an in depth rewiring of our theoretical models. Ignoring these paradoxes is no longer sustainable. By avoiding these conundrums, the scientific community will deprive itself of the opportunity to achieve real progress in this important biomedical field. To remedy this situation, we need to embrace new theoretical perspectives, taking the cell-microenvironment interplay as the privileged pathogenetic level of observation, and by assuming new explanatory models based on truly different premises. New theoretical frameworks dawned in the last two decades principally focus on the complex interaction between cells and their microenvironment, which is thought to be the critical level from which carcinogenesis arises. Indeed, both molecular and biophysical components of the stroma can dramatically drive cell fate commitment and cell outcome in opposite directions, even in the presence of the same stimulus. Therefore, such a novel approach can help in solving apparently inextricable paradoxes that are increasingly observed in cancer biology.

Background: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention., Objective: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader® by Brainreader)., Methods: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n = 161) and quantitative vMRI (n = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models., Results: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87)., Conclusion: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia.

Background. Health and social management of the SARS-CoV-2 epidemic, responsible for the COVID-19 disease, requires both screening tools and diagnostic procedures. Reliable screening tests aim at identifying (truely) infectious individuals that can spread the viral infection and therefore are essential for tracing and harnessing the epidemic diffusion. Instead, diagnostic tests should supplement clinical and radiological findings, thus helping in establishing the diagnosis. Several analytical assays, mostly using RT-PCR-based technologies, have become commercially available for healthcare workers and clinical laboratories. However, such tests showed some critical limitations, given that a relevant number of both false-positive and false-negative cases have been so far reported. Moreover, those analytical techniques demonstrated to be significantly influenced by pre-analytical biases, while the sensitivity showed a dramatic time dependency. Aim. Herein, we critically investigate limits and perspectives of currently available RT-PCR techniques, especially when referring to the required performances in providing reliable epidemiological and clinical information. Key Concepts. Current data cast doubt on the use of RT-PCR swabs as a screening procedure for tracing the evolution of the current SARS-COV-2 pandemic. Indeed, the huge number of both false-positive and false-negative results deprives the trustworthiness of decision making based on those data. Therefore, we should refine current available analytical tests to quickly identify individuals able to really transmit the virus, with the aim to control and prevent large outbreaks.

Background: Since its approval, the use of alteplase had been limited to patients aged ≤80 years., Aims: TESPI trial had been designed to evaluate whether alteplase treatment within 3 h in patients with acute ischemic stroke aged >80 years resulted in favorable benefit/risk ratio compared with standard care. The meta-analysis of randomized controlled trials was updated to put findings in the context of all available evidence., Methods: TESPI was a multicenter, open-label with blinded outcome evaluation, randomized, controlled trial. Main clinical endpoints were 90-day favorable functional outcome (mRS score 0-2) and mortality and symptomatic intracerebral hemorrhage. The trial was prematurely terminated for ethical reasons after publication of IST-3 trial which provided evidence of treatment benefit in elderly., Results: Of the planned 600 patients, 191 (88 assigned to alteplase) were enrolled. Overall, 24/83 (28.9%) alteplase patients had a favorable outcome compared to 22/95 (23.2%) controls (non-significant absolute difference of 5.7% for alteplase; OR 1.35, 95% CI 0.69-2.64, P  = 0.381). Rates of death were non-significantly lower in the alteplase patients (18.1% vs. 26.5%); rates of symptomatic intracerebral hemorrhage were similar between the two groups (5.9% vs. 5.1%). The updated meta-analysis showed consistent results with prior estimates and add weights., Conclusions: The effects of alteplase observed in this interrupted trial did not reach statistical significance, probably for the small numbers, but are consistent with and add weight to the sum total of the randomized evidence demonstrating that alteplase is beneficial in patients with acute ischemic stroke aged over 80 years, particularly if given within 3 h.

