Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1.
Homozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a very rare hereditary cerebral small-vessel disease (SVD). Recently, the relationship between some heterozygous HTRA1 mutations, most of which are missense, and the occurrence of cerebral SVD has been reported. We herein report a patient with cerebral SVD carrying a heterozygous nonsense p.R302X mutation in HTRA1. This patient had a family history of cerebral infarction. This report suggests that a heterozygous p.R302X mutation in HTRA1 causes an autosomal dominant cerebral SVD.


FOXA2 activates HIF2α expression to promote tumor progression and is regulated by the E3 ubiquitin ligase VHL in renal cell carcinoma.
Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system with high mortality and morbidity. However, the molecular mechanisms underlying RCC progression are still largely unknown. In this study, we identified FOXA2, a pioneer transcription factor, as a driver oncogene for RCC. We show that FOXA2 was commonly upregulated in human RCC samples and promoted renal cancer cell proliferation, as evidenced by assays of cell viability, colony formation, migratory and invasive capabilities, and stemness properties. Mechanistically, we found that FOXA2 promoted RCC cell proliferation by transcriptionally activating HIF2α expression in vitro and in vivo. Furthermore, we found that FOXA2 could interact with VHL (von Hippel‒Lindau), which ubiquitinated FOXA2 and controlled its protein stability in RCC cells. We showed that mutation of lysine at position 264 to arginine in FOXA2 could mostly abrogate its ubiquitination, augment its activation effect on HIF2α expression, and promote renal cancer cell proliferation in vitro and RCC progression in vivo. Importantly, elevated expression of FOXA2 in RCC patients positively correlated with the expression of HIF2α and was associated with shorter overall and disease-free survival. Together, these findings reveal a novel role of FOXA2 in RCC development and provide insights into the underlying molecular mechanisms of FOXA2-driven pathological processes in RCC.


IgG4 autoantibodies induce dermal-epidermal separation.
Bullous pemphigoid (BP) is a sub-epidermal autoimmune blistering disease associated with autoantibodies to the dermal-epidermal junction (DEJ). Patients' autoantibodies induce dermal-epidermal separation when co-incubated with cryosections of human skin and leucocytes from healthy volunteers. IgG autoantibodies trigger complement and/or leucocyte activation resulting in specific pathology in several autoimmune conditions. In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage. The capacity of IgG4 autoantibodies to mediate tissue damage has not yet been demonstrated. In this study, we isolated IgG1 and IgG4 autoantibodies from bullous pemhigoid patients'serum and analysed their blister-inducing potential in our cryosection assay. As expected, complement-fixing IgG1 autoantibodies induced sub-epidermal splits in this experimental model. Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal-epidermal separation. The potential of IgG4 autoantibodies to induce Fc-dependent dermal-epidermal separation was significantly lower compared to IgG1. Our results demonstrate that IgG4 autoantibodies are able to activate leucocytes and point to a hitherto less recognized function of IgG4. Moreover, for the first time, we clearly demonstrate that BP IgG4 autoantibodies have the capacity to induce leucocyte-dependent tissue damage.


Effects of oxygen toxicity on regional ventilation and perfusion in the primate lung.
Since the effect of prolonged exposure to high concentrations of oxygen on regional ventilation and perfusion has not been previously, a reproducible primate model of oxygen toxicity was developed to investigate the pathophysiologic changes that occur. Regional ventilation and perfusion were measured by 133Xe techniques in 10 baboons before and after 108 hours of continuous exposure to an inspired oxygen concentration of more than 90%. Arterial blood gases, shunt fraction (QS/QT), cardiac output, physiologic dead space (VD/VT), and pulmonary vascular resistance were also measured. Light and electron microscopic histology confirmed early pathologic changes of oxygen toxicity in every animal after exposure. PaO2 in room air decreased markedly after exposure from 90 +/- 4 to 46 +/- 5 mm Hg, and QS/QT rose to 30 +/- 2%. VD/VT, PaCO2, and pH were not altered by exposure to hyperoxia. Similarly, cardiac output and pulmonary vascular resistance remained unchanged. The distribution of regional ventilation and perfusion remained normal during and after prolonged high-oxygen exposure. Early oxygen toxicity was characterized by profound hypoxemia without regional ventilation-perfusion mismatch. Although impaired diffusion through a thickened alveolar membrane may be partially responsible for this hypoxemia, the markedly increased alveolar-arterial oxygen gradient when FIO2 = 1.0 indicates that shunting at the alveolar level (secondary to absorptive collapse or pulmonary edema) is a major cause of the hypoxemia.


Conservation of regulatory sequences and gene expression patterns in the disintegrating Drosophila Hox gene complex.
Homeotic (Hox) genes are usually clustered and arranged in the same order as they are expressed along the anteroposterior body axis of metazoans. The mechanistic explanation for this colinearity has been elusive, and it may well be that a single and universal cause does not exist. The Hox-gene complex (HOM-C) has been rearranged differently in several Drosophila species, producing a striking diversity of Hox gene organizations. We investigated the genomic and functional consequences of the two HOM-C splits present in Drosophila buzzatii. Firstly, we sequenced two regions of the D. buzzatii genome, one containing the genes labial and abdominal A, and another one including proboscipedia, and compared their organization with that of D. melanogaster and D. pseudoobscura in order to map precisely the two splits. Then, a plethora of conserved noncoding sequences, which are putative enhancers, were identified around the three Hox genes closer to the splits. The position and order of these enhancers are conserved, with minor exceptions, between the three Drosophila species. Finally, we analyzed the expression patterns of the same three genes in embryos and imaginal discs of four Drosophila species with different Hox-gene organizations. The results show that their expression patterns are conserved despite the HOM-C splits. We conclude that, in Drosophila, Hox-gene clustering is not an absolute requirement for proper function. Rather, the organization of Hox genes is modular, and their clustering seems the result of phylogenetic inertia more than functional necessity.


Using NMR chemical shift imaging to monitor swelling and molecular transport in drug-loaded tablets of hydrophobically modified poly(acrylic acid): methodology and effects of polymer (in)solubility.
A new technique has been developed using NMR chemical shift imaging (CSI) to monitor water penetration and molecular transport in initially dry polymer tablets that also contain small low-molecular weight compounds to be released from the tablets. Concentration profiles of components contained in the swelling tablets could be extracted via the intensities and chemical shift changes of peaks corresponding to protons of the components. The studied tablets contained hydrophobically modified poly(acrylic acid) (HMPAA) as the polymer component and griseofulvin and ethanol as hydrophobic and hydrophilic, respectively, low-molecular weight model compounds. The water solubility of HMPAA could be altered by titration with NaOH. In the pure acid form, HMPAA tablets only underwent a finite swelling until the maximum water content of the polymer-rich phase, as confirmed by independent phase studies, had been reached. By contrast, after partial neutralization with NaOH, the polyacid became fully miscible with water. The solubility of the polymer affected the water penetration, the polymer release, and the releases of both ethanol and griseofulvin. The detailed NMR CSI concentration profiles obtained highlighted the clear differences in the disintegration/dissolution/release behavior for the two types of tablet and provided insights into their molecular origin. The study illustrates the potential of the NMR CSI technique to give information of importance for the development of pharmaceutical tablets and, more broadly, for the general understanding of any operation that involves the immersion and ultimate disintegration of a dry polymer matrix in a solvent.


Epilepsy and autoimmunity in pediatric patients.
Our aim was to determine the presence and possible role of autoantibodies in epileptic patients with an undetermined etiology. Eighty epilepsy patients, who were referred to the Pediatric Neurology Department at Ankara University between November 2011 and April 2012, were enrolled in the study. Antinuclear antibodies (ANA), anticardiolipin IgG, antiphospholipid, antithyroid peroxidase, paraneoplastic, glutamic acid decarboxylase (GAD), and N-methyl-d-aspartate (NMDA) receptor antibodies were studied in our university laboratory. In addition, NMDA receptor (NMDAR), voltage-gated potassium channel (VGKC)-complex, leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) antibodies were studied at the Oxford University Immunology Laboratory. The study included 35 girls (44%) and 45 boys (56%) with a mean symptom age of 8.6 ± 4.53 years. ANA was detected in 15 (18.8%), antiphospholipid Ab in 3 (3.75%), anticardiolipin Ab in 1 (1.25%), and antithyroid peroxidase in 3 (3.75%) epileptic patients. In addition, anti-GAD Ab was detected in 7 (8.75%), anti-Yo Ab in 3 (3.75%), and anti-Ma2 in 3 (3.75%) epileptic patients. Anti-VGKC was positive in 13 (16.25%) epileptic patients. We performed a pioneer study to investigate the association between autoimmunity and pediatric epilepsy and we conclude that autoimmunity should be considered in epileptic patients with an undetermined etiology.


In Vivo Nanodetoxication for Acute Uranium Exposure.
Accidental exposure to uranium is a matter of concern, as U(VI) is nephrotoxic in both human and animal models, and its toxicity is associated to chemical toxicity instead of radioactivity. We synthesized different PAMAM G4 and G5 derivatives in order to prove their interaction with uranium and their effect on the viability of red blood cells in vitro. Furthermore, we prove the effectiveness of the selected dendrimers in an animal model of acute uranium intoxication. The dendrimer PAMAM G4-Lys-Fmoc-Cbz demonstrated the ability to chelate the uranyl ion in vivo, improving the biochemical and histopathologic features caused by acute intoxication with uranium.


Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice.
Genome-wide association studies have established ADAMTS7 as a locus for coronary artery disease in humans. However, these studies fail to provide directionality for the association between ADAMTS7 and coronary artery disease. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell migration, but a role for and the direction of impact of this gene in atherogenesis have not been shown in relevant model systems. We bred an Adamts7 whole-body knockout mouse onto both the Ldlr and Apoe knockout hyperlipidemic mouse models. Adamts7(-/-)/Ldlr(-/-) and Adamts7(-/-)/Apoe(-/-) mice displayed significant reductions in lesion formation in aortas and aortic roots compared with controls. Adamts7 knockout mice also showed reduced neointimal formation after femoral wire injury. Adamts7 expression was induced in response to injury and hyperlipidemia but was absent at later time points, and primary Adamts7 knockout vascular smooth muscle cells showed reduced migration in the setting of tumor necrosis factor-α stimulation. ADAMTS7 localized to cells positive for smooth muscle cell markers in human coronary artery disease lesions, and subcellular localization studies in cultured vascular smooth muscle cells placed ADAMTS7 at the cytoplasm and cell membrane, where it colocalized with markers of podosomes. These data represent the first in vivo experimental validation of the association of Adamts7 with atherogenesis, likely through modulation of vascular cell migration and matrix in atherosclerotic lesions. These results demonstrate that Adamts7 is proatherogenic, lending directionality to the original genetic association and supporting the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans, making it an attractive target for novel therapeutic interventions.


Detection of intravascular injection of regional anaesthetics in children.
Detection of intravascular injection of local anaesthetic during placement of regional blocks in children by using epinephrine-induced tachycardia or hypertension may produce false positive and false negative findings. This study evaluates ECG changes as markers of intravascular injection of local anaesthetics with epinephrine, during placement of epidural blocks in children. Observational study in a teaching hospital of all epidural anaesthetics administered to paediatric patients during one year. General anaesthesia, where used, was not controlled. An ECG rhythm strip was recorded during test dose injection and analyzed for changes in rate, rhythm, and T-wave configuration. During the study period, 742 paediatric epidural blocks were administered. There were 644 caudal (284 without catheters), 97 lumbar, and one thoracic epidural anaesthetics. Satisfactory placement was achieved in 97.7% of patients. Intravascular injection was detected in 42 (5.6%) of epidural anaesthetics (3.8% and 6.7% of straight needle and catheter injections, respectively). Detection was by immediate aspiration of blood in six patients, and by heart rate increases > 10 bpm in 30. Five had heart rate decreases suggesting a baroreceptor response. Five had heart rate increases < 10 bpm that were possible responses to noxious stimuli. Of 30 patients with known intravascular injection and for whom ECG strips were available, 25 (83%) had T-wave amplitude increases > 25%, and 29 (97%) had ECG changes in T-wave or rhythm in response to the epinephrine injection. There were no false positives. In order to reduce risks associated with epidural anaesthesia in children, epinephrine should be added to the local anaesthetic test dose, the ECG should be monitored continuously for changes in heart rate, rhythm, and T-wave amplitude. Epidural injections should be given in small increments.


Assessing the severity of sleep apnea syndrome based on ballistocardiogram.
Sleep Apnea Syndrome (SAS) is a common sleep-related breathing disorder, which affects about 4-7% males and 2-4% females all around the world. Different approaches have been adopted to diagnose SAS and measure its severity, including the gold standard Polysomnography (PSG) in sleep study field as well as several alternative techniques such as single-channel ECG, pulse oximeter and so on. However, many shortcomings still limit their generalization in home environment. In this study, we aim to propose an efficient approach to automatically assess the severity of sleep apnea syndrome based on the ballistocardiogram (BCG) signal, which is non-intrusive and suitable for in home environment. We develop an unobtrusive sleep monitoring system to capture the BCG signals, based on which we put forward a three-stage sleep apnea syndrome severity assessment framework, i.e., data preprocessing, sleep-related breathing events (SBEs) detection, and sleep apnea syndrome severity evaluation. First, in the data preprocessing stage, to overcome the limits of BCG signals (e.g., low precision and reliability), we utilize wavelet decomposition to obtain the outline information of heartbeats, and apply a RR correction algorithm to handle missing or spurious RR intervals. Afterwards, in the event detection stage, we propose an automatic sleep-related breathing event detection algorithm named Physio_ICSS based on the iterative cumulative sums of squares (i.e., the ICSS algorithm), which is originally used to detect structural breakpoints in a time series. In particular, to efficiently detect sleep-related breathing events in the obtained time series of RR intervals, the proposed algorithm not only explores the practical factors of sleep-related breathing events (e.g., the limit of lasting duration and possible occurrence sleep stages) but also overcomes the event segmentation issue (e.g., equal-length segmentation method might divide one sleep-related breathing event into different fragments and lead to incorrect results) of existing approaches. Finally, by fusing features extracted from multiple domains, we can identify sleep-related breathing events and assess the severity level of sleep apnea syndrome effectively. Experimental results on 136 individuals of different sleep apnea syndrome severities validate the effectiveness of the proposed framework, with the accuracy of 94.12% (128/136).


A Novel PiRNA Enhances CA19-9 Sensitivity for Pancreatic Cancer Identification by Liquid Biopsy.
Pancreatic cancer is one of the deadliest tumours worldwide, and its poor prognosis is due to an inability to detect the disease at the early stages, thereby creating an urgent need to develop non-invasive biomarkers. P-element-induced wimpy testis (PIWI) proteins work together with piwi-interacting RNAs (piRNAs) to perform epigenetic regulation and as such hold great potential as biomarkers for pancreatic cancer. PIWIL2 and PIWIL4 are associated with better prognosis, while PIWIL1 and PIWIL3 involvement appears to be associated with carcinogenesis. We aimed to discover PIWIL3- and PIWIL4-modulated piRNAs and determine their potential mechanisms in pancreatic cancer and the clinical implications. PIWIL3 or PIWIL4 was downregulated in pancreatic cancer-derived cell lines or in a non-tumour cell line. Differentially expressed piRNAs were analysed by next generation sequencing of small RNA. Nine fresh-frozen samples from solid human pancreases (three healthy pancreases, three intraductal papillary mucinous neoplasms, and three early-stage pancreatic cancers) were included in the sequencing analysis. Two piRNAs associated with PIWIL3 (piR-168112 and piR-162725) were identified in the neoplastic cells; in untransformed samples, we identified one piRNA associated with PIWIL4 (pir-366845). After validation in pancreatic cancer-derived cell lines and one untransformed pancreatic cell line, these piRNAs were evaluated in plasma samples from healthy donors (n = 27) or patients with pancreatic cancer (n = 45). Interestingly, piR-162725 expression identified pancreatic cancer patients versus healthy donors in liquid biopsies. Moreover, the potential of the serum carbohydrate antigen 19-9 (CA19-9) biomarker to identify pancreatic cancer patients was greatly enhanced when combined with piR-162725 detection. The enhanced diagnostic potential for the early detection of pancreatic cancer in liquid biopsies of these new small non-coding RNAs will likely improve the prognosis and management of this deadly cancer.


Human T-lymphotropic virus type-1 p30 alters cell cycle G2 regulation of T lymphocytes to enhance cell survival.
Human T-lymphotropic virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma and is linked to a number of lymphocyte-mediated disorders. HTLV-1 contains both regulatory and accessory genes in four pX open reading frames. pX ORF-II encodes two proteins, p13 and p30, whose roles are still being defined in the virus life cycle and in HTLV-1 virus-host cell interactions. Proviral clones of HTLV-1 with pX ORF-II mutations diminish the ability of the virus to maintain viral loads in vivo. p30 expressed exogenously differentially modulates CREB and Tax-responsive element-mediated transcription through its interaction with CREB-binding protein/p300 and while acting as a repressor of many genes including Tax, in part by blocking tax/rex RNA nuclear export, selectively enhances key gene pathways involved in T-cell signaling/activation. Herein, we analyzed the role of p30 in cell cycle regulation. Jurkat T-cells transduced with a p30 expressing lentivirus vector accumulated in the G2-M phase of cell cycle. We then analyzed key proteins involved in G2-M checkpoint activation. p30 expression in Jurkat T-cells resulted in an increase in phosphorylation at serine 216 of nuclear cell division cycle 25C (Cdc25C), had enhanced checkpoint kinase 1 (Chk1) serine 345 phosphorylation, reduced expression of polo-like kinase 1 (PLK1), diminished phosphorylation of PLK1 at tyrosine 210 and reduced phosphorylation of Cdc25C at serine 198. Finally, primary human lymphocyte derived cell lines immortalized by a HTLV-1 proviral clone defective in p30 expression were more susceptible to camptothecin induced apoptosis. Collectively these data are consistent with a cell survival role of p30 against genotoxic insults to HTLV-1 infected lymphocytes. Collectively, our data are the first to indicate that HTLV-1 p30 expression results in activation of the G2-M cell cycle checkpoint, events that would promote early viral spread and T-cell survival.


The Self-Care Needs and Behaviors of Dementia Informal Caregivers: A Systematic Review.
More than 5.4 million informal caregivers (ICGs) in the United States care for persons with dementia (PWD). Failure of ICGs to incorporate self-care into their routine may lead to adverse health consequences. Caregivers and researchers need to understand the evidence around dementia ICGs' self-care practices. To synthesize evidence on the self-care needs and behaviors of Alzheimer's and dementia ICGs and its research implications. PubMed, CINAHL, Scopus, and Web of Science were searched to conduct a systematic review of research. Orem's self-care theory and a concept analysis of self-management behaviors provided a framework for the review. Three themes emerged from 29 included studies: self-care needs and behaviors of ICGs, barriers to performing self-care, and enablers of self-care. The self-care needs of dementia ICGs included sleep, social engagement and support, and leisure activities. Self-care behaviors identified by this review were engaging in activities with the PWD, spiritual and religious activities, and taking a break from caregiving. Barriers to self-care were gender roles, self-sacrificing, minority ethnicity, and burden of caregiving. Enabling self-care involved acknowledging personal consequences of caregiving, balancing self-care needs with the PWD's needs, and positioning oneself as an objective/subjective duality. Self-care is a dynamic, challenging aspect to caregiving, but supporting evidence is often limited or cannot be generalized. More studies are needed that include random sampling, heterogeneous samples, and quantitative methods. Additional research is needed to understand how self-care needs, behaviors, and barriers differ by caregiver race/ethnicity, gender, or relationship to the PWD.


