Geometric control by active mechanics of epithelial gap closure.

Epithelial wound healing is one of the most important biological processes occurring during the lifetime of an organism. It is a self-repair mechanism closing wounds or gaps within tissues to restore their functional integrity. In this work we derive a new diffuse interface approach for modelling the gap closure by means of a variational principle in the framework of non-equilibrium thermodynamics. We investigate the interplay between the crawling with lamellipodia protrusions and the supracellular tension exerted by the actomyosin cable on the closure dynamics. These active features are modeled as Korteweg forces into a generalised chemical potential. From an asymptotic analysis, we derive a pressure jump across the gap edge in the sharp interface limit. Moreover, the chemical potential diffuses as a Mullins-Sekerka system, and its interfacial value is given by a Gibbs-Thompson relation for its local potential driven by the curvature-dependent purse-string tension. The finite element simulations show an excellent quantitative agreement between the closure dynamics and the morphology of the edge with respect to existing biological experiments. The resulting force patterns are also in good qualitative agreement with existing traction force microscopy measurements. Our results shed light on the geometrical control of the gap closure dynamics resulting from the active forces that are chemically activated around the gap edge.

T cell therapy against cancer: A predictive diffuse-interface mathematical model informed by pre-clinical studies.

T cell therapy has become a new therapeutic opportunity against solid cancers. Predicting T cell behaviour and efficacy would help therapy optimization and clinical implementation. In this work, we model responsiveness of mouse prostate adenocarcinoma to T cell-based therapies. The mathematical model is based on a Cahn-Hilliard diffuse interface description of the tumour, coupled with Keller-Segel type equations describing immune components dynamics. The model is fed by pre-clinical magnetic resonance imaging data describing anatomical features of prostate adenocarcinoma developed in the context of the Transgenic Adenocarcinoma of the Mouse Prostate model. We perform computational simulations based on the finite element method to describe tumor growth dynamics in relation to local T cells concentrations. We report that when we include in the model the possibility to activate tumor-associated vessels and by that increase the number of T cells within the tumor mass, the model predicts higher therapeutic effects (tumor regression) shortly after therapy administration. The simulated results are found in agreement with reported experimental data. Thus, this diffuse-interface mathematical model well predicts T cell behavior in vivo and represents a proof-of-concept for the role such predictive strategies may play in optimization of immunotherapy against cancer.

The Föppl-von Kármán equations of elastic plates with initial stress.

Initially, stressed plates are widely used in modern fabrication techniques, such as additive manufacturing and UV lithography, for their tunable morphology by application of external stimuli. In this work, we propose a formal asymptotic derivation of the Föppl-von Kármán equations for an elastic plate with initial stresses, using the constitutive theory of nonlinear elastic solids with initial stresses under the assumptions of incompressibility and material isotropy. Compared to existing works, our approach allows us to determine the morphological transitions of the elastic plate without prescribing the underlying target metric of the unstressed state of the elastic body. We explicitly solve the derived FvK equations in some physical problems of engineering interest, discussing how the initial stress distribution drives the emergence of spontaneous curvatures within the deformed plate. The proposed mathematical framework can be used to tailor shape on demand, with applications in several engineering fields ranging from soft robotics to four-dimensional printing.

Accuracy of CT and MRI to assess resection margins in primary malignant bone tumours having histology as the reference standard.