Investigators report greater parietal tau deposition and alternate frontoparietal network involvement in early onset Alzheimer's Disease (EOAD) with onset <65 years as compared with typical late onset AD (LOAD). To determine whether clinical brain MRI volumes reflect these differences in EOAD compared with LOAD. This study investigated the clinical MRI scans of 45 persons with Clinically Probable AD with onset <65 years, and compared them to 32 with Clinically Probable AD with onset ≥65 years. Brain volumes on their T1 MRI scans were quantified with a volumetric program. Receiver operating curve analyses were performed. Persons with EOAD had significantly smaller parietal lobes (volumetric percentiles) than LOAD. Late onset Alzheimer's Disease had a smaller left putamen and hippocampus. Area Under the Curve was 96 . 5% with brain region delineation of EOAD compared to LOAD. This study indicates parietal atrophy less than 30% of normal on clinical MRI scans is suggestive of EOAD compared to LOAD.

Most drugs have a natural compound 'ancestor' acting as the lead molecule. Classic pharmacology does not explicitly take into consideration the peculiarities of natural origin compounds, the mechanism of action of which is interpreted by the same target-specific mode of action used for synthetic molecules. Over the past few decades, this approach has entered a crisis of efficacy, requiring general reconsideration of the nature of chemobiological interactions. Taking both the unique properties of natural compounds and their original presence in complex mixtures into account pushes researchers to enlarge the range of mechanisms of action well beyond the drug-receptor interaction and has the potential to overcome the current drug discovery crisis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs., Competing Interests: None declared., (© The Korean Society for Laboratory Medicine.)

Competing Interests: None declared.

Background: Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer's disease (AD)., Objective: Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD., Methods: This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen's D effect sizes were calculated for statistically significant structures. Partial correlations between bilingualism and brain volumes adjusted for age, gender, and TIV., Results: Bilinguals had higher brain volumes in 37 structures. Statistical significance (p < 0.05) was observed in brainstem (t = 2.33, p = 0.02, Cohen's D = 0.71) and ventral diencephalon (t = 3.01, p = 0.004, Cohen's D = 0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp = 0 . 37, p = 0.01), thalamus (rp = 0.31, p = 0.04), ventral diencephalon (rp = 0.50, p = 0.001), and pallidum (rp = 0.38, p = 0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp = 0.17, p = 0.26). No brain volumes were larger in monolinguals., Conclusion: Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD.

A major challenge facing most countries is the growing cost of healthcare. Laboratory testing costs constitute approximately 3% of all clinical costs, while waste of funds due to inappropriate admissions to clinical departments is reported to be as high as 15%. A frequently used approach to save money in healthcare is random reduction of laboratory budgets, focusing on decreasing the number of unnecessary laboratory tests. The World Health Assembly has approached this problem by publishing a list of essential in vitro diagnostic tests, to achieve a global rationalization of the problem. A much more thoughtful strategy to reducing healthcare expenditure is to improve the efficiency of the diagnostic process. Decreasing the time to a correct diagnosis provides considerable financial and clinical benefits. Additionally, reducing both overutilization and underutilization of laboratory tests while achieving the correct diagnosis is of great benefit to challenged healthcare budgets. Examining the situation in the United States and Italy, this review presents an opportunity for reducing diagnostic error and increasing the efficiency of diagnostic testing worldwide. One approach taken to achieve major savings in healthcare in the United States, which can be applied in Italy and other countries, is the creation of "diagnostic management teams," comprising experts in specialty areas of medicine, primarily based in the clinical laboratory, who can advise physicians on the selection of necessary tests and the interpretation of complex test results., Competing Interests: No potential conflicts of interest relevant to this article are reported., (© The Korean Society for Laboratory Medicine.)

Background: While traumatic brain injury (TBI) is recognized as a risk factor for dementia, there is lack of clinical tools to identify brain changes that may confer such vulnerability. Brain MRI volumetric quantification can sensitively identify brain atrophy., Objective: To characterize regional brain volume loss in persons with TBI presenting with cognitive impairment., Methods: IRB approved review of medical records in patients with cognitive decline focused on those who had documented TBI histories and brain MRI scans after TBI (n = 40, 67.7±14.5 years) with volumetric quantification by applying an FDA cleared software program. TBI documentation included head trauma mechanism. Brain volumes were compared to a normative database to determine the extent of atrophy. Correlations between these regions and global tests of cognition (MMSE in n = 17, MoCA in n = 27, n = 14 in both) were performed., Results: Multiple regions demonstrated volume loss in TBI, particularly ventral diencephalon, putamen, and pallidum with smaller magnitude of atrophy in temporal lobes and brainstem. Lobar structures showed strongest correlations between atrophy and lower scores on MMSE and MoCA. The hippocampus, while correlated to tests of cognitive function, was the least atrophic region as a function of TBI history., Conclusion: Persons with TBI history exhibit show regional brain atrophy. Several of these areas, such as thalamus and temporal lobes, also correlate with cognitive function. Alzheimer's disease atrophy was less likely given relative sparing of the hippocampi. Volumetric quantification of brain MRI in TBI warrants further investigation to further determine its clinical potential in TBI and differentiating causes of cognitive impairment.

