Transmyocardial revascularization induces mesenchymal stem cell engraftment in infarcted hearts.
Transmyocardial revascularization (TMR) prior to mesenchymal stem cell (MSC) transplantation augments repair of infarcted hearts. We evaluated the effects of TMR on homing and engraftment of circulating MSCs and mediators of this effect. Three weeks after left anterior descending coronary artery ligation in female rats, 10-channel needle TMR was performed in the infarct, followed by daily intravenous injections of 1 million male MSCs for 5 days. Control rats had MSC infusions without TMR (n=16/group). Donor MSC survival was evaluated at 3 days and at 1 week by quantitative polymerase chain reaction, as well as expression of stem cell factor (SCF), stromal derived factor-1 (SDF-1), c-kit, and chemokine receptor type 4 (CXCR4). The MSCs engrafted into the infarct, clustering around TMR channels. The MSC engraftment was greater in TMR hearts at 3 days and at 1 week. Both SCF (p=0.03) and c-kit (p=0.01) were upregulated by TMR at 3 days, but their levels fell at 1 week (p=0.3, p=0.5, respectively). The SDF-1 levels were higher in TMR hearts at both 3 days (p=0.04) and at 1 week (p=0.04). The CXCR4 was upregulated early by TMR (p=0.0002) but levels dropped dramatically at 1 week (p=0.045). Transmyocardial revascularization induces transmigration and engraftment of circulating MSCs. Post TMR, the transcription of SCF and c-kit is rapid and corresponds temporally to MSC engraftment, while SDF-1 levels rise slowly. The CXCR4 is also transiently upregulated. The TMR-augmented repair of infarcted hearts by stem cell transplantation may be mediated by a novel mechanism: transmigration and engraftment of circulating progenitor cells.


Ruthenium oxide based microelectrode arrays for in vitro and in vivo neural recording and stimulation.
We have characterized the in vitro and in vivo extracellular neural recording and stimulation properties of ruthenium oxide (RuOx) based microelectrodes. Cytotoxicity and functional neurotoxicity assays were carried out to confirm the in vitro biocompatibility of RuOx. Material extract assays, in accordance to ISO protocol "10993-5: Biological evaluation of medical devices", revealed no significant effect on neuronal cell viability or the functional activity of cortical networks. In vitro microelectrode arrays (MEAs), with indium tin oxide (ITO) sites modified with sputtered iridium oxide (IrOx) and RuOx in a single array, were developed for a direct comparison of electrochemical and recording performance of RuOx to ITO and IrOx deposited microelectrode sites. The impedance of the RuOx-coated electrodes measured by electrochemical impedance spectroscopy was notably lower than that of ITO electrodes, resulting in robust extracellular recordings from cortical networks in vitro. We found comparable signal-to-noise ratios (SNRs) for RuOx and IrOx, both significantly higher than the SNR for ITO. RuOx-based MEAs were also fabricated and implanted in the rat motor cortex to demonstrate manufacturability of the RuOx processing and acute recording capabilities in vivo. We observed single-unit extracellular action potentials with a SNR >22, representing a first step for neurophysiological recordings in vivo with RuOx based microelectrodes. STATEMENT OF SIGNIFICANCE: A critical challenge in neural interface technology is the development of microelectrodes that have recording and electrical stimulation capabilities suitable for bidirectional communication between the external electronic device and the nervous system. The present study explores the feasibility and functional capabilities of ruthenium oxide microelectrodes as a neural interface. Significant improvement in electrochemical properties and neuronal recordings are reported when compared to commercially available indium tin oxide and was similar to that of iridium oxide electrodes. The data demonstrate the potential for future development of chronic neural interfaces using ruthenium oxide based microelectrodes for recording and stimulation.


Targeted Modulation of Human Brain Interregional Effective Connectivity With Spike-Timing Dependent Plasticity.
The ability to selectively up- or downregulate interregional brain connectivity would be useful for research and clinical purposes. Toward this aim, cortico-cortical paired associative stimulation (ccPAS) protocols have been developed in which two areas are repeatedly stimulated with a millisecond-level asynchrony. However, ccPAS results in humans using bifocal transcranial magnetic stimulation (TMS) have been variable, and the mechanisms remain unproven. In this study, our goal was to test whether ccPAS mechanism is spike-timing-dependent plasticity (STDP). Eleven healthy participants received ccPAS to the left primary motor cortex (M1) → right M1 with three different asynchronies (5 milliseconds shorter, equal to, or 5 milliseconds longer than the 9-millisecond transcallosal conduction delay) in separate sessions. To observe the neurophysiological effects, single-pulse TMS was delivered to the left M1 before and after ccPAS while cortico-cortical evoked responses were extracted from the contralateral M1 using source-resolved electroencephalography. Consistent with STDP mechanisms, the effects on synaptic strengths flipped depending on the asynchrony. Further implicating STDP, control experiments suggested that the effects were unidirectional and selective to the targeted connection. The results support the idea that ccPAS induces STDP and may selectively up- or downregulate effective connectivity between targeted regions in the human brain.


A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA.
The recalcitrance of many bacterial infections to antibiotic treatment is thought to be due to the presence of persisters that are non-growing, antibiotic-insensitive cells. Eventually, persisters resume growth, accounting for relapses of infection. Salmonella is an important pathogen that causes disease through its ability to survive inside macrophages. After macrophage phagocytosis, a significant proportion of the Salmonella population forms non-growing persisters through the action of toxin-antitoxin modules. Here we reveal that one such toxin, TacT, is an acetyltransferase that blocks the primary amine group of amino acids on charged tRNA molecules, thereby inhibiting translation and promoting persister formation. Furthermore, we report the crystal structure of TacT and note unique structural features, including two positively charged surface patches that are essential for toxicity. Finally, we identify a detoxifying mechanism in Salmonella wherein peptidyl-tRNA hydrolase counteracts TacT-dependent growth arrest, explaining how bacterial persisters can resume growth.


Mechanisms of Surveillance of Dendritic Cells by Regulatory T Lymphocytes.
Regulatory T cells (Tregs) are critical to maintain the homeostasis of the organism, i.e., to prevent (excessive) inflammatory reactions against self and nonself. Data in the literature suggest that a variety of suppressive mechanisms exist that may act selectively depending on the tissue environment. An interesting question is whether dendritic cells (DCs), which are involved in immunity and tolerance, are targets of Tregs. We review herein some experimental evidence indicating that some suppressive mechanisms involve DCs, altering their function and inducing an immune control at the very first step of the immune response.


Reduced blood glucose levels, increased insulin levels and improved glucose tolerance in alpha2A-adrenoceptor knockout mice.
Alpha(2)-Adrenoceptors regulate insulin secretion and sympathetic output. In the present study, alpha(2A)-adrenoceptor knockout (alpha(2A)-KO) mice and their C57BL/6J wild-type (WT) controls were used to assess the glucoregulatory role of the alpha(2A)-adrenoceptor subtype in vivo. Fasting and glucose-stimulated blood glucose and plasma insulin levels were determined with or without (+/-)-propranolol (5 mg/kg) or atropine (10 mg/kg) pre-treatment. Intraperitoneal glucose (1 g/kg) and insulin (0.5 and 1.0 IU/kg) tolerance tests were performed. Fasting plasma glucagon and corticosterone levels were measured. Blood glucose levels (mean+/-S.E.M.) were lower in alpha(2A)-KO males (7.2+/-0.6 mM) and females (7.2+/-0.2 mM) than in WT males (9.8+/-0.3 mM) and females (9.1+/-0.3 mM). Plasma insulin levels were higher in alpha(2A)-KO males (2.2+/-0.5 microg/l) and females (1.7+/-0.3 microg/l) than in WT males (0.7+/-0.1 microg/l) and females (0.8+/-0.2 microg/l). These differences remained after pharmacological beta-adrenoceptor and muscarinic acetylcholine receptor inhibition. In spite of a tendency for slightly decreased insulin sensitivity in alpha(2A)-KO mice, glucose tolerance in alpha(2A)-KO mice was significantly better than in WT mice. However, glucose-stimulated insulin secretion was not increased in alpha(2A)-KO mice compared to WT controls. Plasma glucagon levels, but not corticosterone levels, were elevated in alpha(2A)-KO mice. These results suggest that lack of inhibitory pancreatic beta-cell alpha(2A)-adrenoceptor function results in hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance in alpha(2A)-KO mice, and demonstrate a key role for the alpha(2A)-adrenoceptor in adrenergic regulation of blood glucose and insulin homeostasis.


Correction to: Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort.
In the original publication of the article, the funding statement was published incompletely. The corrected funding statement should read as below.


Stable E rosette-forming lymphocytes in the peripheral blood in non-Hodgkin's lymphoma.
The peripheral blood of 49 patients with non-Hodgkin's lymphoma and the same number of normal controls was examined for the presence of lymphocytes forming rosettes with sheep erythrocytes at 37 degrees C (stable E rosettes). Nineteen lymphoma patients but only five normal controls showed increased absolute levels. (P less than 0.01). There was no correlation between the occurrence of increased Stable E Rosette levels and the histological type of lymphoma but there appears to be a positive relationship with the presence of clinical stage III-IV disease at presentation (P = 0.011). It is suggested that stable E rosettes represent an immunological response to residual lymphoma in our patients. A longitudinal study in one patient is reported in detail to demonstrate the occurrence of fluctuations in stable E rosette levels coinciding with clinical changes.


Progress against childhood and adolescent acute lymphoblastic leukaemia in the Netherlands, 1990-2015.
We assessed the epidemiologic progress against childhood and adolescent acute lymphoblastic leukaemia (ALL) in the Netherlands over a 26 year period. ALL patients <18 years were selected from the Netherlands Cancer Registry and the Dutch Childhood Oncology Group. Trend analyses were performed over time and by age group and ALL subtype. Between 1990 and 2015, 2997 ALL patients were diagnosed, i.e. 115 patients (range 87-147) per year. Overall incidence remained stable at 37 per million children, despite increases for B-cell precursor ALL (BCP-ALL) at age 10-14 years (AAPC + 1.4%, p = 0.04) and T-cell ALL at 15-17 years (AAPC + 3.7%, p = 0.01). Five-year survival increased from 80% in 1990-94 to 91% in 2010-15 (p < 0.01). Mortality decreased by 4% annually (p < 0.01). Patients 15-17 years were increasingly treated in a paediatric oncology centre, from 35% in 1990-94 to 87% in 2010-15 and experienced a 70% reduction of risk of death compared to those treated outside such a centre (p < 0.01). Significant progress against childhood ALL has been made in the Netherlands, visible by improved survival rates coinciding with declining mortality rates. These outcomes were accompanied by stable incidence rates, despite increases for BCP-ALL at age 10-14 years and T-cell ALL at age 15-17 years.


The global extrapolation of numerical methods for computing concentration profiles in percutaneous drug absorption.
A family of numerical methods is developed and analyzed for the numerical solution of the parabolic partial differential equation together with the associated initial and boundary conditions, which arise in a mathematical model of the transient stage of percutaneous drug absorption. Two global extrapolation procedures are described, the first in time only, the second in both space and time, for improving the accuracy of the computed concentration profiles. The behaviours of two members of the family of methods, before and after extrapolation, are examined by repeating a number of experiments reported in the literature. Modifications to the algorithms, which are necessary in computing concentration profiles after the ointment is removed at the steady state, are outlined.


The past and the future of experimental gerontology.
This paper is based on a lecture on the history and the perspectives of experimental gerontology at the symposium in Nürnberg on the occasion of the 10th year jubilee of the Institute of Gerontology of the University of Erlangen. The discussion links the studies and ideas of the founders of gerontology as an interdisciplinary science (Metchnikoff, Korenchevsky, Bogomolets, Verzár) with some modern trends in experimental gerontology and ageing-related fields of biotechnology.


The projection of the calcified pineal gland on slightly rotated AP films as a reliable landmark. A CT study.
The projection of the pineal gland between the two outer tables of the skull in the AP film has been reconstructed on the basis of the CT print of the head, with and without lateral rotation. In this experimental approach it is proven that rotation up to 5 degrees does not influence the position of the pineal gland on the AP film. The range of the normal position of the pineal in the frontal plane is defined and the normal distribution is given.


Implications of Universal Autism Screening: Perspectives From Culturally Diverse Families With False-Positive Screens.
The American Academy of Pediatrics (AAP) recommends that pediatricians screen all young children for autism spectrum disorder (ASD). However, the US Preventive Services Task Force stated that there is insufficient evidence about the potential harms and benefits of universal ASD screening. To address this gap, we conducted qualitative interviews with caregivers of children who received a false-positive ASD screen to learn about families' perceptions of the harms and benefits of universal ASD screening. Culturally diverse caregivers (N = 26) of children with false-positive ASD screens completed qualitative interviews focused on parents' experiences with and recommendations to improve the ASD screening and evaluation process. Interviews were transcribed verbatim, coded, and analyzed using applied thematic analysis. Parents explained that the ASD screening and evaluation process increased their knowledge about child development and substantiated existing concerns. The ASD screening and evaluation process resulted in connecting their child to services, which parents felt led to improvements in their child's delays. Parents endorsed anxiety during wait times for the formal developmental assessment. However, all parents expressed that, if given the option, they would repeat the screening and evaluation process again. Caregivers recommended universal screening for ASD and suggested that screening extend beyond the pediatrician to other settings. From parents' perspectives, the connection to developmental services and increased knowledge of child development that resulted from the false-positive ASD screen outweighed the time-limited emotional distress triggered by a positive ASD screen. Overall, parents' preferences for universal ASD screening align with the AAP's recommendations.


A Metrics-Based Research Salary Award System and Its 9-Year Impact on Publication Productivity.
Although metrics-based systems may incentivize academic output, no prior studies have evaluated the impact on publication metrics in academic radiology. This study presents a metrics-based system of awarding research protected time, and retrospectively evaluates its 9-year impact on publication productivity and impact factor. Based on a metrics-based algorithm to award department funded Research Protected Time (RPT), metrics pre-RPT (2003-2009) and during the RPT period (2010-2018) from an academic radiology department were retrospectively analyzed to test the hypothesis that the RPT program resulted in higher publication productivity and journal impact factor at the departmental level and for faculty members receiving the award. Comparison was made between (1) pre-RPT and RPT periods and (2) during the RPT period, between RPT and non-RPT faculty members, for annual publication productivity normalized to faculty count (Student's t test) and median impact factor (Wilcoxon rank sum test). For the evaluation period of 2003-2018, 724 unique publications were identified: 15% (107/724) pre-RPT period and 85% (617/724) RPT period. Normalized annual publication productivity was higher during the RPT period compared to the Pre-RPT period (1.2 vs. 0.3, p = 0.002), and within the RPT period, higher among faculty who received RPT vs. non-RPT faculty (3.5 vs. 0.4, p = 0.002). Median impact factor was higher during the RPT period compared to pre-RPT period (2.843 vs. 2.322, p = 0.044), and within the RPT period, higher in RPT vs. non-RPT faculty (3.016 vs. 2.346, p < 0.001). The implementation of a metrics-based system of funded, research protected time, was associated with increased publication productivity and increased impact factor.


Chromosomal localization of two genes encoding human ras exchange factors: SOS1 maps to the 2p22-->p16 region and SOS2 to the 14q21-->q22 region of the human genome.
The human SOS1 and SOS2 genes encode proteins that control GDP-->GTP exchange on ras proteins and are involved in signal transduction by tyrosine kinase receptors. In situ hybridization shows that SOS1 maps to 2p22-->p16 and SOS2 to 14q21-->q22 in the human genome.


Effects of cyclic parenteral nutrition on parenteral-associated liver dysfunction parameters.
One of the most common complications of parenteral nutrition (PN) is liver dysfunction (LD). Therapeutic approaches for LD include, among others, administering cyclic parenteral nutrition (cPN), allowing some hours for metabolic rest. The purpose of this study was to evaluate the effectiveness of cPN in treating PN-associated LD. A retrospective observational study was carried out at the Costa del Sol Hospital in Spain between 2013 and 2014. The study involved inpatients ≥18 years old prescribed with cPN due to the development of PN-associated LD. The hepatic biochemical parameters measured at baseline and after completion of cPN included aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and total bilirubin (TB). Quantitative values (age, biochemical parameters) were compared using matched Student's t-test; the mean change in qualitative variables (sex, indication of PN, hepatic comorbidities, presence of insulin in cPN, infection during cPN, management of LD prior to cPN administrarion) was estimated using Mann-Whitney U test, and bivariate correlation between quantitative variables was determined by Spearman's coefficient of correlation. Thirty-seven patients met inclusion criteria. All hepatic function parameters except ALP improved after the administration of cPN, with statistically significant differences (p < 0.05) in AST GGT and TB. cPN improves PN-associated LD by restoring abnormal AST, GGT, and BT levels to normal, and reducing ALT levels close to normal. The results obtained suggest that the administration of cPN is effective in reverting PN-associated LD.


Dorsal Root Ganglion Stimulation for Chronic Postoperative Pain Following Thoracic Surgery: A Pilot Study.
Post-thoracotomy pain syndrome (PTPS) is defined as persistent pain following a thoracotomy and has an incidence of 21-61%. Dorsal root ganglion stimulation (DRG-S) is a form of neuromodulation that modulates pain signal transmission to the spinal cord. The aims of this study were to investigate the efficacy of DRG-S for the management of PTPS and to assess the role of thoracic paravertebral blocks (t-PVB) as a tool for prediction of success of DRG-S. In this prospective study, we included all patients undergoing thoracic surgery, with PTPS not responding to pharmacotherapy and treated with DRG-S from September 2018 to February 2019. t-PVB followed by a percutaneous DRG-S trial was performed on all patients. Pain intensity was assessed through a numeric rating scale (NRS) and Douleur Neuropathique en 4 Questions (DN4) at baseline, post-trial, at 14 days, 90 days, and at one year after DRG-S implantation. Data summarized as continuous variables were expressed as means and standard deviations (SDs), and categorical variables were expressed as raw numbers and percentages. Four patients out of 51 who underwent thoracic surgery at our institution surveyed were included (mean age ± SD, 56 ± 16 years old). Mean NRS and DN4 were, respectively, 7.2 ± 0.96 SD and 8.2 ± 0.5 SD at baseline, 2.5 ± 0.6 SD and 3.2 ± 0.5 SD after t-PVB, 2.2 ± 0.5 SD and 2.2 ± 0.5 SD at 14 days, 90 days, and at one year after DRG-S implantation. No complications or side effects were reported. Our preliminary results show that DRG-S is an effective therapy for PTPS after thoracic surgery. In addition, thoracic paravertebral blocks performed prior to DRG-S correlated with a positive outcome with treatment.


Structural changes in the temporal lobe and piriform cortex in frontal lobe epilepsy.
Neuronal networks involved in seizure generation, maintenance and spread of epileptic activity comprise cortico-subcortical circuits. Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common structures in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity. In this study, we aimed to identify common areas of structural abnormalities in patients with frontal lobe epilepsy (FLE). T1-weighted MRI scans of 43 FLE patients and 25 healthy controls were analysed using voxel based morphometry. Differences in regional grey matter volume were examined across the whole brain, and correlated with age at epilepsy onset, duration and frequency of seizures. We detected areas of increased grey matter volume in the piriform cortex, amygdala and parahippocampal gyrus bilaterally, as well as left mid temporal gyrus of patients relative to controls, which did not correlate with any of the clinical variables tested. No common areas of atrophy were detected across the FLE group. Structural abnormalities within the piriform cortex and adjacent structures of patients with FLE provide further evidence for the involvement of this area in the epileptogenic network of focal epilepsies. Lack of correlation with duration or age of onset of epilepsy suggests that this area of abnormality is not a consequence of seizure activity.


Improving cell distribution on 3D additive manufactured scaffolds through engineered seeding media density and viscosity.
In order to ensure the long-term in vitro and in vivo functionality of cell-seeded 3D scaffolds, an effective and reliable method to control cell seeding efficiency and distribution is crucial. Static seeding on 3D additive manufactured scaffolds made of synthetic polymers still remains challenging, as it often results in poor cell attachment, high cell sedimentation and non-uniform cell distribution, due to gravity and to the intrinsic macroporosity and surface chemical properties of the scaffolds. In this study, the biocompatible macromolecules dextran and Ficoll (Ficoll-Paque) were used for the first time as temporary supplements to alter the viscosity and density of the seeding media, respectively, and improve the static seeding output. The addition of these macromolecules drastically reduced the cell sedimentation velocities, allowing for homogeneous cell attachment to the scaffold filaments. Both dextran and Ficoll-Paque -based seeding methods supported human mesenchymal stromal cells viability and osteogenic differentiation post-seeding. Interestingly, the improved cell distribution led to increased matrix production and mineralization compared to scaffolds seeded by conventional static method. These results suggest a simple and universal method for an efficient seeding of 3D additive manufactured scaffolds, independent of their material and geometrical properties, and applicable for bone and various other tissue regeneration. STATEMENT OF SIGNIFICANCE: Additive manufacturing has emerged as one of the desired technologies to fabricate complex and patient-specific 3D scaffolds for bone regeneration. Along with the technology, new synthetic polymeric materials have been developed to meet processability requirements, as well as the mechanical properties and biocompatibility necessary for the application. Yet, there is still lack of methodology for a universal cell seeding method applicable to all additive manufactured 3D scaffolds regardless of their characteristics. We believe that our simple and reliable method, which is based on adjusting the cell settling velocity to aid cell attachment, could potentially help to maximize the efficiency, and therefore, functionality of cell-seeded constructs. This is of great importance when aiming for both in vitro and future clinical applications.


Doppler sonography of vertebral arteries in patients with tinnitus.
The accuracy and the reliability of extracranial vertebral artery Doppler flow for the detection of the possible cause of the tinnitus was studied prospectively and Doppler findings were compared with controls. Vertebral artery measurements have been made in 28 patients (56 vertebral arteries) with tinnitus and 12 sex- and age-matched controls. Maximal flow velocity and mean flow velocity were measured and total vertebral artery flow was calculated by adding flows from the right and left sides. When compared with each other and controls, there was significant difference with respect to mean flow velocities of the right and left vertebral arteries in the patients with tinnitus (p < or = 0.05), and also total mean flow velocity between patients with tinnitus and controls (p < or = 0.05). It has been concluded that Doppler sonography gave useful information on the vertebral artery flow in patients with tinnitus.


Low FasL levels promote proliferation of human bone marrow-derived mesenchymal stem cells, higher levels inhibit their differentiation into adipocytes.
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can differentiate into several cell types. Bone marrow (BM)-MSCs mainly differentiate into osteoblasts or adipocytes. MSC interactions with their microenvironment directly affect their self-renewal/differentiation program. Here, we show for the first time that Fas ligand (FasL), a well-explored proapoptotic cytokine, can promote proliferation of BM-derived MSCs in vitro and inhibits their differentiation into adipocytes. BM-MSCs treated with a low FasL dose (0.5 ng/ml) proliferated more rapidly than untreated cells without undergoing spontaneous differentiation or apoptosis, whereas higher doses (25 ng/ml) induced significant though not massive BM-MSC death, with surviving cells maintaining a stem cell phenotype. At the molecular level, 0.5 ng/ml FasL induced ERK1/2 phosphorylation and survivin upregulation, whereas 25 ng/ml FasL induced caspase activation. Importantly, 25 ng/ml FasL reversibly prevented BM-MSC differentiation into adipocytes by modulating peroxisome proliferator-activated receptor gamma (PPARγ) and FABP4/aP2 expression induced by adipogenic medium. All such effects were inhibited by anti-Fas neutralizing antibody. The in vitro data regarding adipogenesis were confirmed using Fas(lpr) mutant mice, where higher PPARγ and FABP4/aP2 mRNA and protein levels were documented in whole tibia. These data show for the first time that the FasL/Fas system can have a role in BM-MSC biology via regulation of both proliferation and adipogenesis, and may have clinical relevance because circulating Fas/FasL levels decline with age and several age-related conditions, including osteoporosis, are characterized by adipocyte accumulation in BM.


Improved survival trend of patients with hepatocellular carcinoma at an Australian tertiary hospital between 1995-2009.
To evaluate trends in survival of patients with hepatocellular carcinoma (HCC) at The Alfred over a 15-year period from 1995-2009 A retrospective cohort study of patients with HCC comparing epidemiology, clinical presentation, treatment parameters and overall survival of those diagnosed between 1995-2001 and 2002-2009. Overall survival of patients with primary liver cancer. The study population consisted of 215 patients; 110 diagnosed between 1995-2001 (Cohort A) and 105 between 2002-2009 (Cohort B). Overall survival increased significantly between 1995-2010 (P = 0.016); median survival was 365 days in Cohort A compared with 665 in Cohort B. The improvement in survival was associated with an increase in the proportion of cases detected at an asymptomatic stage (P = 0.012), a decline in the severity of liver disease at diagnosis (P = 0.002) and increased utilisation of loco-regional therapy (P = 0.001) over the same period. Survival of patients detected through screening was significantly higher than those detected through non-screening methods (1309 vs 233 days, P < 0.001). The survival of patients with HCC managed at a tertiary referral centre has improved over the period 1995-2009. This improvement may relate to the increased detection of the disease at an asymptomatic stage (e.g. through screening) as well as increased utilisation of effective loco-regional therapies for HCC.


Importance of fundoscopy in refractive surgery.
To examine the incidence, treatment, and outcomes of retinal lesions before and after refractive laser surgery. Private refractive surgery practice. A retrospective review was conducted of patients attending the laser clinic over a 3-year period. Examined were the incidence, type, management, and outcomes of the posterior segment abnormalities encountered. Fifty two (1.1%) of 4800 patients had posterior segment pathology requiring intervention. Forty-five cases (0.86%) were detected preoperatively and had a mean refraction of -4.5 diopters (D) +/- 3.0 (SD). Seven cases (0.14%) were detected postoperatively at a mean follow-up of 19 +/- 18.3 months; none had preoperative pathology. The mean refraction in this group was -4.4 +/- 2.3 D. Ninety-five percent had myopic prescriptions. All maintained best corrected visual acuity postoperatively. The incidence of retinal detachment was 0.03% per year in the myopic candidates; however, no cases occurred after the refractive procedure. Dilated fundus examination is an integral part of optimum clinical care in refractive patients, and shared preoperative assessment by a retinal specialist is advisable in those with predisposing retinal pathology.


Photosynthetic electron-transfer reactions in the gametophyte of Pteris multifida reveal the presence of allelopathic interference from the invasive plant species Bidens pilosa.
To date, the response of the fern gametophyte to its environment has received considerable attention. However, studies on the influence of plant invasion on the fern gametophyte are fewer. Allelopathy has been hypothesized to play an important role in biological invasion. Hence, it is necessary to study the allelopathy of invasive plant species to the fern gametophyte and elucidate the mechanisms by which invasive plants cause phytotoxicity. As one of the main invasive plants in China, Bidens pilosa exhibits allelopathic effects on the gametophytic growth of Pteris multifida. The root exudate plays an important role among various allelochemical delivery mechanisms in B. pilosa. The effect invasive plant species has on photosynthesis in native species is poorly understood. To elucidate this effect, the changes in photosynthesis in the gametophytes of P. multifida are analyzed to examine the mechanisms of the root exudates of B. pilosa. Meanwhile, a non-invasive plant, Coreopsis basalis, was also applied to investigate the effects on fluorescence and pigments in P. multifida gametophytes. We found that gametophytes exposed to both B. pilosa and C. basalis had decreased fluorescence parameters in comparison with the control, except for non-photochemical quenching. Furthermore, it was found that these parameters were markedly affected from day 2 to day 10 in the presence of both exudates at a concentration of 25% or above. B. pilosa exudate had a negative dose-dependent effect on chlorophyll a, chlorophyll b, carotenoid, and the total chlorophyll in the gametophyte. The inhibitory effects increased with increasing exudate concentrations of both species, exhibiting the greatest inhibition at day 10. In conclusion, B. pilosa irreversibly affected the photosynthesis of P. multifida on both PS I and PS II. Root exudates caused the primary damage with respect to the decrease of the acceptors and donors of photon and electron in photosynthetic units and the production and the relative yield of photochemical quantum in PS II. With the effects of exudates, part of the energy is released as heat in chloroplasts. The comparison of invasive and non-invasive plants in allelopathic experiments demonstrated that invasive plants were responsible for the critical damage to the photosynthetic process in local species.


Serum complement factor 5a levels are associated with nonalcoholic fatty liver disease in obese children.
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of progressive and chronic liver injury. Complement factor 5a (C5a) may be involved in many inflammation disorders. This study investigated levels of systemic C5a in patients with and without NAFLD and lean controls. A cross-sectional study was conducted from July 2012 to June 2013 among 96 Chinese children, aged 6-17 years, recruited from the Pediatric Department of the Second Affiliated Hospital of Xi'an Jiao Tong University: 40 obese children with NAFLD, 31 obese children without NAFLD and 25 lean controls. Anthropometric parameters, clinical data and circulating C5a levels were measured. Obese children had higher serum concentrations of complement factor C5a compared with lean controls, especially in obese children with NAFLD. C5a was positively correlated with body mass index (BMI), waist circumference, diastolic blood pressure (BP), triglycerides and homoeostasis model of insulin resistance, independent of their body mass index standard deviations score and age. Of the well-known risk factors, C5a was a significant predictor of NAFLD in obese children. Serum C5a was elevated in obese children, especially in those with NAFLD and it may be proposed as a novel marker to predict advanced disease.


Astragalus polysaccharide combined with 10-hydroxycamptothecin inhibits metastasis in non-small cell lung carcinoma cell lines via the MAP4K3/mTOR signaling pathway.
Non‑small cell lung carcinoma (NSCLC) is a life‑threatening malignancy. The level of the cell growth regulator mitogen‑activated protein kinase kinase kinase kinase 3 (MAP4K3) has been shown to be correlated with a high risk of NSCLC recurrence and poor recurrence‑free survival rate. The present study examined the effects of Astragalus polysaccharide (APS) and 10‑hydroxycamptothecin (HCPT), which are associated with marked suppression and dephosphorylation of the MAP4K3/mammalian target of rapamycin (mTOR) signaling pathway, in the H1299 NSCLC cell line. APS and HCPT decreased H1299 cell viability, induced apoptosis and altered the cell cycle stages, as evaluated using an 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay and flow cytometric analysis. Furthermore, APS increased the expression of apoptosis‑associated genes B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (BAX), of proteases cysteine‑aspartic acid protease (caspase)‑3 and ‑9, and of cytochrome c. HCPT promoted autophagy in H1299 cells, with concomitant suppression of the expression of MAP4K3 and downregulation of mTOR signaling. Notably, combination treatment with the two agents reduced the migration and invasion of H1299 cells compared with the single treatments. It was also demonstrated that the overexpression of MAP4K3 promoted the migration and invasion of H1299 cells, and that the kinase activity was essential to this. These findings suggested that MAP4K3 may be an attractive target for the treatment of NSCLC.


Adolescent males involved in pregnancy: associations of forced sexual contact and risk behaviors.
To determine whether sexually active adolescent males who report being the victim of forced sexual contact and engaging in health risk and problem behaviors are more likely to report getting someone pregnant. In 1995, 4159 students in Grades 9-12 in 59 randomly selected public high schools in Massachusetts were anonymously surveyed using the Youth Risk Behavior Survey (YRBS). Data were analyzed for 824 sexually active males. Demographic variables and indicators of sexual behavior, pregnancy, violence, and suicide were assessed. Data were analyzed with multiple logistic regression. A total of 12.0% of sexually active males reported having been involved in a pregnancy. The proportion of males who reported getting a partner pregnant increased with age. Of the sample, 8.1% gave a history of having had sexual contact against their will. Of those who reported forced sexual contact, 36.4% reported having been involved in a pregnancy; of the males who did not report a history of forced sexual contact, 9.4% were involved in a pregnancy (CV = 0.23; p < 0.00001). Based on multiple logistic regression, forced sexual contact [odds ratio (OR) 3.56; 95% confidence interval (CI) 1.79-7.09], frequency of weapon carrying on school property (OR 1.39; 95% CI 1.18-1.64), number of cigarettes smoked per day (OR 1.22; 95% CI 1.08-1.38), number of sexual partners in the previous 3 months (OR 1.43; 95% CI 1.25-1.65), and condom nonuse at last intercourse (OR 1.80; 95% CI 1.06-3.02) correctly classified 89.9% of the males who were involved in a pregnancy. This study highlights the association between health-risk and problem behaviors, forced sexual contact, and involvement in pregnancy among sexually active male high school students. In our analysis, a history of forced sexual contact was associated with a higher risk of high school males' involvement in pregnancy. These results strongly suggest the importance of screening sexually active males for a history of forced sexual intercourse and health risk and problem behaviors in the effort to prevent teenage pregnancy and childbearing.


Proconvulsant effects of theophylline on hippocampal afterdischarges.
We tested the effects of the adenosine antagonist, theophylline, on electrically induced afterdischarges in the hippocampus of rats. Theophylline did not significantly alter the threshold for afterdischarge initiation or the duration of the initial afterdischarge. However, theophylline greatly prolonged the duration of secondary afterdischarges, and permitted generalization to motor seizures. Because theophylline antagonizes adenosine, and the hippocampus is a region rich in adenosine binding sites, we interpret these results to mean that endogenous adenosine has little action on focal seizure initiation, but a strong action to suppress secondary seizures and to inhibit seizure generalization.


Pulmonary hypertension is an independent predictor of cardiovascular events and mortality in haemodialysis patients.
The evidence about prevalence, associated factors of pulmonary hypertension (PH) and its impact on patient's outcomes is limited. We included 211 haemodialysis patients, we estimated the systolic pulmonary artery pressure (SPAP) by 2D Doppler echocardiography defining PH as a SPAP above 35 mmHg, the median follow-up was 39 (19-56) moths, and the primary endpoints were all cause mortality and cardiovascular events. We found PH in 91 patients (43.9%). Independent determinants of PH were age, previous cardiovascular disease, the Nt-pro-BNP level hs-TnT, the systolic dysfunction, diastolic dysfunction and left ventricular hypertrophy. Over the follow-up 94 cardiovascular events occurred, variables associated were: PH, age, history cardiovascular disease, dyslipidaemia, elevated concentration of Nt-pro-BNP and hs-TnT, systolic and diastolic dysfunction, in a multivariate model, the PH maintained its independent association. Mortality data: 88 patients died (41.7%); 35 (29.5%) in the no PH group and 53 (58.5%) in the PH group (P < 0.001). In the Cox survival analysis, we found an association between mortality and age, previous cardiovascular disease, history of peripheral vascular disease, Nt-pro-BNP levels. In a multivariate model the PH remains as independent predictor of mortality. Pulmonary hypertension is a common finding in HD patients and a valuable predictor of mortality and cardiovascular events. Prospective studies are needed to assess the effect of intervention on risk factors in improving patient's outcomes.


Challenges of students and residents of human medicine in the first four months of the fight against the Covid-19 pandemic - Implications for future waves and scenarios.
In the fight against the Covid-19 pandemic, medical students and residents are expected to adapt and contribute in a healthcare environment characterized by ever-changing measures and policies. The aim of this narrative review is to provide a summary of the literature that addresses the challenges of students and residents of human medicine in the first 4 months of the fight against the Covid-19 pandemic in order to identify gaps and find implications for improvement within the current situation and for potential future scenarios. We performed a systematic literature search and content analysis (CA) of articles available in English language that address the challenges of students and residents of human medicine in the first 4 months of the fight against the Covid-19 pandemic. We retrieved 82 articles from a wide range of journals, professional backgrounds and countries. CA identified five recurring subgroup topics: "faculty preparation", «uncertainties and mental health», «clinical knowledge», «rights and obligations» and «(self-) support and supply». Within these subgroups the main concerns of (re-)deployment, interruption of training and career, safety issues, transmission of disease, and restricted social interaction were identified as potential stressors that hold a risk for fatigue, loss of morale and burnout. Students and residents are willing and able to participate in the fight against Covid-19 when provided with appropriate deployment, legal guidance, safety measures, clinical knowledge, thorough supervision, social integration and mental health support. Preceding interviews to decide on reasonable voluntary deployment, the use of new technology and frequent feedback communication with faculties, educators and policymakers can further help with a successful and sustainable integration of students and residents in the fight against the pandemic. It is critical that faculties, educators and policymakers have a thorough understanding of the needs and concerns of medical trainees during pandemic times. Leaders should facilitate close communication with students and residents, value their intrinsic creativeness and regularly evaluate their needs in regards to deployment, knowledge aspects, safety measures, legal concerns and overall well-being.


Impact of H&E Stain Normalization on Deep Learning Models in Cancer Image Classification: Performance, Complexity, and Trade-Offs.
Accurate classification of cancer images plays a crucial role in diagnosis and treatment planning. Deep learning (DL) models have shown promise in achieving high accuracy, but their performance can be influenced by variations in Hematoxylin and Eosin (H&E) staining techniques. In this study, we investigate the impact of H&E stain normalization on the performance of DL models in cancer image classification. We evaluate the performance of VGG19, VGG16, ResNet50, MobileNet, Xception, and InceptionV3 on a dataset of H&E-stained cancer images. Our findings reveal that while VGG16 exhibits strong performance, VGG19 and ResNet50 demonstrate limitations in this context. Notably, stain normalization techniques significantly improve the performance of less complex models such as MobileNet and Xception. These models emerge as competitive alternatives with lower computational complexity and resource requirements and high computational efficiency. The results highlight the importance of optimizing less complex models through stain normalization to achieve accurate and reliable cancer image classification. This research holds tremendous potential for advancing the development of computationally efficient cancer classification systems, ultimately benefiting cancer diagnosis and treatment.


Use of subcutaneous transponders to monitor body temperature in laboratory rats.
Implantable radiofrequency transponders may be adequate for the characterization of hazardous chemicals targeting body temperature control in experimental animals when colonic probes and automated monitoring systems based on intraperitoneal transmitters are not available, installable or applicable for any reason. In this work, we summarize a series of experiments showing the implantation protocol and utility of rice-grain size transponders to monitor subcutaneous temperature (Tsc) after exposure to pharmacological or toxicological treatments targeting body temperature control in laboratory rats. In addition, to explore the responsiveness of this thermometric system, the influence of physiological activity on Tsc readings was examined by monitoring Tsc after a motor exercise in a RotaRod system. Moreover, we characterized the effects of acute oral administration of the pyrethroid insecticide permethrin (PRM) in corn oil (1 mL/kg) on Tsc. PRM has been previously reported to cause dose-related increases in core temperature after administering oral doses ≥75 mg/kg, with peak effects at 2-4 h in adult rats. We monitored Tsc at 30 min intervals over a 4 h period after exposure to PRM (40-160 mg/kg). PRM caused a moderate increase in Tsc starting at ~3.5 h. Overall, Tsc assays showed minimal animal stress (if any) and rapid animal recovery from transponder implantation, simplicity to collect data, convenient testing room space requirements, and a competitive global cost per animal examined. However, various experimental factors may greatly influence the variability within and between individuals, some of which can be controlled by carefully setting up experimental conditions.


Survival of transplanted nests of the red wood ant Formica aquilonia (Hymenoptera: Formicidae): the effects of intraspecific competition and forest clear-cutting.
The fitness and survival of ant colonies depend on the resources near their nests. These resources may be limited due to poor habitat quality or by intra- and interspecific competitions, which in extreme cases may cause the ant colony to perish. We tested the effect of intraspecific competition and habitat degradation (forest clear-cutting) on colony survival by transplanting 26 nests of the red wood ant (Formica aquilonia Yarrow, 1955) in 26 different forest areas that contained 0-11 conspecific alien nests per hectare. F. aquilonia is highly dependent on canopy-dwelling aphids, thus the removal of trees should cause food limitation. During the course of the 4-year experiment, 9 of the forests were partially clear-cut. We found that while forest clear-cutting significantly decreased the colonies' survival, intraspecific competition did not. As a highly polygynous and polydomous species, F. aquilonia seems to tolerate the presence of alien conspecific colonies to a certain extent.


Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones.
In the CNS, immune-like competent cells (microglia and astrocytes) were first described as potential sites of chemokine synthesis, but more recent evidence has indicated that neurones might also express chemokines and their receptors. The aim of the present work was to investigate further, both in vivo and in vitro, CC Chemokine Family Receptor 2 (CCR2) expression and functionality in rat spinal cord neurones. First, we demonstrated by RT-PCR and western blot analysis that CCR2 mRNA and protein were present in spinal extracts. Furthermore, we showed by immunolabelling that CCR2 was exclusively expressed by neurones in spinal sections of healthy rat. Finally, to test the functionality of CCR2, we used primary cultures of rat spinal neurones. In this model, similar to what was observed in vivo, CCR2 mRNA and protein were expressed by neurones. Cultured neurones stimulated with Monocyte Chemoattractant Protein-1 (MCP-1)/CCL2, the best characterized CCR2 agonist, showed activation of the Akt pathway. Finally, patch-clamp recording of cultured spinal neurones was used to investigate whether MCP-1/CCL2 could modulate their electrophysiological properties. MCP-1 alone did not affect the electrical properties of spinal neurones, but potently and efficiently inhibited GABA(A)-mediated GABAergic responses in these neurones. These data constitute the first demonstration of a modulatory role of MCP-1 on GABAergic neurotransmission and contribute to our understanding of the roles of CCR2 and MCP-1/CCL2 in spinal cord physiology, in particular with respect to nociceptive transmission, as well as the implication of this chemokine in neuronal adaptation or dysfunction during neuropathy.


Epidemiology and microbiological profile comparison between community and hospital acquired infections: A multicenter retrospective study in Lebanon.
The objective of this study is to identify and characterize the species resistance of different pathogens between community acquired and hospital acquired infections pointing at patients' related independent co-morbidities and socio-demographic factors. It was a retrospective cohort, multicenter study from five private hospitals located in Beirut and Mount Lebanon. Two hundred fifty-eight adult patients were included. 110 Gram negative pathogens and 26 Gram positive pathogens were implicated in hospital acquired infections. The Gram-negative bacteria that showed a positive correlation regarding patient's type of infection were Pseudomonas aeruginosa (12%), Klebsiella pneumoniae (6.2%) and Acinetobacter baumannii (3.1%). These bacteria were more frequent in patients with hospital acquired infections (P=0.002, 0.013 and 0.017 respectively). The ratio of methicillin resistant Staphylococcus aureus, Extended Spectrum Beta Lactamase producing Escherichia coli and K. pneumoniae and multi drug P. aeruginosa showed high significance in hospital acquired infections. The logistic regression, showed a significant relationship between resistant bacteria and age (p<0.001, ORa=5.680, CI [2.344; 13.765]) and immunosuppressed state (p=0.003, ORa=3.137, CI [1.485; 6.630]) and an inverse relationship for Chronic Obstructive Pulmonary Disease (COPD) (p=0.006, ORa=0.403, CI [0.212; 0.765]). Our results confirm that hospital acquired infections/bacteria have higher rates of resistance when compared to community acquired; these rates increase with age, immunosuppression and are inversely proportional with COPD. Therefore, physicians should be aware of patients' comorbidities to properly guide initial therapy.


Targeted and untargeted metabolomic analysis of Procambarus clarkii exposed to a "chemical cocktail" of heavy metals and diclofenac.
Water pollution poses an important problem, but limited information is available about the joined effects of xenobiotics of different chemical groups to evaluate the real biological response. Procambarus clarkii (P. clarkii) has been demonstrated to be a good bioindicator for assessing the quality of aquatic ecosystems. In this work, we studied the bioaccumulation of cadmium (Cd), arsenic (As) and diclofenac (DCF) in different tissues of P. clarkii during 21 days after the exposure to a "chemical cocktail" of As, Cd and DCF, and until 28 days considering a depuration period. In addition, a combined untargeted and targeted metabolomic analysis was carried out to delve the metabolic impairments caused as well as the metabolization of DCF. Our results indicate that As and Cd were mainly accumulated in the hepatopancreas followed by gills and finally abdominal muscle. As and Cd show a general trend to increase the concentration throughout the exposure experience, while a decrease in the concentration of these elements is observed after 7 days of the depuration process. This is also the case in the abdominal muscle for Cd, but not for As and DCF, which increased the concentration in this tissue in the depuration phase. The hepatopancreas showed the greatest number of metabolic pathways affected. Thus, we observed a crucial bioaccumulation of xenobiotics and impairments of metabolites in different tissues. This is the first study combining the exposure to metals and pharmaceutically active compounds in P. clarkii by untargeted metabolomics including the biotransformation of DCF.


Repair of Acute Type A Aortic Dissection With Ascending Aorta Replacement Combined With Open Fenestrated Stent Graft Placement.
In the conventional ascending replacement for acute type A aortic dissection, the distal aortic anastomosis is frequently performed at the dissected site, and postoperative residual dissection in the arch and downstream aorta still occurs in most patients. We used open placement of a fenestrated stent graft during this operation. During the conventional ascending replacement in 41 patients with acute type A aortic dissection, a fenestrated stent graft was inserted into the arch and the proximal descending aorta through the distal ascending transection. The distal ascending transection incorporating the proximal end of the fenestrated stent graft was directly anastomosed to the Dacron (DuPont, Wilmington, DE) tube graft. Survivors were examined by computed tomography angiography. The cardiopulmonary bypass time was 134.46 ± 19.03 minutes, aortic cross-clamp time was 46.38 ± 8.57 minutes, and selective cerebral perfusion and lower body arrest time was 12.50 ± 2.19 minutes. There was 1 in-hospital death but no difficult bleeding from the distal aortic anastomosis. On postoperative computed tomography, the false lumen closed, with complete thrombus formation around the inserted fenestrated stent graft found in all survivors (100%), at the diaphragmatic level in 28 patients (70%), and at the superior mesenteric arterial level in 3 (8%). An open fenestrated stent graft placement provided extensive primary repair of the thoracic aorta and a strong distal aortic stump during the conventional ascending aorta replacement for acute type A aortic dissection but did not increase the risk or technical difficulty of the operation.


Discography and magnetic resonance imaging in the diagnosis of lumbar disc disruption.
Four cases of patients with normal magnetic resonance (MR) studies of the lumbar spine and abnormal discography are presented to illustrate that normal lumbar disc signal intensity does not necessarily rule out disc degeneration.


Genetic uniqueness of the Waorani tribe from the Ecuadorian Amazon.
South America and especially the Amazon basin is known to be home to some of the most isolated human groups in the world. Here, we report on a study of mitochondrial DNA (mtDNA) in the Waorani from Ecuador, probably the most warlike human population known to date. Seeking to look in more depth at the characterization of the genetic diversity of this Native American tribe, molecular markers from the X and Y chromosomes were also analyzed. Only three different mtDNA haplotypes were detected among the Waorani sample. One of them, assigned to Native American haplogroup A2, accounted for more than 94% of the total diversity of the maternal gene pool. Our results for sex chromosome molecular markers failed to find close genetic kinship between individuals, further emphasizing the low genetic diversity of the mtDNA. Bearing in mind the results obtained for both the analysis of the mtDNA control region and complete mitochondrial genomes, we suggest the existence of a 'Waorani-specific' mtDNA lineage. According to current knowledge on the phylogeny of haplogroup A2, we propose that this lineage could be designated as subhaplogroup A2s. Its wide predominance among the Waorani people might have been conditioned by severe genetic drift episodes resulting from founding events, long-term isolation and a traditionally small population size most likely associated with the striking ethnography of this Amazonian community. In all, the Waorani constitute a fine example of how genetic imprint may mirror ethnopsychology and sociocultural features in human populations.


Some properties of uridine 5'-diphosphogalactose: N-acetylglucosamine galactosyltransferase in human parotid saliva.
Uridine 5'-diphospho (UDP)-galactose: N-acetylglucosamine galactosyltransferase was separated from human parotid saliva and partially purified. The optimum pH of the enzyme was 7.5. The enzyme required a specific acceptor, and its activity was activated by manganese and magnesium ions.


Factors affecting autolysis of a subtilisin-like serine proteinase secreted by Ophiostoma piceae and identification of the cleavage site.
The extracellular serine proteinase secreted by Ophiostoma piceae was degraded by autoproteolysis under certain conditions. At elevated temperatures the mature protein of 33 kDa was rapidly degraded without any accumulation of protein breakdown products. Glycerol, calcium ions and ammonium sulfate raised the heat stability of the enzyme, increasing its half-life at 45 degrees C from 1.9 min to 9.4 min, 40.4 min and 2 h, respectively. Thermal unfolding of the proteinase also occurred at higher temperatures in the presence of calcium ions and ammonium sulfate. Under conditions of heating, altered pH or partial depletion of protein-bound ions by EDTA, the structure of the proteinase was more susceptible to proteolysis. The major hydrolytic fragments of 19 kDa and 14 kDa, had N-terminal sequences of Ala1-Tyr2-Thr3-Thr4-Gln5-Thr6-Gly7-Ala8-Pro9-and Ser170-Glu171-Pro172-Se173-Val174-X-Thr 176-Val177-Gly178-Ala179-, respectively. Since the former sequence was identical to the N-terminus of the native protein, the major autoproteolytic cleavage site for a class II subtilase appeared to be the N-side of Ser170 using numbering based on the sequence of proteinase K. The secondary structure of the proteinase from O. piceae was similar to that of proteinase K based on circular dichroic spectra in the far ultraviolet region. This cleavage site was in a similar region to that identified for class I subtilases, which was located in an outer exposed loop of the tertiary structure of subtilisin-like serine proteinases.


"Activation" of alveolar leukocytes isolated from cats fed taurine-free diets.
Taurine is a ubiquitous amino sulfonic acid in mammals, present in high concentrations in tissues, including those exposed to elevated levels of oxidants. Experiments were designed to examine the consequences of taurine deficiency on production of ROI in leukocytes isolated from the lungs and blood of cats fed taurine-deficient diets. Cats were maintained on taurine-free or taurine-supplemented diets for at least 12 months at which time taurine deficiency was evident. To analyze alveolar cells, lungs were lavaged to recover lung macrophages and PMNs. Lung lavage fluid from cats contained macrophages and PMNs, although taurine deficiency was associated with a decrease in the percentage of PMNs in the lungs. This is similar to our findings in blood that taurine deficiency reduced the proportion of PMNs. Taurine measurements revealed 2.1 +/- 1.6 mumol/g wet wt of taurine in the lungs from cats fed a taurine-deficient diet versus 8.3 +/- 2.6 in lungs from cats fed a diet supplemented with taurine (n = 16). The effects of taurine deficiency on the functional activity of lung macrophages and PMNs were analyzed including the production of ROI. Alveolar leukocytes from cats fed taurine-deficient diets produced more superoxide anion in response to phorbol myristate acetate than cats fed taurine supplemented diets. Similar results were obtained using a chemiluminescence assay. Using the highly specific H2O2 indicator dye, dichlorofluorescin, and flow cytometry we found that alveolar leukocytes made more H2O2 than cells from cats fed taurine-supplemented diets. Forty-two percent of the cells from cats fed a taurine-supplemented diet expressed class II antigens. In contrast, 72% of cells from the taurine-deficient cats expressed this antigen. We hypothesize that taurine functions to prevent terminal activation and release of cytotoxic mediators by lung macrophages. Thus, a deficiency of taurine will indeed cause an activation of leukocytes, as evidenced by our data which show an increase in ROI, as well as an increase in class II antigen.


Surgical management of subhepatic perforated appendicitis: a case report.
Subhepatic appendicitis is an exceedingly rare presentation, accounting for 0.01% of acute appendicitis cases. It is of prime importance to be aware of variants and manage such challenging cases accordingly. We present a case of a middle-aged Saudi woman with subhepatic perforated appendicitis and peritonitis who underwent an exploratory laparotomy and appendectomy. The initial diagnosis and surgical management of such patients is challenging due to an atypical presentation. The surgical management of such patients is discussed with a brief review of the literature.


Exploring the arachidonic acid-induced structural changes in phagocyte NADPH oxidase p47(phox) and p67(phox) via thiol accessibility and SRCD spectroscopy.
The NADPH oxidase is the sole enzymatic complex that produces, in a controlled way, superoxide anions. In phagocytes, it is constituted by the assembly of four cytosolic (p67(phox) , p47(phox) , p40(phox) and Rac) and two membrane (p22(phox) and Nox2) proteins. In response to pro-inflammatory mediators, the NADPH oxidase is activated. In cells, arachidonic acid (cis-AA), released by activated phospholipase A2, also plays a role in activation of the NADPH oxidase complex, but the mechanism of action of cis-AA is still a matter for debate. In cell-free systems, cis-AA is commonly used for activation. We have shown previously that trans-AA isomers were unable to activate the NADPH oxidase complex. Here, we aim to evaluate the structural changes in p47(phox) and p67(phox) induced by AA. The structural impact of both AA isomers on both cytosolic proteins was investigated by the accessibility of the thiol group and by circular dichroism in the far-UV for global folds. cis-AA induces secondary structure changes of p47(phox) and p67(phox) , while the trans isomer does not, suggesting that the changes observed are of importance for the activation process of these proteins. While five of the nine thiol groups in p67(phox) and all of them in p47(phox) have low access to the solvent when proteins are alone in solution, all of them become fully accessible when proteins are together. In conclusion, the secondary structures of p47(phox) and p67(phox) are both dependent on the presence of the partner protein in solution and on the presence of the activator molecule cis-AA.


Waste remediation: Low-temperature synthesis of hybrid Cu(OH)2/CuO and CuO nanostructures from spent printed circuit boards and their dye degradation studies.
The demand for environmentally friendly and sustainable resource utilization techniques for recycling waste printed circuit boards is significant due to their status as valuable secondary resources, containing high-purity copper and precious metals. In this context, Cu(OH)2/CuO and CuO nanostructures were fabricated using alkaline precipitation and low-temperature aging methods using the strip solution originated from laboratory-scale spent mobile phone printed circuit board recovery process. XRD, FTIR, FESEM-EDX, and TEM were utilized to characterize the as-recovered nanoproducts. A hybrid structure of Cu(OH)2/CuO was formed at 70°, and monoclinic CuO phase was formed at 80 °C aging time. The results show that Cu(OH)2/CuO nanoflakes have an average crystallite size of 24.06 nm and a particle width of 22 ± 3 nm. Cu(OH)2/CuO nanoflakes formed at 70 °C aging temperature and 24-h residence time have finer crystallite and particle sizes than CuO-ridged nanospheres formed at 80 °C aging temperature. The optical band gap energy of Cu(OH)2/CuO and CuO nanostructures formed was found to be 2.28 eV and 2.22 eV, respectively. The hybrid Cu(OH)2/CuO nanostructure photocatalyzed the decomposed 97.28% rhodamine blue using a visible light source, whereas the CuO nanostructure degraded only 14.64% rhodamine blue dye under similar conditions. A surfactant-less hybrid structure is developed without the use of any chemical precursor. Thus, a high value-added product is produced using one waste material to remove another waste in wastewater treatment.


Separate and combined psychopharmacological effects of alprazolam and oxycodone in healthy volunteers.
There are epidemiological data indicating that medical and/or nonmedical use of prescription opioids oftentimes involves concurrent use of other substances. One of those substances is benzodiazepines. It would be of relevance to characterize the effects of an opioid and a benzodiazepine when taken together to determine if measures related to abuse liability-related effects and psychomotor performance impairment are increased compared to when the drugs are taken alone. Twenty volunteers participated in a crossover, randomized, double-blind study in which they received placebo, 0.5mg alprazolam, 10mg oxycodone, and 0.5mg alprazolam combined with 10 mg oxycodone, all p.o. Subjective, psychomotor, and physiological measures were assessed during each of the four sessions. Oxycodone by itself increased drug liking and "take again" ratings relative to placebo, but these ratings were not increased when oxycodone was taken with alprazolam, which by itself did not increase either of these ratings. The two drugs in combination produced stronger effects (larger in magnitude or longer lasting) than when either was taken alone on a number of measures, including psychomotor performance impairment. In healthy volunteers, abuse liability-related subjective effects of oxycodone were not enhanced by alprazolam. There was enhanced behavioral toxicity when the drugs were taken together, and thus, this is of significant concern from a public safety standpoint.


Effect of loading frequency on cyclic fatigue lifetime of a standard-diameter implant with an internal abutment connection.
To investigate the effect of loading frequency on the fatigue lifetime of one standard-diameter titanium dental implant system. Thirty-six titanium dental implant specimens (Bone Level RC, Straumann) were assembled following manufacturer's instructions and torqued into cylindrical holder blocks following the apparatus specified by the ISO 14801 test standard. Stainless steel loading hemispheres were bonded on the abutments with a moment arm of 11mm. The holder blocks had layers of differing stiffness to simulate human jaw bone. Constant-stress fatigue lifetime testing was conducted at two frequencies (2Hz and 15Hz) with a stress ratio of 0.1 until fracture in deionized water at 37°C on servo-hydraulic load frames (MTS). The fractured specimens were retrieved and examined using fractographic technique to determine the failure mode. The lifetime data were fit to a general log-linear regression model. The coefficient for the load amplitude term of the regression model indicated that increasing load amplitude had a statistically significant negative effect on the fatigue lifetime. The coefficients for the cyclic frequency term and the load-frequency interaction term were not significantly different from zero, which indicated that increasing loading frequency did not have an influence on the number of cycles to failure. Fractographic analysis showed that all specimens exhibited an identical combined fracture of abutment and abutment screw adjacent to the bone level. Higher loading frequency at least up to 15Hz may be used for future studies of some implant systems to improve the efficiency of fatigue testing.


Realization of a tilted reference wave for electron holography by means of a condenser biprism.
As proposed recently, a tilted reference wave in off-axis electron holography is expected to be useful for aberration measurement and correction. Furthermore, in dark-field electron holography, it is considered to replace the reference wave, which is conventionally diffracted in an unstrained object area, by a well-defined object-independent reference wave. Here, we first realize a tilted reference wave by employing a biprism placed in the condenser system above three condenser lenses producing a relative tilt magnitude up to 20/nm at the object plane (300kV). Paraxial ray-tracing predicts condenser settings for a parallel illumination at the object plane, where only one half of the round illumination disc is tilted relative to the optical axis without displacement. Holographic measurements verify the kink-like phase modulation of the incident beam and return the interference fringe contrast as a function of the relative tilt between both parts of the illumination. Contrast transfer theory including condenser aberrations and biprism instabilities was applied to explain the fringe contrast measurement. A first dark-field hologram with a tilted - object-free - reference wave was acquired and reconstructed. A new application for bright/dark-field imaging is presented.


A complementary density gradient of zwitterionic polymer brushes and NCAM peptides for selectively controlling directional migration of Schwann cells.
Selective enhancement of directional migration of Schwann cells (SCs) over fibroblasts (FIBs) plays a significant role in peripheral nerve regeneration, because this behavior facilitates neuron repair and avoids fibrosis. Herein a complementary density gradient of poly(3-dimethyl-methacryloyloxyethyl ammonium propane sulfonate) (PDMAPS, a zwitterionic polymer with antifouling property) and KHIFSDDSSE peptide (KHI, derived from neural cell adhesion molecule NCAM which mediates cell-cell adhesion) was fabricated. The gradient was visualized by fluorescent labeling, and further characterized by X-ray photoelectron spectrometry (XPS) and quartz crystal microbalance with dissipation (QCM-d). The SCs exhibited preferential orientation and enhanced directional migration on the gradient surface toward the region of lower PDMAPS density and higher KHI peptide density, while FIBs showed random migration. Moreover, the migration rate of the SCs was significantly enhanced to 2 folds, whereas that of the FIBs was reduced to 60% compared to their natural state on glass, leading to a faster migration rate of SCs than FIBs. The success of the complementary gradient relies on the appropriate interplay between the PDMAPS brushes and the cell-specific ligands, enabling the selective guidance of SCs migration.


A controlled trial of extended radical mastectomy.
One hundred twenty-three women younger than 70 years of age and at clinical Stages I or II were enrolled in a randomized clinical trial of radical versus extended radical mastectomy. The 5-year survival rates in the radical and extended radical groups were 75 +/- 6.7% and 80 +/- 6.7%, respectively. (Cox P value for comparison of survival curves = 0.32.) Of the total series, 112 were treated by the same surgeon and confirmed pathologically as having invasive mammary carcinoma. In this more homogeneous subgroup, the 5-year survival rates for the radical and extended radical groups were 71 +/- 7.6% and 85 +/- 6.2%, respectively (P = 0.09). For patients from this subgroup with central or medial tumors, the 5-year survival rates were 66 +/- 10% and 88 +/- 8.2%, respectively (P = 0.06). For patients with lateral tumors, the 5-year survival rates were nearly equal: 79 +/- 11% and 81 +/- 9.7%, respectively. The findings in a nonrandomized series of similar patients were comparable. The results are not definitive, but suggest an advantage of extended radical mastectomy over radical mastectomy for patients with central or medial tumors. Continued follow-up of the randomized series may lead to more conclusive results.


Use of the Edmonton Research Orientation Scale with nurses.
Improved understanding of the determinants of research utilization is fundamental to developing and testing strategies to increase research utilization. Inconsistent findings in this field of research about research utilization may be attributable, in part, to lack of development of measures. This research tested the internal consistency and construct validity of the Edmonton Research Orientation Scale (EROS) and its four subscales (Valuing Research, Research Involvement, Being on the Leading Edge, and Evidence-Based Practice), which are promising measures of research utilization and attitudes towards research. One hundred eighty-five registered nurses in a pediatric teaching hospital completed the EROS. Nurses who reported higher levels of education, better understanding of research topics or participation in quality management or research projects also reported higher levels on the EROS and EROS subscales. The Valuing Research and Evidence-Based Practice subscales were associated with having taken courses in research design and statistics. The findings suggest that the EROS and the Valuing Research and Evidence-Based Practice subscales may be used to measure nurses' attitudes towards research and research utilization.


Effect of monopolar radiofrequency energy on pacemaker function.
This study aimed to quantify the clinical parameters of mono- and bipolar instruments that inhibit pacemaker function. The specific aims were to quantify pacer inhibition resulting from the monopolar instrument by altering the generator power setting, the generator mode, the distance between the active electrode and the pacemaker, and the location of the dispersive electrode. A transvenous ventricular lead pacemaker overdrive paced the native heart rate of an anesthetized pig. The primary outcome variable was pacer inhibition quantified as the number of beats dropped by the pacemaker during 5 s of monopolar active electrode activation. Lowering the generator power setting from 60 to 30 W decreased the number of dropped paced events (2.3 ± 1.2 vs 1.6 ± 0.8 beats; p = 0.045). At 30 W of power, use of the cut mode decreased the number of dropped paced beats compared with the coagulation mode (0.6 ± 0.5 vs 1.6 ± 0.8; p = 0.015). At 30 W coagulation, firing the active electrode at different distances from the pacemaker generator (3.75, 7.5, 15, and 30 cm) did not change the number of dropped paced beats (p = 0.314, analysis of variance [ANOVA]). The dispersive electrode was placed in four locations (right/left gluteus, right/left shoulder). More paced beats were dropped when the current vector traveled through the pacemaker/leads than when it did not (1.5 ± 1.0 vs 0.2 ± 0.4; p < 0.001). Clinical parameters that reduce the inhibition of a pacemaker by monopolar instruments include lowering the generator power setting, using cut (vs coagulation) mode, and locating the dispersive electrode so the current vector does not traverse the pacemaker generator or leads.


Antiviral treatment of a serious herpes simplex infection: encephalitis.
Herpes simplex encephalitis is the most common cause of sporadic encephalitis in the western world. Patients usually have altered levels of consciousness, altered levels of mentation, fever, headache, and personality changes. These may progress to hemiparesis and seizures. Exact diagnosis must be established by brain biopsy and identification of the virus in biopsy material. There is a great need for a noninvasive test that is positive early in the disease. Without antiviral treatment the mortality rate is greater than 70%, and many survivors have serious disabilities. Both adenine arabinoside and acyclovir decrease death and morbidity, but acyclovir is the preferred drug. With acyclovir about 40% of patients will survive with normal development or minor levels of impairment but more than half of the patients will die or suffer significant impairment. It is essential to treat early; patients who are young and have not reached coma or impaired consciousness may show 65% recovery and return to normal function. Development of new antiviral drugs or other types of therapies is desirable. Herpetic skin lesions are likely to be more confusing than diagnostic because other types of encephalitis with fever often precipitate recurrent herpes that is unrelated to the encephalitis.


Thioredoxin as a reducing agent for mammalian methionine sulfoxide reductases B lacking resolving cysteine.
Previous reports described thioredoxin (Trx) as a very poor reductant for mammalian MsrB2 and MsrB3, which lack a resolving Cys residue. In contrast, we here report that Trx could reduce both MsrB2 and MsrB3 enzymes, similarly to the reduction of mammalian MsrA. We demonstrated that functional Trx is required for the reduction of these enzymes. We further identified MsrB2- or MsrB3-Trx complexes formed through intermolecular disulfide bonds involving catalytic residue of Trx. The present study provides evidence that the sulfenic acid intermediate of oxidized MsrBs lacking resolving Cys could interact with Trx and be directly reduced by this protein.


Indirect interactions of membrane-adsorbed cylinders.
Biological and biomimetic membranes often contain aggregates of embedded or adsorbed macromolecules. In this paper, the indirect interactions of cylindrical objects adhering to a planar membrane are considered theoretically. The adhesion of the cylinders causes a local perturbation of the equilibrium membrane shape, which leads to membrane-mediated interactions. For a planar membrane under lateral tension, the interaction is repulsive for a pair of cylinders adhering to the same side of the membrane, and attractive for cylinders adhering at opposite membrane sides. For a membrane in an external harmonic potential, the interaction of adsorbed cylinders is always attractive and increases if forces perpendicular to the membrane act on the cylinders.


Evaluation of the effectiveness of amendments derived from vermicompost combined with modified shell powder on Cd immobilization in Cd-contaminated soil by multiscale experiments.
The widespread heavy metal contamination of agricultural soils poses an enormous challenge to food safety. To evaluate the Cd immobilization potential of vermicompost combined with modified shell powder (VMSP) on Cd-contaminated soil, batch adsorption tests and field experiments were conducted. First, the Cd2+ removal characteristics and adsorption mechanisms of vermicompost (V), vermicompost combined with shell powder (VSP), and VMSP in an aqueous solution were investigated by batch tests. Then, 3 kg·m2 V, VSP, and VMSP doses were applied to Cd-contaminated farmland soils as soil amendments to plant green garlic (Allium sativum L.) and investigate their Cd immobilization effects in Cd-contaminated soils. Batch adsorption tests showed that VMSP was most effective for Cd2+ removal, with adsorption rates as high as 85.7-99.79% and desorption rates of approximately 1.25-1.34%. Combining further characterization analysis of VMSP, it was demonstrated that the adsorption mechanism of Cd2+ was monolayer chemisorption, mainly involving the complexation reaction of Cd2+ with organic functional groups and the precipitation reaction of Cd2+ with mineral elements. The field experiment showed that adding V, VSP, and VMSP effectively inhibited the enrichment of Cd in green garlic, and the Cd content was reduced by 42.18%, 46.88%, and 68.75%, respectively. However, only the Cd content of green garlic treated with VMSP was lower than the national standard for food safety in China (Cd≤ 0.2 mg·kg-1). V, VSP, and VMSP additions improved soil fertility and reduced Cd bioavailability in the soil by 15.5%, 18.9%, and 36.3%, respectively. In addition, V, VSP, and VMSP addition increased bacterial diversity and improved bacterial communities and functions in the soil by improving basic soil properties and reducing Cd-related toxicity. The results indicated that VMSP is a promising amendment for Cd immobilization in Cd-contaminated farmland soils.


Rare species disproportionally contribute to functional diversity in managed forests.
Functional diversity is linked with critical ecosystem functions, yet its relationship with numerical diversity, e.g. species richness, is not fully understood. The mechanisms linking changes of species richness, e.g. random and non-random species losses and gains, with changes of functional diversity become more relevant in the face of rapid environmental changes. In particular, non-random species changes including rare species may affect functional diversity, and the overall ecosystem function, disproportionately compared to random species changes including common species. In this study, I investigated how changes in numerical diversity of bird assemblages are related to functional diversity, and how the environment, and in particular forest management, influences such a relationship. I collected bird count data in the extensively-managed forest landscape of the Black Forest (Germany), at 82 sampling sites over three years. Data included species richness and abundance per site, and functional traits related to diet and habitat type for each species to compute functional diversity. By partitioning numerical diversity changes into five components using Price Equations, I calculated the contribution of random and non-random species losses and gains, and the abundance of common species, to functional diversity. Then I modelled these contributions as a function of several environmental variables describing broad forest conditions, and including forest management intensity. I found that, beside the major contribution of random species losses to functional diversity, non-random species losses also play a role, indicating that rare species that contribute more to functional diversity are often lost earlier than common species. The overall contribution to functional diversity of species losses is larger than that of species gains, pointing toward an ongoing simplification of the forest bird assemblage. Among all Price components, random species gains were influenced by management intensity, while other components were not influenced by any management variable. This highlight that potential conservation actions may not be effective in halting ecosystem functioning decline, as species gains do not result in increased functional diversity.


Biomarkers in Locally Advanced Rectal Cancer: A Review.
Locally advanced rectal cancers (LARC) are the subject of a rapidly evolving treatment paradigm. The critical timepoints where management decisions are required during the care of the LARC patient are: prior to the institution of any treatment, post neoadjuvant therapy and post-surgery. This article reviews the clinical, imaging, blood-based, tissue-based, and molecular biomarkers that can assist clinicians at these timepoints in the patient's management, in prognosticating for their LARC patients or in predicting responses to therapy in the multi-modality neoadjuvant treatment era.


Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas.
We aimed to evaluate the prevalence of armadillo repeat-containing 5 (ARMC5) genetic defects in our cohort of bilateral adrenal incidentaloma (BAI) patients and to evaluate the possible existence of genotype-phenotype correlations. Cross-sectional study. Tertiary care center. 72 BAI patients. The following data have been collected: morning adrenocorticotropic hormone (ACTH) concentrations; cortisol levels after 1 mg overnight dexamethasone suppression test (F-1mgDST); urinary free cortisol (UFC) levels; diameter of the adrenal masses; and the association with overweight/obesity, arterial hypertension, diabetes mellitus, dyslipidemia, cardiovascular events, unrelated neoplasia, osteoporosis, thyroid nodular disease, and primary hyperparathyroidism. A search for ARMC5 germline and somatic pathogenic variants was performed in all patients and in the adrenal tissue of patients operated on, respectively. The prevalence of germline ARMC5 pathogenic variants among patients with mild autonomous cortisol secretion (MACS+, defined as F-1mgDST > 1.8 µg/dL) was 18.8%. No germline pathogenic variants were detected in patients without MACS. Moreover, somatic ARMC5 pathogenic variants were also found in the adrenal tissue of six patients without germline ARMC5 variants. The F-1mgDST levels >5 µg/dL predicted with a poor sensitivity but a 90.5% specificity in identifying the presence of ARMC5 germline pathogenic variants. We did not find any clinical parameter predictive of the ARMC5 mutation presence. In MACS+ BAI patients, germline ARMC5 gene pathogenic variants are frequent. Further studies are needed to elucidate the pathophysiological role of somatic ARMC5 pathogenic variants on adrenal tumor development in otherwise wild-type (WT) patients.


Impact of early ICU admission for critically ill cancer patients: Post-hoc analysis of a prospective multicenter multinational dataset.
Early intensive care unit (ICU) admission, in Critically Ill Cancer Patients (CICP), is believed to have contributed to the prognostic improvement of critically ill cancer patients. The primary objective of this study was to assess the association between early ICU admission and hospital mortality in CICP. Retrospective analysis of a prospective multicenter dataset. Early admission was defined as admission in the ICU < 24 h of hospital admission. We assessed the association between early ICU admission and hospital mortality in CICP via survival analysis and propensity score matching. Of the 1011patients in our cohort, 1005 had data available regarding ICU admission timing and were included. Overall, early ICU admission occurred in 455 patients (45.3%). Crude hospital mortality in patients with early and delayed ICU admission was 33.6% (n = 153) vs. 43.1% (n = 237), respectively (P = 0.02). After adjustment for confounders, early compared to late ICU admission was not associated with hospital mortality (HR 0.92; 95%CI 0.76-1.11). After propensity score matching, hospital mortality did not differ between patients with early (35.2%) and late (40.6%) ICU admission (P = 0.13). In the matched cohort, early ICU admission was not associated with mortality after adjustment on SOFA score (HR 0.89; 95%CI 0.71-1.12). Similar results were obtained after adjustment for center effect. In this cohort, early ICU admission was not associated with a better outcome after adjustment for confounder and center effect. The uncertainty with regard to the beneficial effect of early ICU on hospital mortality suggests the need for an interventional study.


Emerging and re-emerging infectious diseases: influenza as a prototype of the host-pathogen balancing act.
To respond to emerging and re-emerging infections, it is necessary to understand the interactions between microbial pathogens and their hosts and the impact of environmental and social factors on these interactions. The importance of understanding host-pathogen interactions is underscored by the emergence of virulent H5N1 avian influenza viruses and their transmission to humans, and the potential pandemic threat they pose.


Early vascular ageing phenotypes and urinary targeted metabolomics in children and young adults: the ExAMIN Youth SA and African-PREDICT studies.
Some individuals are susceptible to accelerated biological ageing, resulting in premature alterations in arterial structure and function. Identifying early-onset vascular ageing characterised by arterial stiffening is vital for intervention and preventive strategies. We stratified and phenotyped healthy children (5-9 yrs) and young adults (20-30 yrs) into their vascular ageing extremes established by carotid-femoral pulse wave velocity (cfPWV) percentiles (i.e., healthy vascular ageing (HVA) and early vascular ageing (EVA)). We compared anthropometric, cardiovascular, and metabolomic profiles and explored associations between cfPWV and urinary metabolites. Children and adults in the EVA groups displayed higher levels of adiposity, cardiovascular, and lifestyle risk factors (adults only) (all p ≤ 0.018). In adults, several urinary metabolites were lower in the EVA group (all q ≤ 0.039) when compared to the HVA group, with no differences observed in children. In multiple regression analysis (adults only), we found inverse associations between cfPWV with histidine (adj. R2 = 0.038; β = -0.192; p = 0.013) and beta-alanine (adj. R2 = 0.034; β = -0.181; p = 0.019) in the EVA group, but with arginine (adj. R2 = 0.021; β = -0.160; p = 0.024) in the HVA group. The inverse associations of beta-alanine and histidine with cfPWV in the EVA group is suggestive that asymptomatic young adults who present with an altered metabolomic and less desired cardiovascular profile in combination with unfavourable lifestyle behaviours may be predisposed to early-onset vascular ageing. Taken together, screening on both a phenotypic and metabolic level may prove important in the early detection, prevention, and intervention of advanced biological ageing.


Effectiveness of routine and spontaneous follow-up visits for breast cancer.
The effectiveness of routine (initiated by the health services) and spontaneous (initiated by the patient) follow-up visits were compared based on a 5 year follow-up of all (551) breast cancer patients residing in one of the Finnish central hospital districts and diagnosed in 1977-1980. There were altogether 8248 visits, i.e. 4.6 per follow-up woman year, of which 2.7 visits were based on the recommended follow-up schedule. Recurrence (252) was detected in 14.7% of spontaneous visits which was five times more often than at the regular visit. False positive clinical diagnosis (63) was three times more frequent for spontaneous than for regular visits. The follow-up system should probably not be based solely on detecting of recurrences of the disease only but aspects related to the patient's quality of life may be decisive.


Effect of repeated IOP challenge on rat retinal function.
To characterize the effect of repeated brief intraocular pressure (IOP) elevations and the effect of IOP fluctuation on retinal function. The effects of one, two, and four episodes (70 mm Hg, 15 minutes) are compared by defining the time course of functional recovery after insults. The effect of IOP variation is considered by comparing a constant with a varying insult, keeping a common IOP-time integral (one 60-minute vs. two 30-minute vs. four 15-minute insults; 70 mm Hg). IOP elevation is induced by anterior chamber cannulation in anesthetized, dark-adapted rats (n = 5-7 per group). Electroretinograms are recorded every 6 minutes throughout each event. Recovery time course is modeled using a logistic function, and time for 50% recovery is compared by nonparametric bootstrap. Electroretinographic recovery becomes progressively slower with more IOP episodes for bipolar cell and ganglion cell response (P < 0.05) but not for photoreceptor response (P > 0.05). With regard to IOP variation, bipolar cell recovery after four 15-minute insults is faster than it is after two 30-minute insults (P < 0.05), which is faster than after one 60-minute insult (P < 0.05). Ganglion cell recovery after varying (four 15-minute and two 30-minute) insults is faster than after a constant (one 60-minute) insult (P < 0.05). This improved recovery with varying IOP challenge is greater for bipolar cell than for ganglion cell responses (P < 0.05). Repeated IOP insults lead to cumulative dysfunction in the inner retina. For the conditions used in this study, IOP variation per se is not detrimental but appears to be beneficial.


Manual reconstruction of tumor volumes from CT scans for radiotherapy planning.
Using a computed tomographic scan to construct a tumor volume on a simulation film has become an important part of radiation therapy treatment planning. Techniques for reconstruction of brain tumor volumes from computed tomographic scans onto simulation films are discussed. A technique for reconstructing by hand the tumor volume projection at a different angle from the plane of the computed tomographic scan is outlined. Ignoring beam divergence simplifies reconstruction, allowing it to be done by hand but introduces an additional error of at most 0.06, 0.15, 0.26 and 0.42 cm for tumors with maximum diameters of 5, 7.5, 10 and 12.5 cm, respectively. This technique provides the capability for limited 3-dimensional volume reconstruction of small tumors without the use of the computer.


Multiple developmental processes underlie sex differentiation in angiosperms.
The production of unisexual flowers has evolved numerous times in dioecious and monoecious plant taxa. Based on repeated evolutionary origins, a great variety of developmental and genetic mechanisms underlying unisexual flower development is predicted. Here, we comprehensively review the modes of development of unisexual flowers, test potential correlations with sexual system, and end with a synthesis of the genetics and hormonal regulation of plant sex determination. We find that the stage of organ abortion in male and female flowers is temporally correlated within species and also confirm that the arrest of development does not tend to occur preferentially at a particular stage, or via a common process.


[Faults and dangers in treating hand injuries (including tendons and bones) (author's transl)].
Diagnostic procedures include: critical examination of the wound of sensibility, of vascularization, of tendon function, of stability of bones and joints, and examination by roentgen diagnosis. Therapeutic procedures include: the operation, immobilization, active training of noninjured joints, and rehabilitation. Injuries of flexor tendons are treated by the specialist following the method of Kleinert; those of bones and joints can be easily stabilized by Kirschner pins.


Dietary Approaches to Treating Multiple Sclerosis-Related Symptoms.
Although there is no dietary pattern than has been proven to be effective for reducing the number of relapses or enhancing lesions in patients with multiple sclerosis (MS), several pilot studies have demonstrated the efficacy of dietary plans to reduce MS-related symptoms. Low saturated fat (Swank), low fat vegan (McDougall), modified Paleolithic (Wahls), gluten free, Mediterranean, intermittent fasting, calorie restriction, and intermittent calorie restriction (fasting mimicking diet) all have been associated with reduction of MS-related symptoms such as reduced fatigue, improved mood, and improved quality of life. Mediterranean diet has proven effectiveness for prevention and reduction of comorbid disease severity.


Total Syntheses of Aporphine Alkaloids via Benzyne Chemistry: An Approach to the Formation of Aporphine Cores.
Total syntheses of lysicamine, (±)-nuciferine, (±)-nornuciferine, (±)-zanthoxyphylline iodide, (±)-O-methylisothebaine, and (±)-trimethoxynoraporphine were accomplished by an approach that involves the formation of aporphine cores through reactions between an isoquinoline derivative and silylaryl triflates promoted by CsF. Unprecedented formations of aporphine cores proceeded in good yields presumably through [4 + 2] cycloaddition reactions followed by hydrogen migrations.


A novel hematopoietic progenitor cell mobilization regimen, utilizing bortezomib and filgrastim, for patients undergoing autologous transplant.
Adequate hematopoietic progenitor cell (HPC) collection is critical for patients undergoing autologous HPC transplant (AHPCT). Historically, 15 - 30% of patients failed HPC mobilization with granulocyte-colony stimulating factor (G-CSF) alone. Bortezomib, a proteasome inhibitor, has been shown to down regulate very late antigen-4 (VLA-4), an adhesion molecule expressed on HPCs. In this pilot study, bortezomib was administered on days -11 and -8 at a dose of 1.3 mg/m2 intravenously (IV) or subcutaneously (SQ), followed by G-CSF 10 mcg/kg SQ, on days -4 to -1 prior to HPC collection (Day 1). Nineteen patients, with multiple myeloma (n = 12) or non-Hodgkin lymphoma (n = 7) undergoing AHPCT for the first time, were enrolled. Patients were excluded if they had worse than grade II neuropathy or platelet count less than 100 x 109 /L. Bortezomib was well tolerated and all patients had adequate HPC collections with no mobilization failures. One patient (6%) had a CD34+ cell count of 3.9 cells/µL on Day 1 and received plerixafor per institutional algorithm. Eleven patients completed HPC collection in 1 day and eight in 2 days. All patients underwent AHPCT and had timely neutrophil and platelet engraftment. Comparison with a historical control group of 70 MM and lymphoma patients, who were mobilized with G-CSF, showed significantly higher CD 34+ cells/kg collected in the bortezomib mobilization study group. Bortezomib plus G-CSF is an effective HPC mobilizing regimen worth investigating further in subsequent studies. J. Clin. Apheresis 31:559-563, 2016. © 2015 Wiley Periodicals, Inc.


Vasoactive intestinal peptide induces a transient release of growth hormone in the rat.
Effects of vasoactive intestinal peptide (VIP) on growth hormone (GH) secretion were investigated both in vivo on freely moving, intact or mediobasal hypothalamic lesioned rats, and in vitro in incubation or superfusion systems of anterior pituitary tissue. In vivo, IV injection of VIP induced a rapid but transient increase in plasma GH levels in all animals and in vitro, VIP stimulated GH release from incubated or superfused rat pituitaries in a concentration dependent manner. This increase was potentiated by forskolin, a potent activator of adenylate cyclase. These findings indicate that VIP exerts a direct stimulating action on somatotrophs and that the effect seems to imply a coupling of VIP receptors with cAMP production.