AIM: To evaluate the accuracy of magnetic resonance imaging (MRI) and computed tomography (CT) in assessing the resection margins of primary malignant bone tumours. MATERIALS AND METHODS: Resected primary malignant bone tumour specimens removed from 46 patients (27 male; mean age: 48±22 years) were imaged using MRI (fat-saturated proton density-weighted and three-dimensional fat-suppressed T1-weighted gradient-recalled-echo) and CT immediately after surgery. A radiologist and an orthopaedist evaluated bone and soft-tissue margins of the specimens on both examinations. Histological evaluation was performed by a senior orthopaedic oncology pathologist. Margins were classified as R0 (safe margins), R1 (residuals between 0 and 1 mm), and R2 (macroscopic residuals). Cohen's k, chi-square, and McNemar's statistics were used. RESULTS: Having histology as the reference standard, reproducibility of the radiologist ranged from moderate (k=0.544) to substantial (k=0.741) for bone and soft-tissue margins on CT, respectively, while that of the orthopaedist ranged from fair (k=0.316) to moderate (k=0.548). When comparing R2 and R0+R1 scores, reproducibility of readers' evaluation of bone margins increased ranging from substantial (k=0.655) to perfect (k=1.000). Inter-reader agreement ranged from fair (k=0.308) to substantial (k=0.633). Accuracy of the radiologist and orthopaedist ranged from 76% to 83% and from 68% to 72%, respectively. When comparing R2 and R0+R1 scores, the accuracy of both readers ranged from 83% to 100%. There was no association between local recurrence and margin scores of histology, MRI, and CT (p≥0.058). CONCLUSIONS: MRI and CT may be useful for extemporaneous analysis of resection margins of primary malignant bone tumours, although wide accuracy variability between the different imaging methods was observed.

Working conditions and mental health in teachers: a preliminary study.

BACKGROUND: Unfavourable working conditions are associated with poor mental health and many studies show that teachers are at risk of this. AIMS: To investigate if and to what extent specific dimensions of working conditions are associated with symptoms of depression and anxiety in teachers in state schools in Italy. METHODS: A cross-sectional questionnaire survey of Italian state schoolteachers using the Karasek Job Content Questionnaire, the Self-Rating Anxiety Scale (SAS) and the Center for Epidemiologic Studies Depression Scale (CES-D). We tested the hypotheses that high job demand, low decision latitude and low support are associated with anxiety and depression in teachers using a correlation matrix and hierarchical multiple regression models. RESULTS: 113/180 (63%) of schoolteachers invited to participate completed the survey. 49% scored above the cut-off on CES-D and 11% on SAS. CES-D was positively correlated with job demand (r = 0.517, P < 0.01) and negatively with social support (r = -0.226, P < 0.05). SAS was positively correlated with job demand (r = 0.408, P < 0.01). Hierarchical multiple regression analysis showed that job demand was significantly associated with CES-D and SAS scores, explaining 28 and 25% of variance respectively. CONCLUSIONS: About half of the teachers in this study scored above the threshold for depression and ~1 in 10 for anxiety on self-rating questionnaires. Poor mental health in teachers is significantly associated with high job demand and low social support. These results should be confirmed in larger, more representative samples.

Counting elementary charges on nanoparticles by electron holography.

The distribution and movement of charge is fundamental to many physical phenomena, particularly for applications involving nanoparticles, nanostructures, and electronic devices. However, there are very few ways of quantifying charge at the necessary length scale. Here, we show that aberration-corrected electron holography is capable of counting the charge on individual nanoparticles to a precision of one elementary unit of charge. We present a method that measures charges within predefined contours by directly applying Gauss's law at the nanoscale. We perform a statistical analysis to reveal the relationship between the size of the contours and the precision of the charge measurement and present strategies to optimize the spatial and signal resolution for the presented method.

Aripiprazole, alcohol and substance abuse: a review.

Aripiprazole is an atypical antipsychotic used for schizophrenia, manic and mixed episodes associated with bipolar I disorder and as adjunctive therapy for major depressive disorder. It functions as a partial agonist at dopamine D2 and 5-HT1A receptors, and as an antagonist at the 5-HT2A receptor. The most recent results obtained from scientific research showed that dopaminergic mechanisms are involved in motivation, reward, and reinforcement of substance abuse. The use of aripiprazole and partial dopamine agonists could represent a novel strategy for normalizing dopamine neurotransmission. Many studies in the last few years have highlighted aripiprazole as a potential candidate for the treatment of different types of substance dependence. This review aims to describe recent scientific research using aripiprazole in different substance abuse disorders (i.e., alcoholism, cocaine, amphetamine and nicotine use). Furthermore, the efficacy of aripiprazole compared to other pharmacological therapies will be described. Given the low number of studies, the frequent absence of placebo or active comparators, and the low statistical power of the studies, a clear conclusion about the use of aripiprazole in alcohol/substance dependence cannot be drawn. Therefore, we suggest the need for further studies, preferably randomized and placebo-controlled.