Objective: Cancer patients frequently experience Chemotherapy-Induced Peripheral Neuropathy (CIPN), as a typical side effect related to time of administration and dose of anticancer agents. Yet, CIPN pathophysiology is poorly understood, and there is a lack of well-tolerated pharmacological remedies helpful to prevent or treat it. Therefore, new safe and effective compounds are highly warranted, namely if based on an adequate understanding of the pathogenic mechanisms., Material and Methods: Herein we reviewed and discussed scientific data related to the beneficial role of some non-conventional treatments able to counteract CIPN, focusing our attention on alpha-lipoic acid (ALA) and L-acetyl-carnitine (LAC), two natural products that have been demonstrated to be promising preventive drugs., Results: Although a growing body of in vitro and in vivo studies support ALA as a molecule able to counteract CIPN symptoms, mostly due to its antioxidant and anti-inflammatory properties, only two randomized clinical trials evaluated ALA usefulness in preventing chemotherapy-related neuropathy. Unfortunately, these studies were inconclusive and clinical outcomes showed to be highly dependent on the route of administration (oral versus or intravenous injection). LAC has demonstrated beneficial effects on both in vitro and in animal studies. Yet, some controversies aroused from randomized clinical trials. Indeed, while CIPN-patients treated with Taxane showed no benefit from LAC treatment, CIPN-patients treated with platinum compounds exhibit significant improvement of CIPN-related symptoms. Therefore, LAC treatment should be used, and thoroughly investigated only in patients treated with chemotherapy protocols Taxanes-free., Conclusions: Mechanisms of toxicity triggered by each single drug need to be deeply explored to better identify effective compounds to prevent or treat them. Moreover, additional experiments are mandatory to establish effective doses and length of treatment for each clinical situation in order to perform large and long-term randomized studies.

Objective: Delineation of treatment volumes is a major source of uncertainties in radiotherapy (RT). This is also true for rectal cancer patients undergoing neoadjuvant RT, with a potential impact on treatment quality. We investigated the role of the digital platform Anatom-e (Anatom-e Information Sytems Ltd., Houston, Texas) in increasing the compliance to follow a specific treatment protocol in a multicentric setting., Materials and Methods: Two clinical cases of locally advanced rectal cancer were chosen. Participants were instructed to follow the 2009 Radiation Therapy Oncology Group consensus atlas and asked to manually segment clinical target volumes (CTVs), for both patient 1 and 2, on day 1 with and without the use of Anatom-e. After one week (day 2), the same radiation oncologist contoured again, with and without Anatom-e, the same CT series. Intraobserver (Intra-OV) and interobserver (Inter-OV) variability were evaluated with the Dice similarity coefficient (DSC), the Hausdorff distance (HD) and mean distance to agreement (MDA)., Results: For clinical case 1, no significant difference was found for Intra-OV and Inter-OV. For clinical case 2, no significant difference was found for Intra-OV but a statistically significant difference was found for Inter-OV in DSC when using or not the platform. Mean DCS was 0.65 (SD: ±0.64; range: 0.58-0.79) for day 1 vs reference volume without Anatom-e and 0.72 (SD: ±0.39; range: 0.67-0.77) (p = 0.03) with it. Mean MDA was lower with Anatom-e (3.61; SD: ±1.33; range: 2.85-4.78) than without (4.14; SD: ±2.97; range: 2.18-5.21), with no statistical significance (p = 0.21) The use of Anatom-e decreased the SD from 2.97 to 1.33. Mean HD was lower with Anatom-e (26.06; SD: ±2.05; range: 24.08-32.62), with no statistical significance (p = 0.14) compared to that without (31.39; SD: ±1.31; range: 26.14-48.72)., Conclusions: The use of Anatom-e decreased the Inter-OV in the CTV delineation process for locally advanced rectal cancer with complex disease presentation planned for neoadjuvant RT. This system may be potentially helpful in increasing the compliance to follow shared guidelines and protocols.

Vascular access is the commonest invasive procedure in secondary care. Vascular access is understood as being access to the bloodstream of acute and chronic patients for diagnostic and therapeutic purposes such as blood sampling, vessel pressure monitoring, fluid infusions (blood transfusions, parenteral nutrition), pharmacological treatments (e.g. antibiotic therapies, chemotherapy, analgesic therapies) or apheresis/dialysis through catheters that may remain in the vessels for weeks or months. There is a wide variety of options available for venous access. Device selection for venous access must be adapted to the patient's needs, and to the type, duration and frequency of the infusion. The scenario is rapidly evolving and hence treatments such as cancer chemotherapy, total parenteral nutrition, long-term parenteral antimicrobial therapies are increasing not only in hospitalized patients, but also in contexts other than traditional ones, such as local care, in response to needs related to healthcare expenditure or patients' needs. This paper originates from the idea of a multidisciplinary group of experts to analyze the main, most recent international guidelines and recommendations on vascular access and to evaluate its implementation in Italy. It often happens that documents acquired in different contexts, however extraordinarily effective and exhaustive, are difficult to apply in contexts where the healthcare organization, professional resources, communication dynamics and regulations are different. The consequence is a progressive departure from international standards and evidence-based medicine, which is particularly burdensome in sectors (such as vascular access and devices used for access) where technological innovation requires constant updating, alignment and method sharing. The work motivation of this group of authors, which sees its final finding in the welfare standards and criteria of appropriateness contained in this document, lies in the particular ongoing and future Italian epidemiological scenario and in the assessments of health economics that demand conscious and appropriate decisions in the interest of the citizen and the healthcare system. The vascular access field is undergoing a veritable revolution; once upon a time the leading lights were those who possessed the best technical skills, the best manual skills, whereas nowadays vascular access decisions are strategic decisions involving specially trained health professionals, able to assess complex interactions and work in teams. There is a strong cultural need, not only with regard to technical aspects, but also for the execution of procedures in daily clinical practice that comply with the recommendations set out in the guidelines published and elaborated by public and private bodies and institutions, as well as by scientific societies and recognized technical and scientific associations. This document is not a manual on vascular access for consultation by all those who intend to go deeper into operating aspects (selection of the device, implantation and management), but a reflection on the most recent pointers in the field of vascular access within Italy's complex healthcare situation.

