Insights into the Microstructural Origin of Brain Viscoelasticity : Prospects for Microstructure-Informed Constitutive Modeling

Mechanical aspects play an important role in brain development, function, and disease. Therefore, continuum-mechanics-based computational models are a valuable tool to advance our understanding of mechanics-related physiological and pathological processes in the brain. Currently, mainly phenomenological material models are used to predict the behavior of brain tissue numerically. The model parameters often lack physical interpretation and only provide adequate estimates for brain regions which have a similar microstructure and age as those used for calibration. These issues can be overcome by establishing advanced constitutive models that are microstructurally motivated and account for regional heterogeneities through microstructural parameters. In this work, we perform simultaneous compressive mechanical loadings and microstructural analyses of porcine brain tissue to identify the microstructural mechanisms that underlie the macroscopic nonlinear and time-dependent mechanical response. Based on experimental insights into the link between macroscopic mechanics and cellular rearrangements, we propose a microstructure-informed finite viscoelastic constitutive model for brain tissue. We determine a relaxation time constant from cellular displacement curves and introduce hyperelastic model parameters as linear functions of the cell density, as determined through histological staining of the tested samples. The model is calibrated using a combination of cyclic loadings and stress relaxation experiments in compression. The presented considerations constitute an important step towards microstructure-based viscoelastic constitutive models for brain tissue, which may eventually allow us to capture regional material heterogeneities and predict how microstructural changes during development, aging, and disease affect macroscopic tissue mechanics

SEX-RELATED DIFFERENCES IN THE PHARMACOLOGICAL TREATMENT OF MAJOR DEPRESSION - ARE WOMEN AND MEN TREATED DIFFERENTLY?

Background: In the last decade, sex-related medicine has become an increasingly important area of research as insights in this field can improve treatment strategies and recovery. The aim of this study was to investigate sex-related differences in the prescription and kinds of psychopharmacological treatment in individuals with unipolar affective disorder. Subjects and methods: Data collected on 388 patients attending a psychiatric rehabilitation clinic (194 females, 194 males, mean age 52.3 years, standard deviation 7.8 years), who were matched by age and severity of depression, were analyzed. Depression severity and information on drug type and quantity were assessed at the beginning of the rehabilitation program and compared between women and men. Results: A significant difference between females and males was found in the frequency of prescribing bupropion (females: 3.61%, males: 12.89%; p=0.001) and mirtazapine (females: 5.15%, males: 13.40%; p=0.005). In terms of polypharmacy, the results showed that over 53% of the patients were taking two or more psychotropic substances as a long-term therapy and that 34% of them were taking three to five different substances. No sex-related differences were found concerning the number of psychotropic drugs taken by the patients. Conclusion: The higher frequency of prescriptions for bupropion and mirtazapine in men might be explained by the adverse drug reactions of the drugs (e.g., fewer sexually adverse drug reactions, weight gain) and a known interaction with oral contraception. It remains unclear whether these aspects are taken into consideration for each patient in terms of their special needs and conditions or whether it is a decision based on the patient’s sex. Given a similar severity of depression, men and women are prescribed a similar number of psychotropic substances. However, the high number of psychotropic drugs prescribed on average should be noted. Well-trained healthcare professionals should focus on regularly assessing and optimizing treatment regimens

Automated discovery of interpretable hyperelastic material models for human brain tissue with EUCLID

We propose an automated computational algorithm for simultaneous model selection and parameter identification for the hyperelastic mechanical characterization of human brain tissue. Following the motive of the recently proposed computational framework EUCLID (Efficient Unsupervised Constitutive Law Identitication and Discovery) and in contrast to conventional parameter calibration methods, we construct an extensive set of candidate hyperelastic models, i.e., a model library including popular models known from the literature, and develop a computational strategy for automatically selecting a model from the library that conforms to the available experimental data while being represented as an interpretable symbolic mathematical expression. This computational strategy comprises sparse regression, i.e., a regression problem that is regularized by a sparsity promoting penalty term that filters out irrelevant models from the model library, and a clustering method for grouping together highly correlated and thus redundant features in the model library. The model selection procedure is driven by labelled data pairs stemming from mechanical tests under different deformation modes, i.e., uniaxial compression/tension and simple torsion, and can thus be interpreted as a supervised counterpart to the originally proposed EUCLID that is informed by full-field displacement data and global reaction forces. The proposed method is verified on synthetical data with artificial noise and validated on experimental data acquired through mechanical tests of human brain specimens, proving that the method is capable of discovering hyperelastic models that exhibit both high fitting accuracy to the data as well as concise and thus interpretable mathematical representations

Dendritic/antigen presenting cell mediated provision of T-cell receptor gamma delta (TCRγδ) expressing cells contributes to improving antileukemic reactions ex vivo