"Fast track surgery" in the north-west of Italy: influence on the orientation of surgical practice.

Fast track surgery is a peri-operative management model, including different strategies to improve patients' convalescence, avoid metabolic alterations, reduce complications, and shorten hospital stay. Prerequisite is coordination between different practitioners (surgeon, anaesthetist, nurse, nutritionist, physiotherapist). The purpose of our investigation is to understand the level of fast track surgery application in Piedmont and to evidence analogies and differences among departments. We projected an investigation proposing, to every surgery department in Piedmont, a multiple-choice questionnaire evaluating the level of fast track surgery peri-operative interventions' application. Data analysis was conducted in two points of view: the transversal one with an overview of answer's percentages, the longitudinal one correlating data through Pearson's index (r). We collected answers by 78 % of balloted departments (38 on 49). Transversal analysis, including the evaluation of percentages of each question, shows that intra-operative period is the most influenced by fast track principles, and that only 12 departments of 38 apply complete protocols. Longitudinal analysis, estimating the whole of each department's answers, demonstrates the absence of statistical significance in the correlation between fast track surgery application and territorial (r = 0.18), economic (r = 0.31), or age (r = 0.06) variables. Influence of fast track surgery is significantly present in our territory, even though it is not fully concretized in protocols. The choice of fast track depends on the instruction, the environment and the sensibility of each surgeon. Knowledge of geographic distribution of departments applying this model can be useful to organize common protocols, starting from more experienced hospitals.

Diffusion-weighted MR imaging in differentiation between osteoporotic and neoplastic vertebral fractures.

PURPOSE: To assess the usefulness of magnetic resonance imaging (MRI) with spin-echo echo-planar diffusion-weighted imaging (SE-EPI-DWI) in differentiation between vertebral osteoporotic fractures and pathological neoplastic fractures. MATERIALS AND METHODS: Thirty-three patients with both osteoporotic or neoplastic vertebral fractures diagnosed with X-ray or TC were studied with MRI exam, (1.5 T unit) with DWI sequences. DWI sequences were qualitatively analyzed. Apparent diffusion coefficient (ADC) values were also determined and compared to the definitive histologic diagnosis. RESULTS: DWI of neoplastic lesions showed hyperintensity signal in 22 out of 23 cases. Mean ADC value of neoplastic fractures was 1.241 ± 0.4 × 10(-3) mm(2)/s; mean ADC value of osteoporotic fractures was 0.646 ± 0.368 × 10(-3) mm(2)/s. Neoplastic fractures showed ADC values significantly higher than osteoporotic ones (p < 0.001). DWI imaging and histology showed a significant correlation. CONCLUSION: DWI provides reliable information to support MRI diagnosis of neoplastic versus osteoporotic fractures. ADC value appears as a useful adjunctive parameter.

[Diagnosis of deficit and attention/hyperactivity disorders (ADHD) in patients with bipolar or unipolar depression: an experimental study]. / Diagnosi pregressa di Disturbo da Defi cit d'Attenzione/Iperattività (ADHD) in pazienti con Depressione Bipolare e Unipolare: uno studio sperimentale.