Data obtained by studying mammalian cells in absence of gravity strongly support the notion that cell fate specification cannot be understood according to the current molecular model. A paradigmatic case in point is provided by studying cell populations growing in absence of gravity. When the physical constraint (gravity) is 'experimentally removed', cells spontaneously allocate into two morphologically different phenotypes. Such phenomenon is likely enacted by the intrinsic stochasticity, which, in turn, is successively 'canalized' by a specific gene regulatory network. Both phenotypes are thermodynamically and functionally 'compatibles' with the new, modified environment. However, when the two cell subsets are reseeded into the 1g gravity field the two phenotypes collapse into one. Gravity constraints the system in adopting only one phenotype, not by selecting a pre-existing configuration, but more precisely shaping it de-novo through the modification of the cytoskeleton three-dimensional structure. Overall, those findings highlight how macro-scale features are irreducible to lower-scale explanations. The identification of macroscale control parameters - as those depending on the field (gravity, electromagnetic fields) or emerging from the cooperativity among the field's components (tissue stiffness, cell-to-cell connectivity) - are mandatory for assessing boundary conditions for models at lower scales, thus providing a concrete instantiation of top-down effects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Through activation of the ERK pathway, nicotine, in both normal MCF-10A and low-malignant breast cancer cells (MCF7), promotes increased motility and invasiveness. Melatonin antagonizes both these effects by inhibiting almost completely ERK phosphorylation. As melatonin has no effect on nonstimulated cells, it is likely that melatonin can counteract ERK activation only downstream of nicotine-induced activation. This finding suggests that melatonin hampers ERK phosphorylation presumably by targeting a still unknown intermediate factor that connects nicotine stimulation to ERK phosphorylation. Furthermore, downstream of ERK activation, melatonin significantly reduces fascin and calpain activation while restoring normal vinculin levels. Melatonin also counteracts nicotine effects by reshaping the overall cytoskeleton architecture and abolishing invasive membrane protrusion. In addition, melatonin decreases nicotine-dependent ROCK1/ROCK2 activation, thus further inhibiting cell contractility and motility. Melatonin actions are most likely attributable to ERK inhibition, although melatonin could display other ERK-independent effects, namely through a direct modulation of additional molecular and structural factors, including coronin, cofilin, and cytoskeleton components., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components-as phytates and inositols-for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability., Competing Interests: The authors declare no conflict of interest.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The older patient population is growing rapidly around the world and in the USA. Almost half of seniors over age 65 who live at home are dissatisfied with their sleep, and nearly two-thirds of those residing in nursing home facilities suffer from sleep disorders. Chronic and pervasive sleep complaints and disturbances are frequently associated with excessive daytime sleepiness and may result in impaired cognition, diminished intellect, poor memory, confusion, and psychomotor retardation all of which may be misinterpreted as dementia. The key sleep disorders impacting patients with dementia include insomnia, hypersomnolence, circadian rhythm misalignment, sleep disordered breathing, motor disturbances of sleep such as periodic leg movement disorder of sleep and restless leg syndrome, and parasomnias, mostly in the form of rapid eye movement (REM) sleep behavior disorder (RBD). RBD is a pre-clinical marker for a class of neurodegenerative diseases, the "synucleinopathies", and requires formal polysomnographic evaluation. Untreated sleep disorders may exacerbate cognitive and behavioral symptoms in patients with dementia and are a source of considerable stress for bed partners and family members. When left untreated, sleep disturbances may also increase the risk of injury at night, compromise health-related quality of life, and precipitate and accelerate social and economic burdens for caregivers.

Aim: Brain metastases (BMs) are a common event in the progression of many human cancers. The aim of this study was to evaluate the potential prognostic factors for the clinical identification of a subgroup of patients that could benefit from whole brain conformal radiotherapy (WBRT)., Materials and Methods: From January 2010 to February 2014, 80 patients with a diagnosis of BMs underwent WBRT at our Radiation Oncology Department, San Luigi Hospital, Italy. Among them, 36 medical records were retrospective reviewed. Gender, age, Karnofsky performance status (KPS), number of BMs on computed tomography and/or magnetic resonance images, presence or absence of perilesional edema, presence or absence of necrosis pattern, and histology of primary tumor were analyzed. Univariate and multivariate analyses were performed., Results: In our cohort of patients, significant prognostic factors for 20 months overall survival was KPS> 70, while a statistical trend (P = 0.098) was registered regarding primary breast., Conclusion: WBRT can be still considered a standard and effective treatment in patients with BMs. High KPS and breast cancer primary tumor seem to be useful parameters for characterize a subgroup of patients with more favorable prognosis.

This article gives an account of the origins, evolution and properties of chocolate. Chocolate is processed from the pod or cabosside of the cacao plant, grown in the tropical belt. The origins of chocolate are traced back to the Maya people who were probably the first to cultivate the cacao plant. The early chocolate drink, considered a "drink of the Gods" was mixed with cinnamon and pepper, tasting bitter and strong, and was most appreciated for its invigorating and stimulating effects than for its taste. Imported from the Americas, the softened version soon spread in Europe. From the 1800s to the 20th Century, it evolved from a drink to its current pleasurable varieties (such as fondant, Gianduja, milky and white chocolate), gaining much momentum in industry and also made great impact as a romantic item and art form. Important components in chocolate are flavonoids (antioxidants), cocoa butter, caffeine, theobromine and phenylethylamine, whereas the presence of psychoactive substances account for its pleasurable effects. Caffeine, theophylline and theobromine constitutes the methylxanthines, known to enhance the action of cAMP, which plays an important role in the transmission of intracellular signals. Chocolate is noted to have anti-inflammatory, neuroprotective and cardioprotective effects, and improves the bioavailability of nitric oxide, which action improves the pressure, platelet function and fluidity of blood.

In thalassemia intermedia (TI), the increase in bone marrow hemopoietic activity frequently leads to extramedullary erythropoeisis (EMH), but its relationship with the soluble form of transferrin receptor (sTfR) which fully reflects the marrow erythropoietic activity, has not yet been explored. From January 2007 to December 2010, all TI patients attending at our center were prospectively enrolled to undergo sTfR assay and MRI or CT (if claustrophobic) scan evaluation for the presence of paraspinal EMH. A total of 59 patients with TI were studied; EMH involved 23 (39%) patients; overall, the concentration of sTfR varied from 2.6 to 20.6 (mean = 8.7) mg/L, but in splenectomized group and in unsplenectomized group, it varied from 4.2 to 17.8 (mean ± SD = 9.86 ± 3.33) mg/L and from 2.6 to 20.6 (mean ± SD = 7.25 ± 3.9) mg/L, respectively with a statistically significant intergroup difference (p < 0.01). The cutoff point at 8.6 mg/L using the ROC curve showed a sensitivity of 78.3% and a specificity of 72.2%, in predicting EMH but, in unsplenectomized subgroup, they raised to 100% and 90.9%, respectively. These data showed that in TI the level of sTfR could represent a predictive factor of EMH particularly in patients with spleen.

Background: The impact of low-fat diets on the plasma lipoprotein profile is incompletely understood., Methods: We conducted two 16-week dietary studies to compare the effects of a moderate-fat (mod-FAT) baseline diet with isocaloric and ad libitum low-fat diets rich in either carbohydrates (high-CHO, n = 16) or protein (high-PRO, n = 19) on plasma lipids, post-heparin lipase activities, cholesteryl ester transfer protein, and phospholipid transfer protein., Results: Switching from the mod-FAT to the isocaloric high-CHO diet lowered plasma high-density lipoprotein cholesterol concentrations (P < 0.001) and tended to increase triglyceride levels (P = 0.087). Cholesterol content in the larger, buoyant low-density lipoprotein (LDL) fractions decreased, whereas those of the very-low-density lipoprotein, intermediate-density lipoprotein, and smaller, denser LDL fractions tended to increase. These changes were largely reversed when subjects lost weight by consuming this high-CHO diet ad libitum. Switching from the mod-FAT diet to the isocaloric high-PRO diet did not increase cholesterol content in the small-dense LDL fraction and led to decreases in both LDL and high-density lipoprotein cholesterol in plasma (P < 0.001 for both).Consumption of the high-protein ad libitum diet accompanied by weight loss did not change plasma lipids further, except for a shift of cholesterol from dense low-density lipoprotein fractions to more buoyant low-density lipoprotein fractions. Cholesteryl ester transfer protein concentrations decreased with high-cholesterol feeding, whereas cholesteryl ester transfer protein concentrations and hepatic lipase and phospholipid transfer protein activities all decreased during high-protein feeding., Conclusions: Both high-CHO and high-PRO diets improve plasma lipid-related risk of cardiovascular disease when consumed ad libitum.

Objective: Autosomal recessive hypercholesterolemia (ARH) is a lipid disorder caused by mutations in a specific adaptor protein for the LDL receptor. ARH is rare except in Sardinia where three alleles (ARH1, ARH2 and ARH3) explain most of cases. The prevalence of ARH heterozygotes in Sardinia is not well determined as well as inconclusive data are available on the effect of the ARH carrier status on LDL cholesterol (LDL-C) and coronary risk., Methods: 3410 Sardinians (986 blood donors, 1709 with hypertension and 715 with myocardial infarction (MI)) were screened for ARH alleles. For comparison purposes, lipid data of 60 ARH heterozygous carriers and 60 non-carriers identified within 24 ARH families were also considered., Results: In the whole study cohort, no ARH homozygotes were found, but 15 ARH1 (0.44%) and 9 ARH2 (0.26%) heterozygous carriers were identified. The frequency of ARH alleles in blood donors was 0.0030, not different from that in hypertensive subjects (0.0032). ARH alleles tended to be more common in MI patients (0.0049), but no association between ARH carrier status and MI risk was detected after controlling for conventional risk factors. ARH carriers and non-carriers showed similar LDL-C levels. This result was confirmed when ARH carriers and non-carriers identified throughout family-based and population-based screenings were combined and compared (141.0+/-41 mg/dl vs. 137.0+/-41 mg/dl, respectively; p=0.19)., Conclusions: These data indicate that the frequency of ARH heterozygotes in Sardinia is approximately 1:143 individuals, thus making this condition one of the most common in the Sardinian population. However, ARH carrier status does not influence LDL-C concentration and coronary risk, thus suggesting that ARH can be regarded as a truly recessive disorder.

Aims and Background: Major salivary gland cancers are rare, with many histologic types and subtypes. The low incidence and heterogeneity of primary parotid carcinomas makes their outcome difficult to evaluate. Treatment remains primarily surgical, but optimal therapeutic regimens have yet to be fully realized. The present study reviews the experience of three Italian institutions in the treatment of primary parotid carcinomas in order to describe the clinicopathological presentation and treatment options with emphasis on radiotherapy and to analyze the factors influencing survival., Methods and Study Design: The records of 110 patients with primary parotid neoplastic lesions treated at three Italian institutions from 1993 to 2004 were retrospectively reviewed. Six patients were excluded from the study: 3 received surgery alone and 3 were not assessable, for a total of 104 assessable patients. Acute and late toxicity of radiotherapy was quantified following the recommendations of the RTOG/EORTC. Survival was analyzed by the actuarial Kaplan-Meier product-limit method. The influence of selected factors on 10-year disease-specific survival was analyzed., Results: The 104 assessable patients were treated as follows: 11 patients received radiotherapy as their only treatment (3 with a palliative purpose) and 93 had postoperative radiotherapy. Thirty-two patients underwent neck dissection: neck lymph node metastases were found in all them. Their mean age was 60 years (range, 14-92). According to the UICC/2002 TNM Classification, 8 patients were stage I, 19 stage II, 34 stage III, 25 stage IVA, 5 stage IVB, 3 recurrent and 10 not assessable (Tx). The most frequent histologies were adenoid cystic carcinoma (n = 16), mucoepidermoid carcinoma (n = 15), and acinic cell carcinoma (n = 15). Twenty-three patients had recurrences: 10 had local recurrences, 3 neck recurrences, 9 distant metastases, and 1 patient had both local recurrence and distant metastases. No factors were observed that would negatively influence the prognosis. Actuarial 10-year disease-specific survival was 71% and actuarial 10-year local control 82%., Conclusions: The treatment of salivary gland malignancies remains primarily surgical. Our study confirms the results of the literature with surgery and adjunctive radiotherapy in patients with advanced-stage disease. No variables were observed to influence the prognosis.

Objective: The common C242T polymorphism in the gene for the p22phox subunit of NADPH oxidase has been reported to be negatively associated with oxidative stress, but whether it confers prognostic information is not yet clear., Methods and Results: The incidence of major adverse cardiovascular events (MACE) were determined in 237 patients with coronary stenosis during a median follow-up of 7.8 years. The p22phox genotypes were evaluated in 213 patients (89.9%) by polymerase chain reaction and RsaI. digestion. Plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, were also measured. In the univariate analysis, patients with CT/TT genotypes showed reduced recurrence of cardiovascular deaths, nonfatal MI, and revascularization procedures compared with homozygous carriers of the C allele. After controlling for confounders, a significantly lower risk of new revascularization procedures (HR=0.31, 95% CI 0.12 to 0.70; P=0.014) remained associated with the T allele. The Kaplan-Meier analysis showed a longer survival free from fatal and nonfatal MI in carriers of T allele (P<0.001). The presence of the 242T allele was associated with significantly reduced plasma concentrations of 8-OHdG., Conclusions: The 242T allele was a predictor of lower risk of recurrence of cardiovascular events in high-risk patients and was associated with reduced systemic oxidative stress.