T-cell receptor gamma delta (TCRγδ) expressing T-cells are known to mediate an MHC-independent immune response and could therefore qualify for immune therapies. We examined the influence of dendritic cells(DC)/antigen presenting cell (APC) generated from blast-containing whole blood (WB) samples from AML and MDS patients on the provision of (leukemia-specific) TCRγδ expressing T-cells after mixed lymphocyte culture (MLC). Kit-M (granulocyte-macrophage colony-stimulating factor (GM-CSF) + prostaglandin E1 (PGE1)) or Kit-I (GM-CSF + Picibanil) were used to generate leukemia derived APC/DC (DCleu)from WB, which were subsequently used to stimulate T-cell enriched MLC. Immune cell composition and functionality were analysed using degranulation- (DEG), intracellular cytokine- (INTCYT) and cytotoxicity fluorolysis- (CTX) assays. Flow cytometry was used for cell quantification. We found increased frequencies of APCs/DCs and their subtypes after Kit-treatment of healthy and patients´ WB compared to control, as well as an increased stimulation and activation of several types of immune reactive cells after MLC. Higher frequencies of TCRγδ expressing leukemia-specific degranulation and intracellularly cytokine producing T-cells were found. The effect of Kit-M-treatment on frequencies of TCRγδ expressing cells and their degranulation could be correlated with the Kit-M-mediated blast lysis compared to control. We also found higher frequencies of TCRγδ expressing T-cells in AML patients´ samples with an achieved remission (compared to blast persistence) after induction chemotherapy. This might point to APC/DC-mediated effects resulting in the provision of leukemia-specific TCRγδ expressing T-cells: Moreover a quantification of TCRγδ expressing T-cells might contribute to predict prognosis of AML/MDS patients

Interleukin-6 Gene Expression Changes after a 4-Week Intake of a Multispecies Probiotic in Major Depressive Disorder-Preliminary Results of the PROVIT Study

Major depressive disorder (MDD) is a prevalent disease, in which one third of sufferers do not respond to antidepressants. Probiotics have the potential to be well-tolerated and cost-effcient treatment options. However, the molecular pathways of their effects are not fully elucidated yet. Based on previous literature, we assume that probiotics can positively influence inflammatory mechanisms. We aimed at analyzing the effects of probiotics on gene expression of inflammation genes as part of the randomized, placebo-controlled, multispecies probiotics PROVIT study in Graz, Austria. Fasting blood of 61 inpatients with MDD was collected before and after four weeks of probiotic intake or placebo. We analyzed the effects on gene expression of tumor necrosis factor (TNF), nuclear factor kappa B subunit 1 (NFKB1) and interleukin-6 (IL-6). In IL-6 we found no significant main effects for group (F(1,44) = 1.33, p = ns) nor time (F(1,44) = 0.00, p = ns), but interaction was significant (F(1,44) = 5.67, p < 0.05). The intervention group showed decreasing IL-6 gene expression levels while the placebo group showed increasing gene expression levels of IL-6. Probiotics could be a useful additional treatment in MDD, due to their anti-inflammatory effects. Results of the current study are promising, but further studies are required to investigate the beneficial effects of probiotic interventions in depressed individuals

Sundown Syndrome in Persons with Dementia: An Update

"Sundowning" in demented individuals, as distinct clinical phenomena, is still open to debate in terms of clear definition, etiology, operationalized parameters, validity of clinical construct, and interventions. In general, sundown syndrome is characterized by the emergence or increment of neuropsychiatric symptoms such as agitation, confusion, anxiety, and aggressiveness in late afternoon, in the evening, or at night. Sundowning is highly prevalent among individuals with dementia. It is thought to be associated with impaired circadian rhythmicity, environmental and social factors, and impaired cognition. Neurophysiologically, it appears to be mediated by degeneration of the suprachiasmatic nucleus of the hypothalamus and decreased production of melatonin. A variety of treatment options have been found to be helpful to ameliorate the neuropsychiatric symptoms associated with this phenomenon: bright light therapy, melatonin, acetylcholinesterase inhibitors, N-methyl-d-aspartate receptor antagonists, antipsychotics, and behavioral modifications. To decrease the morbidity from this specific condition, improve patient's well being, lessen caregiver burden, and delay institutionalization, further attention needs to be given to development of clinically operational definition of sundown syndrome and investigations on etiology, risk factors, and effective treatment options

Osteoarticular Infections in Pediatric Hospitals in Europe: A Prospective Cohort Study From the EUCLIDS Consortium

BACKGROUND: Pediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment. METHODS: In this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data. RESULTS: A cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed. Thirty-five patients were admitted to the Pediatric Intensive Care Unit; out of these, six suffered from shock, one needed an amputation of the right foot and of four left toes, and two had skin transplantation. According to the Pediatric Overall Performance Score, 36 (10.5%) showed a mild overall disability, 3 (0.8%) a moderate, and 1 (0.2%) a severe overall disability at discharge. A causative organism was detected in 65% (247/380) of patients. Staphylococcus aureus (S. aureus) was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) methicillin-resistant S. aureus (MRSA) and 6 (4.2%) Panton-Valentine leukocidin (PVL)-producing S. aureus, followed by Group A Streptococcus (18.2%) and Kingella kingae (8.9%). K. kingae and PVL production in S. aureus were less frequently reported than expected from the literature. CONCLUSION: POAIs are associated with a substantial morbidity in European children, with S. aureus being the major detected pathogen. In one-third of patients, no causative organism is identified. Our observations show an urgent need for the development of a vaccine against S. aureus and for the development of new microbiologic diagnostic guidelines for POAIs in European pediatric hospitals

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics