The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis.
We recently discovered that truncated glioma-associated oncogene homolog 1 (TGLI1) is highly expressed in glioblastoma (GBM) and linked to increased GBM vascularity. The mechanisms underlying TGLI1-mediated angiogenesis are unclear. In this study, we compared TGLI1- with GLI1-expressing GBM xenografts for the expression profile of 84 angiogenesis-associated genes. The results showed that expression of six genes were upregulated and five were down-regulated in TGLI1-carrying tumors compared to those with GLI1. Vascular endothelial growth factor-C (VEGF-C) and tumor endothelial marker 7 (TEM7) were selected for further investigations because of their significant correlations with high vascularity in 135 patient GBMs. TGLI1 bound to both VEGF-C and TEM7 gene promoters. Conditioned medium from TGLI1-expressing GBM cells strongly induced tubule formation of brain microvascular endothelial cells, and the induction was prevented by VEGF-C/TEM7 knockdown. Immunohistochemical analysis of 122 gliomas showed that TGLI1 expression was positively correlated with VEGF-C, TEM7 and microvessel density. Analysis of NCBI Gene Expression Omnibus datasets with 161 malignant gliomas showed an inverse relationship between tumoral VEGF-C, TEM7 or microvessel density and patient survival. Together, our findings support an important role that TGLI1 plays in GBM angiogenesis and identify VEGF-C and TEM7 as novel TGLI1 target genes of importance to GBM vascularity.


The effects of anticalmodulin drugs on the ultrastructure of boar spermatozoa.
Trifluoperazine, N-6-aminohexyl-5-chloro-1-naphthalene sulfonamide (W7), and calmidazolium are known to be calmodulin inhibitors and cell membrane soluble substances. In mammalian spermatozoa, calmodulin is present and is retained to mediate several sperm processes, such as sperm activation, sperm-egg fusion, microtubule disassembly, etc. We examined the effects of anticalmodulin drugs on the ultrastructure of freshly ejaculated boar spermatozoa. Whereas all the drugs, at the low concentrations tested, appear to prevent acrosomal alterations, at higher concentrations, they induced these alterations. Unexpectedly, the outer acrosomal membrane appeared to be more sensitive to the drugs than the plasma membrane; vesicles formed within the acrosome from the outer acrosomal membrane even when plasma membrane maintained its structural integrity. These findings were confirmed by the analysis carried out by fluorescent light microscopy by utilizing fluoresceinated Ricinus communis agglutinins to specifically stain the acrosomes.


[Usefulness of lower extremity magnetic resonance venography with two-dimensional spiral gradient echo sequence and effect of patient positioning during the visualization of lower extremity veins].
We examined the two-dimensional-spiral-gradient-echo (2D-spiral-GRE) for magnetic resonance venography (MRV). In addition, five variations in patient positioning of the MRV were investigated to determine the best method of visualizing. First, flow phantom experiments were performed on a 1.5 T scanner. Using a flow phantom, the authors aimed to (1) measure the optimal TR (40, 60, 140, 190 ms), (2) measure the flip angle (20-60 degrees) and (3) determine the optimal combination of saturation pulse (S, I, A, P, R, L) and half acquisition method for MRV. Secondly, ten volunteers without vessel disease were imaged by phase contrast sequence for measured mean value of the venous area and velocity of the femoral and popliteal vein. The volunteers' MRV images were compared qualitatively on visualization. There is better demonstration of the veins under the longer repetition time (TR), resulting in a setting of 2-3 acquisitions ordering. Because the fluid or blood has been irradiated with pulsed radiofrequency multiple times, optimal FA was about 40 degrees. Combination of saturation pulse was slightly effective and the best saturation effect was seen in the half acquisition method. Volunteer study patient positioning, which involves the slight lifting up of the upper half of the body and continuous warming of the feet, has brought about a larger area and a slower velocity in the lower extremity veins. The greater veins and peripheral veins were demonstrated more accurately. 2D-spiral-GRE sequence was a useful method for lower extremity MRV. Furthermore, the most effective patient positioning for the lower extremity MRV was slightly lifting up the upper half of the body and continuously warming the feet. These enabled the best results to be obtained in the lower extremity MRV.


Luminescent metal-organic frameworks as explosive sensors.
Metal organic frameworks (MOFs) are of enormous current interest not only because of their fundamental importance but also due to their great potential for possible applications in gas storage and separation, catalysis, imaging and sensing, to name a few. Recent studies on luminescent MOFs (LMOFs) in both bulk and nanoparticle forms have shown that these materials possess excellent luminescence emission properties that may be utilized to effectively detect high explosive substances. Developing highly sensitive, selective, fast-responding and fully reversible sensors for explosives' detection is in great demand for the homeland security, environmental safety and other humanitarian concerns. In this perspective article, we discuss the development, possible mechanism and future aspects of explosive sensing by LMOF materials.