Attitudes and reported practice of paediatricians and child psychiatrists regarding the assessment and treatment of ADHD in Ireland.
This mixed-method national survey has obtained original data on attention deficit hyperactivity disorder (ADHD) attitudes, assessment and treatment regimes reported by paediatricians and child psychiatrists; and has compared their clinics. It has examined the extent of involvement of Irish paediatricians in the management of ADHD. A questionnaire was designed, based on a review of literature and ADHD guidelines, and piloted by expert clinicians. Universal recruitment was conducted among Child and Adolescent Mental Health Services (CAMHS) consultants (n=71) and community/general paediatric consultants (n=72). Quantitative and qualitative data was collected and analysed. There was an overall response rate of 43%. A dedicated ADHD clinic is offered in 79% of CAMHS services, but only in one paediatric service. Participants reported that the assessment of ADHD involves multidisciplinary work and this was only established in CAMHS clinics. Medication is initiated by 82% of child psychiatrists and only 22% of paediatricians. This first national study of ADHD attitudes and practices presents comprehensive data regarding the management of children with ADHD in CAMHS and paediatric settings in Ireland. Paediatricians reported a minor role in managing ADHD. Study limitations are related to subjective reporting rather than case note audit, and a moderate response rate for the paediatricians' participants.


Progressive mechanical and structural changes in anterior cerebral arteries with Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disease and the main cause for dementia. The irreversible neurodegeneration leads to a gradual loss of brain function characterized predominantly by memory loss. Cerebrovascular changes are common neuropathologic findings in aged subjects with dementia. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain, as cerebrovascular remodeling may render the brain more susceptible to pulse pressure and may be associated with poorer cognitive performance and greater risk of cerebrovascular events. The objective of this study is to provide understanding of cerebrovascular remodeling with AD progression. Anterior cerebral arteries (ACAs) from a total of 19 brain donor participants from controls and pathologically diagnosed AD groups (early-Braak stages I-II; intermediate-Braak stages III-IV; and advanced-Braak stages V-VI) were included in this study. Mechanical testing, histology, advanced optical imaging, and mass spectrometry were performed to study the progressive structural and functional changes of ACAs with AD progression. Biaxial extension-inflation tests showed that ACAs became progressively less compliant, and the longitudinal stress in the intermediate and advanced AD groups was significantly higher than that from the control group. With pathological AD development, the inner and outer diameters of the ACAs remained almost unchanged; however, histology study revealed progressive smooth muscle cell atrophy and loss of elastic fibers which led to compromised structural integrity of the arterial wall. Multiphoton imaging demonstrated elastin degradation at the media-adventitia interface, which led to the formation of an empty band of 21.0 ± 15.4 μm and 32.8 ± 9.24 μm in width for the intermediate and advanced AD groups, respectively. Furthermore, quantitative birefringence microscopy showed disorganized adventitial collagen with AD development. Mass spectrometry analysis provided further evidence of altered collagen content and other extracellular matrix (ECM) molecule and smooth muscle cell changes that were consistent with the mechanical and structural alterations. Collectively, our study provides understanding of the mechanical and structural cerebrovascular deterioration in cerebral arteries with AD, which may be related to neurodegenration and pathology in the brain.


A study of unplanned readmissions to a coronary care unit.
To determine the cause and frequency of unplanned readmissions to a coronary care unit (CCU) after initial transfer to a general cardiac unit, but before hospital discharge. Analysis of 1776 admissions to a CCU during a 16-month period. The CCU of a major teaching hospital in South Australia. All patients admitted to the CCU during the 16-month period. CCU readmissions before hospital discharge were categorized as either "planned" or "unplanned." The latter were investigated for determination of casualty and variations in patient characteristics (including age, sex, initial diagnosis, pharmacotherapy, and duration of stay in the CCU). Of the 1776 CCU admissions examined, 44 (2.5% of total) were unplanned readmissions before hospital discharge. Most of these (39 of 44) were related to "reactivation" of acute myocardial ischemia. Patients whose initial diagnosis was acute myocardial infarction or unstable angina pectoris were more likely to require a further unplanned CCU admission (p < 0.05); those with unstable angina pectoris had a second stay in CCU significantly longer than their first (p < 0.05). Six patients were readmitted within 6 hours of cessation of a heparin infusion (4 of the 6 without aspirin administration), and 11 patients had not received antiplatelet therapy after their initial CCU stay. Overall, a disproportionate number of men were readmitted to CCU (p < 0.05). In the current study, unplanned readmissions to the CCU: (1) were relatively infrequent, (2) were more protracted than initial stays in CCU, (3) may have been prevented in 15 of the 44 cases with more appropriate pharmacotherapy, and (4) involved a disproportionate number of male patients.


The Molecular Information About Deadwood Bacteriomes Partly Depends on the Targeted Environmental DNA.
Microbiome studies mostly rely on total DNA extracts obtained directly from environmental samples. The total DNA consists of both intra- and extracellular DNA, which differ in terms of their ecological interpretation. In the present study, we have investigated for the first time the differences among the three DNA types using microbiome sequencing of Picea abies deadwood logs (Hunter decay classes I, III, and V). While the bacterial compositions of all DNA types were comparable in terms of more abundant organisms and mainly depended on the decay class, we found substantial differences between DNA types with regard to less abundant amplicon sequence variants (ASVs). The analysis of the sequentially extracted intra- and extracellular DNA fraction, respectively, increased the ecological depth of analysis compared to the directly extracted total DNA pool. Both DNA fractions were comparable in proportions and the extracellular DNA appeared to persist in the P. abies deadwood logs, thereby causing its masking effect. Indeed, the extracellular DNA masked the compositional dynamics of intact cells in the total DNA pool. Our results provide evidence that the choice of DNA type for analysis might benefit a study's answer to its respective ecological question. In the deadwood environment researched here, the differential analysis of the DNA types underlined the relevance of Burkholderiales, Rhizobiales and other taxa for P. abies deadwood decomposition and revealed that the role of Acidobacteriota under this scenario might be underestimated, especially compared to Actinobacteriota.


A New Era of Integration between Multiomics and Spatio-Temporal Analysis for the Translation of EMT towards Clinical Applications in Cancer.
Epithelial-mesenchymal transition (EMT) is crucial to metastasis by increasing cancer cell migration and invasion. At the cellular level, EMT-related morphological and functional changes are well established. At the molecular level, critical signaling pathways able to drive EMT have been described. Yet, the translation of EMT into efficient diagnostic methods and anti-metastatic therapies is still missing. This highlights a gap in our understanding of the precise mechanisms governing EMT. Here, we discuss evidence suggesting that overcoming this limitation requires the integration of multiple omics, a hitherto neglected strategy in the EMT field. More specifically, this work summarizes results that were independently obtained through epigenomics/transcriptomics while comprehensively reviewing the achievements of proteomics in cancer research. Additionally, we prospect gains to be obtained by applying spatio-temporal multiomics in the investigation of EMT-driven metastasis. Along with the development of more sensitive technologies, the integration of currently available omics, and a look at dynamic alterations that regulate EMT at the subcellular level will lead to a deeper understanding of this process. Further, considering the significance of EMT to cancer progression, this integrative strategy may enable the development of new and improved biomarkers and therapeutics capable of increasing the survival and quality of life of cancer patients.


Development and validation of nomograms to provide individualised predictions of seizure outcomes after epilepsy surgery: a retrospective analysis.
Half of patients who have resective brain surgery for drug-resistant epilepsy have recurrent postoperative seizures. Although several single predictors of seizure outcome have been identified, no validated method incorporates a patient's complex clinical characteristics into an instrument to predict an individual's post-surgery seizure outcome. We developed nomograms to predict complete freedom from seizures and Engel score of 1 (eventual freedom from seizures allowing for some initial postoperative seizures, or seizures occurring only with physiological stress such as drug withdrawal) at 2 years and 5 years after surgery on the basis of sex, seizure frequency, secondary seizure generalisation, type of surgery, pathological cause, age at epilepsy onset, age at surgery, epilepsy duration at time of surgery, and surgical side. We designed the models from a development cohort of patients who had resective surgery at the Cleveland Clinic (Cleveland, OH, USA) between 1996 and 2011. We then tested the nomograms in an external validation cohort operated on over a similar period in four epilepsy surgery centres, in Brazil, France, Italy, and the USA. We assessed performance of the nomogram by calculating concordance statistics and assessing the calibration of predicted freedom from seizures with the reported freedom from seizures and Engel score of 1. The development cohort included 846 patients and the validation cohort included 604 patients. Variables included in the nomograms were sex, seizure frequency, secondary seizure generalisation, type of surgery, and pathological cause. In the development cohort, the baseline risk of complete freedom from seizures was 0·57 at 2 years and 0·40 at 5 years. The baseline risk of Engel score of 1 was 0·69 at 2 years and 0·62 at 5 years. In the validation cohort, the models had a concordance statistic of 0·60 for complete freedom from seizures and 0·61 for Engel score of 1. Calibration curves showed adequate calibration (judged by eye) of predicted and reported freedom from seizures, throughout the range of seizure outcomes. If validated in prospective cohorts, these nomograms could be used to predict seizure outcomes in patients who have been judged eligible for epilepsy surgery. Cleveland Clinic Epilepsy Center.


Immunological cross-reactions of alpha-lactalbumins from different species.
Four rabbit antibodies have been prepared, which are specifically directed against alpha-lactalbumins from different sources; namely human, cow, goat and sheep milk. Each of these antibodies was tested for its ability to react with, separately, each of the four proteins. The immunological reactions were assessed by means of different techniques: double immunodiffusion in agar gel as well as affinity chromatography of antibodies, using antigens covalently bound to an insoluble matrix. In each case, the strongest reaction was observed between homologous antibody and (matrix-bound) antigen; heterologous antigens were, however, also capable of cross-reaction. Whereas no cross-reaction between human alpha-lactalbumin and antibodies against the bovine protein could be evidenced by immunodiffusion, the occurrence of soluble complexes has been disclosed by means of a gel filtration technique.


Obesity and the risk of early and late mortality after coronary artery bypass graft surgery.
Obesity is often considered to be a significant risk factor for postoperative mortality when selecting candidates for coronary artery bypass grafting (CABG). We included all patients undergoing a first isolated CABG at the Karolinska Hospital in Stockholm, Sweden, between 1980 and 1995 (n = 6728). Patients were categorized on the basis of body mass index (BMI): non-overweight (BMI <25 kg/m2), overweight (25 kg/m2 < or = BMI <30 kg/m2), and obese (BMI > or =30 kg/m2). Multivariate Cox regression was used to assess the risk of re-operation for bleeding, deep sternal wound infection, and early (< or =30 days) and late (< or =5 years) mortality rates. The average length of follow-up was 6.5 years. There were 252 re-operations for bleeding, 53 deep sternal wound infections, and 628 deaths. Patients who were obese had a significantly lower risk of re-operation for bleeding (risk ratio [RR], 0.32; 95% CI, 0.19-0.53), but a greater risk of deep sternal wound infection (RR, 2.66; 95% CI, 1.21-5.88) compared with patients who were not overweight. However, patients who were obese and patients who were not overweight experienced similar 30-day (RR, 0.65; 95% CI, 0.34-1.27), 1-year (RR, 0.56; 95% CI, 0.29-1.10), and 5-year mortality rates (RR, 0.91; 95% CI, 0.66-1.25). Results for patients who were overweight were consistent with those of patients who were obese. Patients who are obese are not at a greater risk of early and late mortality after CABG compared with patients who are not overweight, although they appear to have a lower risk of re-operation for bleeding and a greater risk of deep sternal wound infection. Therefore, obesity per se is not a contraindication for CABG.


Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse.
Eukaryotic voltage-gated K+ channels have been extensively studied, but the structural bases for some of their most salient functional features remain to be established. C-type inactivation, for example, is an auto-inhibitory mechanism that confers temporal resolution to their signal-firing activity. In a recent breakthrough, studies of a mutant of Shaker that is prone to inactivate indicated that this process entails a dilation of the selectivity filter, the narrowest part of the ion conduction pathway. Here, we report an atomic-resolution cryo-electron microscopy structure that demonstrates that the wild-type channel can also adopt this dilated state. All-atom simulations corroborate this conformation is congruent with the electrophysiological characteristics of the C-type inactivated state, namely, residual K+ conductance and altered ion specificity, and help rationalize why inactivation is accelerated or impeded by certain mutations. In summary, this study establishes the molecular basis for an important self-regulatory mechanism in eukaryotic K+ channels, laying a solid foundation for further studies.


High-resolution physical mapping and construction of a porcine contig spanning the intramuscular fat content QTL.
We previously mapped a locus for porcine intramuscular fat content (IMF) by linkage analysis to a 17.1-cM chromosome interval on Sus scrofa chromosome 7 (SSC7) flanked by microsatellite markers SW1083 and SW581. In this study, we identified 34 microsatellite markers and 14 STSs from the 17.1-cM IMF quantitative trait loci (QTL) region corresponding to HSA14q and aligned those loci using the INRA-University of Minnesota porcine radiation hybrid (IMpRH) panel. We then constructed a 5.2-Mb porcine bacterial artificial chromosome (BAC) contig of this region that was aligned using the RH panel. Finally, the IMF QTL was fine-mapped to 12.6 cM between SJ169 and MM70 at the 0.1% chromosome-wise significance level by genotyping the previously studied F2 resource family with 17 additional microsatellites. We also demonstrated that the SJ169-MM70 interval spans approximately 3.0 Mb and contains at least 12 genes: GALC, GPR65, KCNK10, SPATA7, PTPN21, FLJ11806, EML5, TTC8, CHES1, CAP2P1, CHORDC2P and C14orf143.


Down the wrong road - a case report of inadvertent nasogastric tube insertion leading to lung laceration and important pearls to avoid complications.
Nasogastric tube (NGT) insertion is a common procedure performed by residents and nursing staff to access the stomach. Although an apparently simple procedure, it is associated with technical difficulties and complications if proper care is not taken during insertion. We present a case of a 79-year-old female with multiple comorbidities who had a percutaneous enteral gastrostomy tube removed due to infection of an insertion site wound and a NGT was inserted for feeding. A few minutes post-insertion the patient developed shortness of breath and a drop in oxygen saturation. An immediate chest X-ray showed the NG tube traversing along the course of the trachea and the right main bronchus into the right upper abdomen with right-sided pneumothorax. The NG tube was immediately removed and a right chest drain inserted. Subsequent imaging showed right-sided pneumothorax with evidence of lung laceration and underlying lung collapse and diaphragmatic injury. The patient underwent a prolonged course of hospitalisation due to hospital-acquired pneumonia before being discharged upon clinical improvement. We highlight the fact that a simple and routine procedure such as NGT insertion can have devastating complications if due care is not taken. Along with a literature review, we provide and compare different methods to confirm correct placement of a NGT. The article also discusses important pearls for practising physicians and nursing staff to avoid such complications. Owing to the frequency of the procedure in hospitals and long-term care units, appropriate awareness among medical staff is necessary.


[Corneal pachymetry and intraocular pressure].
Just recently studies on glaucoma have emphasised the significance of intraocular pressure in the diagnosis of glaucoma and the importance of intraocular pressure reduction in the management of glaucoma. Central corneal thickness appears to play an important role in the exact measurement of intraocular pressure and in the diagnostic assessment of glaucoma. Numerous studies have verified that corneal thickness shows systematic differences in different forms of glaucoma. Since deviations of corneal thickness from normal can possibly result in an artificial change of Goldmann applanation values, it would be a most important source of error in the diagnosis of glaucoma to ignore central corneal thickness. Corrections of intraocular pressure measured with applanation tonometry can be achieved in various ways but there is considerable divergence in the results. The absence of a generally accepted algorithm for the correction of intraocular pressure measured with applanation tonometry should not prevent us from a wide application of pachymetry, since it delivers valuable additional information on the individual risk of glaucoma.


[Primary mesothelioma of the pericardium. Report of 2 cases and review of the literature].
We described two adult females with primary pericardial mesothelioma. There was not history of asbestos exposure. The clinical picture suggested pericardial constriction, with predominantly right sided heart failure. Anatomically; one case was of a nodular type, being the other diffuse. On histology both cases were of the fibrous type. The second case was less differentiated; it perforated the right atrial wall creating an intracavitary mass. A review of the literature is made.


COVID-19 in humanitarian settings: documenting and sharing context-specific programmatic experiences.
Humanitarian organizations have developed innovative and context specific interventions in response to the COVID-19 pandemic as guidance has been normative in nature and most are not humanitarian specific. In April 2020, three universities developed a COVID-19 humanitarian-specific website ( www.covid19humanitarian.com ) to allow humanitarians from the field to upload their experiences or be interviewed by academics to share their creative responses adapted to their specific country challenges in a standardised manner. These field experiences are reviewed by the three universities together with various guidance documents and uploaded to the website using an operational framework. The website currently hosts 135 guidance documents developed by 65 different organizations, and 65 field experiences shared by 29 organizations from 27 countries covering 38 thematic areas. Examples of challenges and innovative solutions from humanitarian settings are provided for triage and sexual and gender-based violence. Offering open access resources on a neutral platform by academics can provide a space for constructive dialogue among humanitarians at the country, regional and global levels, allowing humanitarian actors at the country level to have a strong and central voice. We believe that this neutral and openly accessible platform can serve as an example for future large-scale emergencies and epidemics.


Femoral bone regeneration subsequent to impaction grafting during hip revision: histologic analysis of a human biopsy specimen.
Cemented revision with impaction grafting shows encouraging early clinical results; postoperative biopsy specimens taken from the proximal femur in humans have demonstrated viable trabecular and cortical bone. Human radiographic studies also illustrate density changes within the proximal femur, consistent with remodeling of bone-graft. In an animal experiment, bone incorporation was shown in the proximal femur, but graft lysis was reported around the distal portion of the implant. We report on a patient who sustained a traumatic femoral fracture at the level of the tip of the femoral component 27 months after revision with impaction grafting and a collarless polished taper stem. At the time of open reduction and internal fixation of the fracture, we obtained circumferential biopsy specimens from the fracture site. Three distinct zones could be identified histologically: i) an inner zone consisting of bone-cement, fibrous tissue, and partially necrotic trabeculae with evidence of bone remodeling; ii) a middle zone consisting of viable trabecular bone and probable neocortex formation with fewer particles of bone-cement; and iii) an outer zone with viable cortex. Fibrous tissue was present around some of the incorporating bone-graft fragments, but no continuous fibrous membrane was present. Cement particles were identified, but no polyethylene debris was found by light microscopy. Biopsy specimens from the distal aspect of the prosthesis may not reflect changes seen proximally, but based on the available tissue, this case illustrated histological evidence of bone-graft remodeling after impaction grafting. These results are consistent with our expectations based on radiographic findings and clinical results.


Single beta-AgVO3 nanowire H2S sensor.
We report the electrical transport and H(2)S sensing properties of single beta-AgVO(3) nanowire device. beta-AgVO(3) nanowires were successfully prepared by ultrasonic treatment followed by hydrothermal reaction using V(2)O(5) sol. The individual beta-AgVO(3) nanowire exhibits a "threshold switching" phenomenon. High bias (i.e., 6 V for Au contacts) is required to initially switch the individual nanowire device from nonconductive to conductive, and it may be related to the formation of nanoscale metallic Ag when enough voltage is applied between the two electrodes. This novel nanomaterial shows good H(2)S sensing performances with short response and recovery time within 20 s, relatively low response concentration of 50 ppm, and good selectivity.


Pearls: visual loss.
The clinician who is evaluating a patient with visual loss faces a large initial differential diagnosis. By taking a systematic approach to the history of the present illness, including reviewing systems, examination, and subsequent testing, several potential pitfalls will be avoided, and a brief differential diagnosis list can be generated. This article uses illustrative cases to present a variety of history, examination, and testing pearls for diagnosing the source of visual loss.


Variations of cocoon external lipids during wolf spiderlings' development.
This study presents the first characterisation of the silk lipids of the cocoons of a wolf spider (Pardosa saltans). Wolf spiders' maternal behaviour is complex and involves guarding a cocoon for several weeks, and so cocoons must emit cues to ensure their care and the development of juveniles. We investigated cues associated with the cocoon silk. We assessed qualitative changes of the lipid contents and the composition of cocoon silk in relation to the development of P. saltans wolf spider juveniles. Gas chromatography-mass spectrometry of P. saltans' cocoon silk revealed 62 different lipid compounds. The compounds were aliphatic alcohols, glycerides, fatty acids and their methylesters containing 13-29 carbon atoms. We reveal for the first time the presence of ethanolamides and phytosterol on cocoon silk. Qualitative and quantitative changes occur during the embryonic period, as some polar compounds, such as diglycerides and ethanolamides, disappeared while hydrocarbons emerge, and fatty acids disappeared later during the post-embryonic period. Qualitative and/or quantitative changes could play a role in tactochemical communication between mothers and their cocoon. However, mothers do not modify their behaviour in relation to the developmental stage of their cocoon. Mothers' behaviour appears to be linked to both internal (physiological state) and external mechanisms (signals from the cocoon).


Towards understanding the relation between citations and research quality in software engineering studies.
The importance of achieving high quality in research practice has been highlighted in different disciplines. At the same time, citations are utilized to measure the impact of academic researchers and institutions. One open question is whether the quality in the reporting of research is related to scientific impact, which would be desired. In this exploratory study we aim to: (1) Investigate how consistently a scoring rubric for rigor and relevance has been used to assess research quality of software engineering studies; (2) Explore the relationship between rigor, relevance and citation count. Through backward snowball sampling we identified 718 primary studies assessed through the scoring rubric. We utilized cluster analysis and conditional inference tree to explore the relationship between quality in the reporting of research (represented by rigor and relevance) and scientiometrics (represented by normalized citations). The results show that only rigor is related to studies' normalized citations. Besides that, confounding factors are likely to influence the number of citations. The results also suggest that the scoring rubric is not applied the same way by all studies, and one of the likely reasons is because it was found to be too abstract and in need to be further refined. Our findings could be used as a basis to further understand the relation between the quality in the reporting of research and scientific impact, and foster new discussions on how to fairly acknowledge studies for performing well with respect to the emphasized research quality. Furthermore, we highlighted the need to further improve the scoring rubric.


Multilevel vertebral body replacement with a titanium mesh spacer for aneurysmal bone cyst: technical note.
A 64-year-old male presented with abrupt tetraparesis caused by a minor impact. Diagnostic images obtained on admission showed an aneurysmal bone cyst visible in the cervical spine at the fourth to upper sixth level, although the patient had been wearing a halo brace to diminish the symptoms. The vertebral body from the fourth to the sixth level was dissected, and this space was packed with a titanium cage filled with ceramic bone fragments mixed with fibrin glue. The combination of a titanium cage and an anterior locking plate can be made easily for anterior spinal fusion with enough rigidity to maintain the necessary space during fusion without any major support equipment. Both edges of the titanium mesh cage cut into the vertebral body to hold the cage in place. The other part, the titanium plate, makes it secure until ceramic bone fragments in the cage promote bony ingrowth for fusion.


Synthesis, crystal structure, resistivity, magnetic, and theoretical study of ScUS3.
Single crystals of ScUS3 were synthesized in high yield in a single step at 1173 K. ScUS3 crystallizes in the FeUS3 structure type in the space group D2h(17)–Cmcm of the orthorhombic system with four formula units in a cell of dimensions a = 3.7500(8) Å, b = 12.110(2) Å, and c = 9.180(2) Å. Its structure consists of edge- and corner-sharing ScS6 octahedra that form two-dimensional layers. U atoms between layers are connected to eight S atoms in a bicapped trigonal-prismatic fashion. ScUS3 can be easily charge-balanced as Sc(3+)U(3+)(S(2–))3 as there are no S–S single bonds present in the crystal structure. High temperature-dependent resistivity measurements on a single crystal of ScUS3 show semiconducting behavior with an activation energy of 0.09(1) eV. A magnetic study on powdered single crystals of ScUS3 reveals an antiferromagnetic transition at 198 K followed by a ferromagnetic transition at 75 K. The weak ferromagnetic behavior at low temperature may originate from canted antiferromagnetic spins. A density functional theory (DFT) calculation predicts ScUS3 to be ferromagnetic and either a very poor metal or a semiconductor with a very small gap.


A combination of LongSAGE with Solexa sequencing is well suited to explore the depth and the complexity of transcriptome.
"Open" transcriptome analysis methods allow to study gene expression without a priori knowledge of the transcript sequences. As of now, SAGE (Serial Analysis of Gene Expression), LongSAGE and MPSS (Massively Parallel Signature Sequencing) are the mostly used methods for "open" transcriptome analysis. Both LongSAGE and MPSS rely on the isolation of 21 pb tag sequences from each transcript. In contrast to LongSAGE, the high throughput sequencing method used in MPSS enables the rapid sequencing of very large libraries containing several millions of tags, allowing deep transcriptome analysis. However, a bias in the complexity of the transcriptome representation obtained by MPSS was recently uncovered. In order to make a deep analysis of mouse hypothalamus transcriptome avoiding the limitation introduced by MPSS, we combined LongSAGE with the Solexa sequencing technology and obtained a library of more than 11 millions of tags. We then compared it to a LongSAGE library of mouse hypothalamus sequenced with the Sanger method. We found that Solexa sequencing technology combined with LongSAGE is perfectly suited for deep transcriptome analysis. In contrast to MPSS, it gives a complex representation of transcriptome as reliable as a LongSAGE library sequenced by the Sanger method.


Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT.
The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.


Comparative epidemiology of pandemic and seasonal influenza A in households.
There are few data on the comparative epidemiology and virology of the pandemic 2009 influenza A (H1N1) virus and cocirculating seasonal influenza A viruses in community settings. We recruited 348 index patients with acute respiratory illness from 14 outpatient clinics in Hong Kong in July and August 2009. We then prospectively followed household members of 99 patients who tested positive for influenza A virus on rapid diagnostic testing. We collected nasal and throat swabs from all household members at three home visits within 7 days for testing by means of quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay and viral culture. Using hemagglutination-inhibition and viral-neutralization assays, we tested baseline and convalescent serum samples from a subgroup of patients for antibody responses to the pandemic and seasonal influenza A viruses. Secondary attack rates (as confirmed on RT-PCR assay) among household contacts of index patients were similar for the pandemic influenza virus (8%; 95% confidence interval [CI], 3 to 14) and seasonal influenza viruses (9%; 95% CI, 5 to 15). The patterns of viral shedding and the course of illness among index patients were also similar for the pandemic and seasonal influenza viruses. In a subgroup of patients for whom baseline and convalescent serum samples were available, 36% of household contacts who had serologic evidence of pandemic influenza virus infection did not shed detectable virus or report illness. Pandemic 2009 H1N1 virus has characteristics that are broadly similar to those of seasonal influenza A viruses in terms of rates of viral shedding, clinical illness, and transmissibility in the household setting.


Structural Changes of the Urinary Bladder After Chronic Complete Spinal Cord Injury in Minipigs.
The aim of this study was to determine the structural changes of the urinary bladder after chronic spinal cord injury (SCI) in minipigs with the primary focus on the analysis of urinary bladder wall proteins and their quantitative distribution. Seven Göttingen minipigs (adult, female) underwent a complete spinal cord transection. Follow-up time was 4 months during which the bladder was drained by frequent single catheterisation and data from the bladder diary and daily urine strip test were collected. Samples from the urinary bladder were taken, fixed in 4% paraformaldehyde and stained for histological analyses. Bladder wall thickness, single tissue quantities/distributions, types I and III collagen, and elastin quantifications were performed. Comparisons to healthy urinary bladder tissue of age-matched minipigs were performed for statistical analyses. No urinary tract infections were observed in our SCI minipig collective during follow-up. A trend towards a reduction in bladder volumes and an increase in incontinence periods were seen. The bladder wall thickness significantly increased after chronic SCI. Furthermore, bladder wall composition was severely altered by a significant loss of smooth muscle tissue and a significant increase in connective tissue. Elastic fibres were reduced in number and altered in their structural appearance after SCI. Type I collagen was significantly increased, while type III collagen was significantly decreased after SCI. Chronic SCI highlighted that the urinary bladder wall undergoes fibrotic events with reduced contractile and elastic properties due to changes of the bladder wall protein composition. These changes show in detail how SCI severely influences the urinary bladder wall composition and depicts the similarities between minipigs and humans.


Ingestion of protein hydrolysate and amino acid-carbohydrate mixtures increases postexercise plasma insulin responses in men.
To optimize the postexercise insulin response and to increase plasma amino acid availability, we studied postexercise insulin levels after the ingestion of carbohydrate and wheat protein hydrolysate with and without free leucine and phenylalanine. After an overnight fast, eight male cyclists visited our laboratory on five occasions, during which a control drink and two different beverage compositions in two different doses were tested. After they performed a glycogen-depletion protocol, subjects received a beverage (3.5 mL. kg(-1)) every 30 min to ensure an intake of 1.2 g. kg(-1). h(-1) carbohydrate and 0, 0.2 or 0.4 g. kg(-1). h(-1) protein hydrolysate (and amino acid) mixture. After the insulin response was expressed as the area under the curve, only the ingestion of the beverages containing wheat protein hydrolysate, leucine and phenylalanine resulted in a marked increase in insulin response (+52 and + 107% for the 0.2 and 0.4 g. kg(-1). h(-1) mixtures, respectively; P: < 0. 05) compared with the carbohydrate-only trial). A dose-related effect existed because doubling the dose (0.2-0.4 g. kg(-1). h(-1)) led to an additional rise in insulin response (P: < 0.05). Plasma leucine, phenylalanine and tyrosine concentrations showed strong correlations with the insulin response (P: < 0.0001). This study provides a practical tool to markedly elevate insulin levels and plasma amino acid availability through dietary manipulation, which may be of great value in clinical nutrition, (recovery) sports drinks and metabolic research.


Beneficial effects of platelet-derived growth factor on hemorrhagic shock in rats and the underlying mechanisms.
Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1–15 μg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+ sensitivity, whereas it did not interfere with the intracellular Ca2+ concentration in hypoxia-treated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis.


Early Development of the Mouse Morphome.
Analytical morphomics focuses on extracting objective and quantifiable data from clinical computed tomography (CT) scans to measure patients' frailty. Studies are currently retrospective in nature; therefore, it would be beneficial to develop animal models for well-controlled, prospective studies. The aim of this study is to develop an in vivo microCT protocol for the longitudinal acquisition of whole-body images suitable for morphomic analyses of bone. The authors performed phantom studies on 2 microCT systems (Inveon and CT120) to study tissue radiodensity and further characterize system performance for collecting animal data. The authors also describe their design of a phantom-immobilization device using phantoms and an ovariectomized (OVX) mouse. The authors discovered increased consistency along the z-axis for scans acquired on the Inveon compared with CT120, and calibration by individual slice reduces variability. Objects in the field of view had more impact on measurement acquired using the CT120 compared with the Inveon. The authors also found that using the middle 80% of slices for data analysis further decreased variability, on both systems. Moreover, bone-mineral-density calibration using the QCT Pro Mini phantom improved bone-mineral-density estimates across energy spectra, which helped confirm our technique. Comparison of weekly body weights and terminal uterine mass between sham and OVX groups validated our model. The authors present a refined microCT protocol to collect reliable and objective data. This data will be used to establish a platform for research animal morphomics that can be used to test hypotheses developed from clinical human morphomics.


Genomic characterization of selfing in the cyclic parthenogen Daphnia magna.
Inbreeding refers to the fusion of related individuals' gametes, with self-fertilization (selfing) being an extreme form of inbreeding-involving gametes produced by the same individual. Selfing is expected to reduce heterozygosity by an average of 50% in one generation; however, little is known about the empirical variation on a genome level surrounding this figure and the factors that affect variation. We selfed genotypes of the cyclic parthenogen Daphnia magna and analysed whole genomes of mothers and selfed offspring, observing the predicted 50% heterozygosity reduction on average. We also saw substantial variation around this value and significant differences among mother-offspring pairs. Crossover analysis confirmed the known trend of recombination occurring more often towards the telomeres. This effect was shown, through simulations, to increase the variance of heterozygosity reduction compared to when a uniform distribution of crossovers was used. Similarly, we simulated inbred line production after several generations of selfing and we observed higher variance in achieved homozygosity when we consider a higher recombination rate towards the telomeres. Our empirical and simulation study highlights that the expected mean values of heterozygosity reduction show remarkable variation, which can help understand, for example, differences among inbred individuals.


Comfort Level in Caregivers of Palliative Care Patients and Affecting Factors: What Should We Know?
Caregivers are an important source of support for patients in palliative care. Comfort is an important concept in nursing care for both patients and their families, and nurses aim to increase comfort. The aim of the study was to determine the comfort level and influencing factors in caregivers of palliative care patients. The research sample consisted of 102 caregivers related to palliative care patients. The data were obtained with an Individual Information Form, the Edmonton Symptom Assessment Scale (ESAS) and the End of Life Comfort Scale (Caregiver/Family). The study was conducted in the palliative care clinic of Aksaray University Training and Research Hospital between October 2018 and April 2019. There was a significant relationship between the total comfort score of the caregivers and the patient's performance status, the caregivers' age, their economic situation, the length of the caregiving period and receiving help in care (social support) (p < 0.05). Providing comfort is an important function and challenge for holistic nursing care, as comfort is a lifelong need in health and disease. Caregivers in the risk group should be aware of this issue and necessary precautions should be taken.


Angioarchitectural characteristics associated with complications of embolization in supratentorial brain arteriovenous malformation.
Embolization is an important therapeutic technique in brain arteriovenous malformations; however, little has been reported on the factors contributing to complications. We retrospectively reviewed a large series of supratentorial brain AVMs to identify the angioarchitectural characteristics that might be associated with the complications of embolization and poor clinical outcomes. The clinical and angiographic features of 130 consecutive patients with supratentorial brain AVMs embolized with ethylene-vinyl alcohol copolymer in our hospital from 2005-2008 were retrospectively reviewed. None of these patients had prior embolization. Complications were classified as transient neurologic deficits, persistent neurologic deficits, and death. Univariate and multivariate analyses were conducted to assess the angiographic features in patients with and without complications. Twenty-three complications occurred in 130 embolization procedures, 13 (10%) were transient neurologic deficits (9 ischemic and 4 hemorrhagic), 9 (6.92%) were persistent neurologic deficits (7 ischemic and 2 hemorrhagic), and 1 death occurred. By univariate analyses, eloquent cortex (OR, 2.57; 95% CI, 1.08-3.42) and exclusive deep venous drainage (OR, 4.56; 95% CI, 1.28-9.67) were correlated with procedural complications. The impaction of eloquent cortical location (P = .001) and exclusive deep venous drainage (P = .035) on complications were also demonstrated by multivariate analysis. Eloquent cortex mainly resulted in permanent ischemic neurologic deficit; occlusion of drainage vein was significantly correlated with periprocedural hemorrhage in supratentorial brain AVMs with subtotal and partial embolization. In a retrospective study on supratentorial brain AVMs with first-time embolization, 6.92% of patients had permanent neurologic deficit or death. Eloquent cortical location and exclusive deep venous drainage were associated with complications.


Relevance of the c-statistic when evaluating risk-adjustment models in surgery.
The measurement of hospital quality based on outcomes requires risk adjustment. The c-statistic is a popular tool used to judge model performance, but can be limited, particularly when evaluating specific operations in focused populations. Our objectives were to examine the interpretation and relevance of the c-statistic when used in models with increasingly similar case mix and to consider an alternative perspective on model calibration based on a graphical depiction of model fit. From the American College of Surgeons National Surgical Quality Improvement Program (2008-2009), patients were identified who underwent a general surgery procedure, and procedure groups were increasingly restricted: colorectal-all, colorectal-elective cases only, and colorectal-elective cancer cases only. Mortality and serious morbidity outcomes were evaluated using logistic regression-based risk adjustment, and model c-statistics and calibration curves were used to compare model performance. During the study period, 323,427 general, 47,605 colorectal-all, 39,860 colorectal-elective, and 21,680 colorectal cancer patients were studied. Mortality ranged from 1.0% in general surgery to 4.1% in the colorectal-all group, and serious morbidity ranged from 3.9% in general surgery to 12.4% in the colorectal-all procedural group. As case mix was restricted, c-statistics progressively declined from the general to the colorectal cancer surgery cohorts for both mortality and serious morbidity (mortality: 0.949 to 0.866; serious morbidity: 0.861 to 0.668). Calibration was evaluated graphically by examining predicted vs observed number of events over risk deciles. For both mortality and serious morbidity, there was no qualitative difference in calibration identified between the procedure groups. In the present study, we demonstrate how the c-statistic can become less informative and, in certain circumstances, can lead to incorrect model-based conclusions, as case mix is restricted and patients become more homogenous. Although it remains an important tool, caution is advised when the c-statistic is advanced as the sole measure of a model performance.


Postnatal development of rat vocal folds.
In this study we aimed to determine the feasibility of using a rat model for the study of postnatal vocal fold (VF) development. Eighteen male rats that were 3 days old, 3 weeks old, or 8 months old were analyzed histologically with Alcian blue stain used for detecting hyaluronic acid, elastin-van Gieson stain for elastin, Oil Red O and gold chloride stains for vitamin A-containing lipid droplets, and immunohistochemistry for vimentin (general fibroblast marker) and collagen types I and III. The macula flava (MF) was observed as a mass of cells that expressed vimentin intensively in the cytoplasm. The MF showed denser hyaluronic acid and collagen type I than did the midmembranous portion of the VF lamina propria. Clear developmental changes were evident in the MF and other regions. The vimentin-positive cells of the 3-day-old MF were mainly oval-shaped and had less cytoplasm, whereas those of the 8-month-old MF were spindle- and stellate-shaped and had more cytoplasm, similar to that reported in humans. Vitamin A-containing lipid droplets were limited to the 3-week-old and 8-month-old MFs and were not present in the 3-day-old VF. These results suggest that a rat model is useful in studying VF development and that vitamin A is related to the maturity of the VF.


Vibrational Profiling of Brain Tumors and Cells.
This study reports vibration profiles of neuronal cells and tissues as well as brain tumor and neocortical specimens. A contact-free method and analysis protocol was designed to convert an atomic force microscope into an ultra-sensitive microphone with capacity to record and listen to live biological samples. A frequency of 3.4 Hz was observed for both cultured rat hippocampal neurons and tissues and vibration could be modulated pharmacologically. Malignant astrocytoma tissue samples obtained from operating room, transported in artificial cerebrospinal fluid, and tested within an hour, vibrated with a much different frequency profile and amplitude, compared to meningioma or lateral temporal cortex providing a quantifiable measurement to accurately distinguish the three tissues in real-time. Vibration signals were converted to audible sound waves by frequency modulation, thus demonstrating, acoustic patterns unique to meningioma, malignant astrocytoma and neocortex.


Effects of natural antimicrobials on bacterial cell hydrophobicity, adhesion, and zeta potential.
Interactions between bacterial cells and contact materials play an important role in food safety and technology. As bacterial strains become ever more resistant to antibiotics, the aim of this study was to analyse adhesion of selected foodborne bacterial strains on polystyrene surface and to evaluate the effects of natural antimicrobials on bacterial cell hydrophobicity, adhesion, and zeta potential as strategies of adhesion prevention. The results showed strain-specific adhesion rate on polystyrene. The lowest and the highest adhesion were found for two B. cereus lines. Natural antimicrobials ferulic and rosmarinic acid substantially decreased adhesion, whereas the effect of epigallocatechin gallate was neglectful. Similar results were found for the zeta potential, indicating that natural antimicrobials reduce bacterial adhesion. Targeting bacterial adhesion using natural extracts we can eliminate potential infection at an early stage. Future experimental studies should focus on situations that are as close to industrial conditions as possible.


Effect of mitoxantrone on proliferation dynamics and cell-cycle progression.
MTX (mitoxantrone), an anti-tumour antibiotic, is known to cause cell death by intercalating the DNA bases. But how it interferes with the cellular proliferation is not well known. Hence, in the present study, we have tried to evaluate the interaction of this drug using proliferation dynamics to gain a better understanding of MTX's antineoplastic action. Inhibition of proliferation by these drugs was detected by evaluating its effect on cell proliferation and growth curve of the cells. MTX was also found to affect the cell viability and, thereby, cell physiology. Typical apoptotic morphologies such as condensation of nuclei and membrane permeabilization were observed through CLSM (confocal laser scanning microscopy) and fluorescence spectroscopy, which implicates commitment to cell death. Cell-cycle distribution was measured by flow cytometric measurements. The analysis demonstrated significant cell-cycle arrest on MTX treatment. Inhibition of lacZ gene expression was also observed on drug treatment, which implicates its interaction with gene expression.


Phosphate-limited growth of the marine diatom Thalassiosira weissflogii (Bacillariophyceae): evidence of non-monod growth kinetics(1).
The marine diatom Thalassiosira weissflogii (Grunow) G. A. Fryxell & Hasle was grown in a chemostat over a series of phosphate-limited growth rates. Ambient substrate concentrations were determined from bioassays involving picomolar spikes of (33) P-labeled phosphate, and maximum uptake rates were determined from analogous bioassays that included the addition of micromolar concentrations of unlabeled phosphate and tracer concentrations of (33) P. The relationship between cell phosphorus quotas and growth rates was well described by the Droop equation. Maximum uptake rates of phosphate spikes were several orders of magnitude higher than steady state uptake rates. Despite the large size of the T. weissflogii cells, diffusion of phosphate through the boundary layer around the cells had little effect on growth kinetics, in part because the cellular N:P ratios exceeded the Redfield ratio at all growth rates. Fitting the Monod equation to the experimental data produced an estimate of the nutrient-saturated growth rate that was ~50% greater than the maximum growth rate observed in batch culture. A modified hyperbolic equation with a curvature that is a maximum in magnitude at positive growth rates gave a better fit to the data and an estimate of the maximum growth rate that was consistent with observations. The failure of the Monod equation to describe the data may reflect a transition from substrate to co-substrate limitation and/or the presence of an inducible uptake system.


Late presentation of Pneumocystis jiroveci pneumonia after cardiac transplantation.
We report the case of a 64-year-old man who had received a heart transplant 9 years previously and was on long-term immunosuppression. He was referred to the intensive care unit of our district general hospital with acute respiratory distress and was diagnosed with community-acquired pneumonia. He was treated with antimicrobials, whose spectrum was extended empirically to cover Pneumocystis jiroveci, and respiratory support was provided with continuous positive airway pressure (CPAP). PCR analysis subsequently confirmed a diagnosis of pneumocystis pneumonia (PCP). Despite appropriate therapy the patient unfortunately died 8 days after admission to the unit. To the author's knowledge, this is the first report in the literature of such a late presentation of PCP after cardiac transplantation. We discuss current diagnostic and treatment strategies for PCP.


Acceptance model of a Hospital Information System.
The purpose of this study is to develop a model of Hospital Information System (HIS) user acceptance focusing on human, technological, and organizational characteristics for supporting government eHealth programs. This model was then tested to see which hospital type in Indonesia would benefit from the model to resolve problems related to HIS user acceptance. This study used qualitative and quantitative approaches with case studies at four privately owned hospitals and three government-owned hospitals, which are general hospitals in Indonesia. The respondents involved in this study are low-level and mid-level hospital management officers, doctors, nurses, and administrative staff who work at medical record, inpatient, outpatient, emergency, pharmacy, and information technology units. Data was processed using Structural Equation Modeling (SEM) and AMOS 21.0. The study concludes that non-technological factors, such as human characteristics (i.e. compatibility, information security expectancy, and self-efficacy), and organizational characteristics (i.e. management support, facilitating conditions, and user involvement) which have level of significance of p<0.05, significantly influenced users' opinions of both the ease of use and the benefits of the HIS. This study found that different factors may affect the acceptance of each user in each type of hospital regarding the use of HIS. Finally, this model is best suited for government-owned hospitals. Based on the results of this study, hospital management and IT developers should have more understanding on the non-technological factors to better plan for HIS implementation. Support from management is critical to the sustainability of HIS implementation to ensure HIS is easy to use and provides benefits to the users as well as hospitals. Finally, this study could assist hospital management and IT developers, as well as researchers, to understand the obstacles faced by hospitals in implementing HIS.


Effect Neonatal Ketamine Treatment on Exploratory and Anxiety-like Behaviours in Adulthood.
In this study, we evaluated the effect of neonatal ketamine exposure on anxiety-like and exploratory behaviours in adult the Balb/c and C57BL/6 strains of mice which anxiety responses are different. Ketamine was administered at two different doses single dose (10, 20 mg/kg, 0.1 ml/10 g body weight, intraperitoneally) and repeated doses (10, 20 mg/kg every 240 minutes; thrice times) on the 7th postnatal day to male Balb/c and C57BL/6 mice. In adulthood, open-field (OF) and elevated plus maze (EPM) apparatuses were used to evaluate exploratory and anxiety-like behaviour. In the C57BL/6 mice, the 20 mg/kg single dose decreased open-arm time and total-arm entries in EPM and increased time of central latency and decreased distance travelled in OF. Both the 10 and 20 mg/kg repetitive doses increased time of central latency and decreased time spent in the centre, frequency of rearing and centre crossing in OF and decreased open-arm time, total-arm entries, number of open-arm entries in EPM. The 20 mg/kg repetitive dose decreased number of head dipping behaviours in EPM. In the Balb/c mice, both the single and repetitive 10-20 mg/kg doses had no significant effect on anxiety-like and exploratory behaviours. There were no significant differences in anxiety-like and exploratory behaviour in different strains by the single 10 mg/kg dose. However, in the C57BL/6 mice, both the single and repetitive 20 mg/kg doses and the 10 mg/kg repetitive dose increased anxiety-like behaviour and decreased exploratory behaviour in EPM and OF. In conclusion, hereditary factors may be effective on the effect of neonatal ketamine treatment on anxiety-like and exploratory behaviour.


New tobacco products, old advertising strategies: point-of-sale advertising in Guatemala.
Capsule cigarettes, electronic cigarettes (e-cigarettes) and heated tobacco products (HTPs) are now readily available in Guatemala. As in most countries, the point-of-sale (POS) remains an important marketing channel for the tobacco industry. Therefore, we sought to characterise the POS marketing of these products in the two largest cities in Guatemala. Convenience stores were randomly surveyed in mid and high socioeconomic status (SES) neighbourhoods in Guatemala City (n=60) and Quetzaltenango (n=15) in 2019. We adapted a previously implemented checklist to assess the availability of interior advertising of capsule cigarettes, e-cigarettes and HTP. Data entry was done in Kobo toolbox and analysis in STATA. All stores sold conventional and flavoured capsule cigarettes, 78% e-cigarettes and 68% HTP. Most cigarette advertising was for capsule cigarettes. E-cigarettes were more likely to be sold in Guatemala City (96%) than in Quetzaltenango (13%). HTPs were only found in Guatemala City (85%), with no difference between high and medium SES neighbourhoods. Median number of ads for cigarettes and capsule cigarettes was higher in the high SES neighbourhood. Most e-cigarettes (83%) and HTP (74%) were found <50 cm from candy. E-cigarettes and HTP were available in a wide range of flavours. All stores that sold HTP had flavoured HEETS (amber, bronze, turquoise, yellow, blue and purple). We found a high prevalence of advertising for capsule cigarettes, e-cigarettes and HTP at the POS. The POS, a crucial advertising channel for the tobacco industry, is now being used for new products and therefore needs to be urgently regulated.


[Atypical course of a multiple acyl-CoA-dehydrogenase deficiency].
In a female newborn presenting with rapid metabolic deterioration (hypoketotic hypoglycaemia and acidosis) clinically accompanied by a "sweaty feet"-odour, the excretion pattern of organic acids in the urine suggested on the fourth day of live multiple acyl-CoA-dehydrogenase-deficiency, a potentially lethal autosomal-recessively inherited inborn error of fatty acid beta-oxidation and of the metabolism of certain amino acids. Diagnosis was confirmed by tandem-mass-spectrometry of acyl-carnitines in blood. Despite the poor prognosis of neonatal-onset multiple acyl-CoA-dehydrogenase-deficiency, treatment with carnitine, riboflavine, and a high-energy diet low in fat and high in carbonhydrates resulted in clinical stabilization. The infant survived various infection-associated decompensations and developed satisfyingly up to the age of 15 months, when another metabolic crisis resulted in multiorgan failure and death. Patients with neonatal-presenting multiple acyl-CoA-dehydrogenase-deficiency but without severe malformations may survive the first months of life. Tandem mass-spectrometry is a suitable tool to differentiate between multiple acyl-CoA-dehydrogenase-deficiency and other defects of fatty acid beta-oxidation.


Vitamin D receptor gene polymorphisms have negligible effect on human height.
Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult individuals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a sample of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1,521] polymorphisms). We genotyped large Caucasian samples from Australia (N = 3,906) and the Netherlands (N = 1,689) for polymorphisms in VDR. The Australian samples were twin families with height measures from 3 time points throughout adolescence. The Dutch samples were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3 cm) to the effect observed in the published adult meta-analysis. An effect of this size explains approximately 0.1% of the phenotypic variance in height - this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.


EEG Source Analysis with a Convolutional Neural Network and Finite Element Analysis.
To reconstruct the electrophysiological activity of brain responses, source analysis is performed through the solution of the forward and inverse problems. The former contains a unique solution while the latter is ill-posed. In this regard, many algorithms have been suggested relying on different prior information for solving the inverse problem. Recently, neural networks have been used to deal with source analysis. However, their underlying training for inverse solutions is based on suboptimal forward modeling. In this work, we propose a CNN that is able to reconstruct EEG brain activity. To train our proposed CNN, a skull-conductivity calibrated and white matter anisotropic head model. Based on this model, we generate simulated EEG data and used them to train our CNN. We first evaluate the performance of our CNN using the simulated EEG data while a realistic application with somatosensory evoked potentials follows. From the results, we observed that the CCN correctly localized the P20/N20 component at the subject-specific Brodmann area 3b and it can potentially localize deeper sources. A comparison is also presented with well-known inverse solutions (single dipole scans and sLORETA) showing similar localization performance. Through these results, an emerging potential for real applications appears on the basis of realistic head modeling.


The cellulase of Penicillium pinophilum. Synergism between enzyme components in solubilizing cellulose with special reference to the involvement of two immunologically distinct cellobiohydrolases.
Two immunologically unrelated cellobiohydrolases (I and II), isolated from the extracellular cellulase system elaborated by the fungus Penicillum pinophilum, acted in synergism to solubilize the microcrystalline cellulose Avicel; the ratio of the two enzymes for maximum rate of attack was approx. 1:1. A hypothesis to explain the phenomenon of synergism between two endwise-acting cellobiohydrolases is presented. It is suggested that the cellobiohydrolases may be two stereospecific enzymes concerned with the hydrolysis of the two different configurations of non-reducing end groups that would exist in cellulose. Only one type of cellobiohydrolase has been isolated so far from the cellulases of the fungi Fusarium solani and Trichoderma koningii. Only cellobiohydrolase II of P. pinophilum acted synergistically with the cellobiohydrolase of the fungi T. koningii or F. solani to solubilize Avicel. Cellobiohydrolase II showed no capacity for co-operating with the endo-1,4-beta-glucanase of T. koningii or F. solani to solubilize crystalline cellulose, but cellobiohydrolase I did. These results are discussed in the context of the hypothesis presented.


Comparison of diagnostic accuracy of current left bundle branch block and ventricular pacing ECG criteria for detection of occlusion myocardial infarction.
Electrocardiographic detection of patients with occlusion myocardial infarction (OMI) can be difficult in patients with left bundle branch block (LBBB) or ventricular paced rhythm (VPR) and several ECG criteria for the detection of OMI in LBBB/VPR exist. Most recently, the Barcelona criteria, which includes concordant ST deviation and discordant ST deviation in leads with low R/S amplitudes, showed superior diagnostic accuracy but has not been validated externally. We aimed to describe the diagnostic accuracy of four available ECG criteria for OMI detection in patients with LBBB/VPR at the emergency department. The unweighted Sgarbossa criteria, the modified Sgarbossa criteria (MSC), the Barcelona criteria and the Selvester criteria were applied to chest pain patients with LBBB or VPR in a prospectively acquired database from five emergency departments. In total, 623 patients were included, among which 441 (71%) had LBBB and 182 (29%) had VPR. Among these, 82 (13%) patients were diagnosed with AMI, and an OMI was identified in 15 (2.4%) cases. Sensitivity/specificity of the original unweighted Sgarbossa criteria were 26.7/86.2%, for MSC 60.0/86.0%, for Barcelona criteria 53.3/82.2%, and for Selvester criteria 46.7/88.3%. In this setting with low prevalence of OMI, positive predictive values were low (Sgarbossa: 4.6%; MSC: 9.4%; Barcelona criteria: 6.9%; Selvester criteria: 9.0%) and negative predictive values were high (all >98.0%). Our results suggests that ECG criteria alone are insufficient in predicting presence of OMI in an ED setting with low prevalence of OMI, and the search for better rapid diagnostic instruments in this setting should continue.


Evaluation of outcomes of a medication therapy management program for patients with diabetes.
To measure the impact of an employer-sponsored, pharmacist-provided medication therapy management (MTM) program on clinical outcomes and social and process measures for patients with diabetes with or without associated comorbid conditions. Prospective longitudinal study that took place at seven independent pharmacies in Lucas County, OH. A total of 228 patients with diabetes were enrolled. At 6-month intervals, patients were counseled by their pharmacists. Outcome measures included clinical outcomes (glycosylated hemoglobin [A1C], systolic blood pressure (SBP), and diastolic blood pressure [DBP]), social measures (caffeine intake, alcohol consumption, smoking, and exercise), and process measures (visits to ophthalmologist, podiatrist, and dentist). Wilcoxon signed-rank test and percentages were used to report findings. Mean (± SD) A1C concentration decreased from 7.08 ± 1.54% to 6.89 ± 1.30% at 12 months. Patients with A1C levels greater than 7% at baseline averaged a decrease of 0.5% at 6 months and 0.75% at 12 months. Mean SBP values decreased significantly from baseline to 12 months. A total of 87 patients with a baseline SBP greater than 130 mm Hg experienced a significant change in blood pressure from baseline to 6 months (-7.1 ± 3.32 mm Hg), and 65 patients experienced a significant change in blood pressure from baseline to 12 months (-11.49 ± 0.15 mm Hg). A total of 104 patients with a baseline DBP more than 80 mm Hg experienced a significant decrease of 4.44 ± 1.25 mm Hg at 6 months. Caffeine and alcohol consumption and smoking decreased and exercise increased. In addition, the percentage of patients who visited specialists increased. Patients with diabetes experienced improvements in multiple clinical, social, and process measures.


Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.
Systemic sclerosis–associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis–related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function. We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis–related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance×compliance product. RV pressure–volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of RV load (arterial elastance [Ea]), and RV pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0±4.5 versus 7.9±4.3 Wood units; Ea=0.9±0.4 versus 1.2±0.5 mm Hg/mL; pulmonary arterial compliance=2.4±1.5 versus 1.7±1.1 mL/mm Hg; P>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (Ees=0.8±0.3 versus 2.3±1.1, P<0.01; Msw=21±11 versus 45±16, P=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 versus 2.1±1.0; P=0.03). This ratio was higher in SSc without PH (Ees/Ea=2.3±1.2; P=0.02 versus SScPAH). RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading.


Antibody repertoire profiling using bacterial display identifies reactivity signatures of celiac disease.
A general strategy to identify serum antibody specificities associated with a given disease state and peptide reagents for their detection was developed using bacterial display peptide libraries and multiparameter flow cytometry (MPFC). Using sera from patients with celiac disease (CD) (n = 45) or healthy subjects (n = 40), bacterial display libraries were screened for peptides that react specifically with antibodies from CD patients and not with those from healthy patients. The libraries were screened for peptides that simultaneously cross-react with CD patient antibodies present in two separate patient groups labeled with spectrally distinct fluorophores but do not react with unlabeled non-CD antibodies, thus affording a quantitative separation. A panel of six unique peptide sequences yielded 85% sensitivity and 91% specificity (AUC = 0.91) on a set of 60 samples not used for discovery, using leave-one-out cross-validation. Individual peptides were dissimilar with known CD-specific antigens tissue transglutaminase (tTG) and deamidated gliadin, and the classifier accuracy was independent of anti-tTG antibody titer. These results demonstrate that bacterial display/MPFC provides a highly effective tool for the unbiased discovery of disease-associated antibody specificities and peptide reagents for their detection that may have broad utility for diagnostic development.