INTRODUCTION: The present research study starts up from the current scientific and academic interest concerning Deficit and Attention/Hyperactivity Disorders, which in this period seems to have an "epidemic" diffusion. Some authors have proved how the Deficit and Attention/Hyperactivity Disorder may predispose to the development of other psychopathological attitude in adulthood. A recent study has underlined a common comorbidity between ADHD in childhood and Bipolar Disorder. The aim of the present was to verify the existence of an ADHD diagnosis in patients with depression (Unipolar and Bipolar) and to verify if such syndrome overstays in the present psychopathological picture. Moreover there has been even the intention to investigate on a difference in ADHD symptomatology in patients with Bipolar and Unipolar Depression. MATERIALS AND METHODS: The study has been conducted on a sample of 67 patients with depression diagnosis (35 patients with bipolar depression diagnosis, 32 patients with depression unipolar diagnosis) enrolled at the Bipolar Disorders Unit of the Clinical Psychiatry and Drug Dependence Institute of the Policlinico Universitario A. Gemelli in Rome. The evaluation has been performed through the supply of the following psychometric tests: Neo Personality Inventory (Mole-pi-R), Brown Attention Deficit Disorder Scale (Brown ADD-Scale), Adult ADHD Self-Report Staircases (ASRS-v1.1), Criteria of the Deficit and Attention / Hyperactivity Disorder for childhood according to the DSM-IV-Tr. RESULTS: The achieved results point out that 42% of the sample has satisfied the ADHD Criterions during their childhood according to the DSM-IV-Tr and that symptomatology seems to remain in the present psychopathological picture. As to polarity of depression it has emerged that patients with Bipolar Depression diagnosis have satisfied with a greater frequency the ADHD criteria during their childhood than patients with Unipolar Depression. CONCLUSIONS: Our results seem to confirm the hypothesis that patients with bipolar depression diagnosis have more Deficit and Attention / Hyperactivity Disorders comorbidity diagnosis than others.

Image simulations of kinked vortices for transmission electron microscopy.

We present an improved model of kinked vortices in high-T(c) superconductors suitable for the interpretation of Fresnel or holographic observations carried out with a transmission electron microscope. A kinked vortex is composed of two displaced half-vortices, perpendicular to the film plane, connected by a horizontal flux-line in the plane, resembling a connecting Josephson vortex (JV) segment. Such structures may arise when a magnetic field is applied almost in the plane, and the line tension of the fluxon breaks down under its influence. The existence of kinked vortices was hinted in earlier observations of high-T(c) superconducting films, where the Fresnel contrast associated with some vortices showed a dumbbell like appearance. Here, we show that under suitable conditions the JV segment may reveal itself in Fresnel imaging or holographic phase mapping in a transmission electron microscope.

The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature.

Cytokines may influence brain activities especially during stressful conditions, and elevated levels of IL-6 and C-reactive protein have been pointed out in subjects with Major Depression. If pro-inflammatory cytokines play a causative role in major depressive disorders, one would expect that antidepressants may down-regulate these cytokines or interfere with their actions, leading to improvement of depressive symptoms. Accumulating evidence has been published that antidepressants modulate cytokine production and this is particularly true for Tricyclics and Selective serotonin reuptake inhibitors (SSRIs), but the influence of newer antidepressants acting on both serotonin (5-HT) and norepinephrine (NE) such as venlafaxine, duloxetine and mirtazapine on cytokine levels has not been extensively studied. However, both pre-clinical and clinical studies examined in this review have demonstrated that newer serotonin-noradrenalin antidepressants can inhibit the production and/or release of pro-inflammatory cytokines and stimulate the production of anti-inflammatory cytokines, suggesting that reductions in inflammation might contribute to treatment response. Moreover, the results of the present review support the notion that the serotonin-noradrenalin antidepressants venlafaxine and mirtazapine may influence cytokine secretion in patients affected by MD, restoring the equilibrium between their physiological and pathological levels and leading to recovery. To date, no studies have evaluated the effect of duloxetine, the newest serotonin-noradrenalin antidepressant, on cytokine levels and therefore this should be evaluated in future studies.

Pregabalin in outpatient detoxification of subjects with mild-to-moderate alcohol withdrawal syndrome.

OBJECTIVE: In this open, prospective study we aimed to investigate the efficacy, medical safety and practicability of pregabalin in outpatient detoxification of alcohol-dependent patients with mild-to-moderate alcohol withdrawal syndrome (AWS). Craving reduction, improvement of psychiatric symptoms and quality of life were the secondary endpoints. METHODS: Forty alcohol dependent patients (DSM-IV) were detoxified receiving 200-450 mg of pregabalin. Withdrawal (Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar)) and craving (Visual Analogue Scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)) rating scales were applied; psychiatric symptoms and quality of life were evaluated using the Symptom Check List-90 Revised (SCL-90-R) and the QL-Index, respectively. Relapsed and abstinent patients in the post-detoxification evaluation have been compared. RESULTS: Alcohol withdrawal symptoms and craving for alcohol resulted significantly reduced (p < 0.001) over time after pregabalin treatment. Pregabalin also resulted in a favourable improvement in psychiatric symptoms and quality of life (p < 0.001). CONCLUSIONS: To our knowledge, this is the first open, prospective study, about the possible use of pregabalin as an outpatient detoxification agent. These preliminary data show its efficacy and safety in the management of patients with mild-to-moderate AWS.

Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial.

Pregabalin (PRE) acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the alpha(2)-delta subunit of voltage-gated calcium channels. In this randomised, double-blind comparison trial with naltrexone (NAL), we aimed to investigate the efficacy of PRE on alcohol drinking indices. Craving reduction and improvement of psychiatric symptoms were the secondary endpoints. Seventy-one alcohol-dependent subjects were detoxified and subsequently randomised into two groups, receiving 50 mg of NAL or 150-450 mg of PRE. Craving (VAS; OCDS), withdrawal (CIWA-Ar) and psychiatric symptoms (SCL-90-R) rating scales were applied. Alcohol drinking indices and craving scores were not significantly different between groups. Compared with NAL, PRE resulted in greater improvement of specific symptoms in the areas of anxiety, hostility and psychoticism, and survival function (duration of abstinence from alcohol). PRE also resulted in better outcome in patients reporting a comorbid psychiatric disorder. Results from this study globally place PRE within the same range of efficacy as that of NAL. The mechanism involved in the efficacy of PRE in relapse prevention could be less related to alcohol craving and more associated with the treatment of the comorbid psychiatric symptomatology.

The role of cholesterol levels in mood disorders and suicide.

The individuation of sensitive and specific biochemical markers, easily assessable on large samples of subjects and usefully employable as predictors of severe psychiatric disorders, such as mood disorders, could help clinicians to improve the diagnostic and therapeutic processes facilitating the long-term follow-up. In particular, serum cholesterol levels may potentially be optimal markers due to their relative easy sampling and low cost. The involvement of cholesterol in affective disorders such as Major Depression (MD), Seasonal Affective Disorder (SAD) and Bipolar Disorders (BD) is a debated issue in current research. However, current literature is controversial and, to date, it is still not possible to reach an agreement on its possible usefulness of cholesterol as a biological marker of affective disorders. Despite the controversial results on the relationships between cholesterol levels and affective disorders, the majority of literature seems to show a more consistent relationship between cholesterol levels and suicidal behaviour, with few studies that have found no relationships. The aim of this review is to elucidate current facts and views about the role of cholesterol levels in mood disorders as well as its involvement in suicidal behaviour.

Characterization of JEOL 2100F Lorentz-TEM for low-magnification electron holography and magnetic imaging.

We present results that characterize the performance and capabilities of the JEOL 2100F-LM electron microscope to carry out holography and quantitative magnetic imaging. We find the microscope is well-suited for studies of magnetic materials, or for semi-conductor dopant profiling, where a large hologram width ( approximately 1 microm) and fine fringe spacing ( approximately 1.5 nm) are obtained with good contrast ( approximately 20%). We present, as well, measurements of the spherical aberration coefficient Cs=(108.7+/-9.6)mm and minimum achievable focal step delta f=(87.6+/-1.4)nm for the specially designed long-focal-length objective lens of this microscope. Further, we detail experiments to accurately measure the optical parameters of the imaging system typical of conventional holography setup in a transmission electron microscope. The role played by astigmatic illumination in the hologram formation is also assessed with a wave-optical model, which we present and discuss. The measurements obtained for our microscope are used to simulate realistic holograms, which we compare directly to experimental holograms finding good agreement. These results indicate the usefulness of measuring these optical parameters to guide the optimization of the experimental setup for a given microscope, and to provide an additional degree of practical experimental possibility.

Molecular detection of Leptospira interrogans in human tissues and environmental samples in a lethal case of leptospirosis.

A forensic case of suspected Leptospirosis with fatal course was resolved by the molecular detection of Leptospira interrogans in postmortem human tissues and in environmental samples. Polymerase chain reaction analysis and DNA sequencing confirmed the clinical diagnosis of Weil syndrome, and the death was considered to be an occupational accident with all the legal implications.

High and low dosage oxcarbazepine versus naltrexone for the prevention of relapse in alcohol-dependent patients.

INTRODUCTION: Oxcarbazepine (OXC) reduces high-voltage-activated calcium currents, thus reducing glutamatergic transmission at corticostriatal synapses. This effect on NMDA glutamatergic transmission may play a role against the increased glutamatergic transmission determined by alcohol withdrawal. To investigate the efficacy and safety of OXC in relapse prevention we compared OXC at different dosages with Naltrexone (NAL) in a 90 days randomised open-label trial. Craving and psychiatric symptoms improvements were the secondary endpoints. METHODS: Eighty-four detoxified alcohol dependent subjects currently meeting clinical criteria for alcohol dependence were randomised into three groups: 27 patients received 50 mg of naltrexone, 29 received 1500-1800 mg of oxcarbazepine (OXC high), 28 patients 600-900 mg of oxcarbazepine (OXC low). Craving (VAS; OCDS) and withdrawal (AWRS) rating scales were applied; psychiatric symptoms were evaluated through the SCL-90-R. RESULTS: A significantly larger number of subjects remained alcohol free in the OXC high group (58.6%) with respect to both the OXC low (42.8%) and the NAL groups (40.7%). Comparing the OCDS total scores at the end of the treatment, the improvement was significantly greater for the NAL group with respect to the OXC low group. The reduction of the Hostility-Aggression subscore of the SCL-90-R was significantly greater in the OXC high group than that of the other groups. Dual diagnosis patients had a better outcome when treated with OXC high. DISCUSSION: OXC at a dosage of 1500-1800 mg/day might be beneficial in terms of alcohol relapse prevention. The low dosage formulation did not show the same trend, but it still remain in the same range as NAL. The mechanism involved in the efficacy of oxcarbazepine in relapse prevention could be less related to craving and more connected to the treatment of the comorbid psychiatric symptomatology and the alcohol protracted withdrawal syndrome.

Anhedonia and substance-related symptoms in detoxified substance-dependent subjects: a correlation study.

Anhedonia is a condition in which the capacity of experiencing pleasure is totally or partially lost, frequently occurring in mood disorders, as a negative symptom in schizophrenia, and in substance use disorders. In order to test a set of instruments for anhedonia in a population of detoxified opiate, alcohol and multiple substance-dependent subjects, 70 individuals were recruited from three different clinical settings. The following scales were applied: Snaith-Hamilton Pleasure Scale (SHAPS), Bech-Rafaelsen Melancholia Scale (BRMS), Scale for the Assessment of Negative Symptoms (SANS), specific withdrawal scales, and visual analogue scales (VAS) for hedonic capability and substance craving. The scales measuring anhedonia either directly (SHAPS, VAS for hedonic capability) or in some key items (SANS, BRMS) were significantly correlated with each other. The period of time since detoxification was inversely correlated with anhedonia and withdrawal symptomatology. Craving was positively correlated with anhedonia. Out of the total sample, only 18.5% could be defined as psychometrically anhedonic. The same correlations were found in this subsample. The composite instrument employed for assessing anhedonia and hedonic capability was found to be sensitive enough to detect such a dimension in the population considered, with the single scales significantly interrelated. In conclusion, we found interrelations between hedonic capability, craving and protracted withdrawal, particularly in opiate-dependent subjects. The strongest association occurred between hedonic capability and craving.