Synthesis and solvatochromism studies of novel bis(indolyl)methanes bearing functionalized arylthiophene groups as new colored materials.
The demand for dyes with solvatochromic properties has increased in the last few years, mainly due to their wide range of applications in the analytical and industrial fields, such as in the textile industry. The phenomenon of solvatochromism is associated with the differential solvation of the ground and excited states of the solvatochromic compounds, leading to an important tool for the study of the nature of solute-solvent interactions. In this paper we report the synthesis of new bis(indolyl)methane derivatives bearing arylthiophene spacers (2a-d) functionalized with electron-donating and electron-withdrawing groups, and the photophysical studies in different solvents, such as ethanol, acetonitrile, dichloromethane, trichloromethane, dimethylsulfoxide, diethylether and 1,4-dioxane. Aiming to explore their solvatochromic behaviour in the ground and excited states, all solvents employed have different hydrogen-bond donor abilities. The largest colour modifications were visualized for compound 2b, the solution colours of which are orange in DMSO, blue in trichloromethane, green in dichloromethane and purple in 1,4-dioxane. A negative solvatochromism was observed in 2b and a positive one in 2a, 2c and 2d.


Abnormalities in small intestine contour and caliber: a working classification.
An organized approach to the radiographic analysis of abnormal small bowel based on evaluation of contour and caliber is presented. Diseases affecting the small bowel can be categorized by performing a suggested sequence of observations, and a more specific diagnosis can then be made by integrating clinical information with the radiographic observations.


Matrix vesicles in bone tumors. Ultrastructural analysis and their significance in neoplastic bone formation.
Bone tumors were categorized into alkaline phosphatase (ALPase)-positive (2 ossifying fibromas, 1 benign osteoblastoma and 16 osteosarcomas) and negative (2 chondromas, 2 chondrosarcomas, 3 non-ossifying fibromas, 2 malignant fibrous histiocytomas and 6 giant cell tumors of bone) groups. Production and distribution of matrix vesicles (MVs) in the tumor tissues were examined to clarify their role in neoplastic bone formation. Four distinct types of MV were isolated primarily in ALPase positive bone tumors: empty, amorphous, crystalline and ruptured MVs. They were formed by budding off from the cytoplasmic projections of the osteoblastic tumor cells. The significance of differences in the production rate of MVs between ALPase-positive and negative bone tumors was investigated in view of the predominantly high production of MVs in ALPase-positive bone tumors. Many more mature MVs (crystalline and ruptured) were observed in the osteoblastic lesions of osteosarcoma than in the fibroblastic and MFH-like lesions, suggesting an intimate relationship with maturation and differentiation of the osteoblastic tumor cells. The above findings indicate that production of MVs is one of the diagnostic parameters for osteoblast-derived bone tumors, as well as ALPase activity, and that vesicle-induced mineralization is a major mineralization mechanism in neoplastic bone formation.


Molecular imaging of PARP in cancer: state-of-the-art.
Poly-ADP-ribose-polymerase inhibitors (PARPi), which exploit the processes of so-called 'synthetic lethality,' have been successfully implemented in oncological practice. However, not all patients respond to PARPi, and there is an unmet need for noninvasive biomarkers suitable for patient selection and monitoring during PARPi therapy. The first clinical applications of molecular imaging with positron emission tomography/computed tomography (PET/CT) with [18F]-FluorThanatrace ([18F]-FTT) and [18F]-PARPi, highly effective PARP-ligands, in patients with several malignancies, (head and neck, ovarian, prostate and breast cancer) are covered, with a particular focus on its potential for pre-treatment selection and follow-up. By a search made on the most common database, such as PubMed and Google Scholar in a period from January 2010 and 2023, first clinical evidence suggests that PET/CT with [18F]-FTT and [18F]-PARPi might represent a reliable tool for in vivo imaging and quantification of PARP-1 expression in ovarian, prostate, breast, head and neck cancer, supporting their potential usefulness for patient selection before PARPi-therapies. In addition, a reduction in [18F]-FTT uptake has been registered after therapy initiation and seems to be correlated with patient outcome after PARPi-based regimens. Further studies are needed to better address the value of PARPI-radiolabeled PET imaging in these clinical settings, especially as it concerns technical features such as optimal scan modality (dynamic vs. static) and timing.


MHC class II+ (HLA-DP-like) cells in the cow reproductive tract: II. Immunolocalization of MHC class II+ cells in oviduct and vagina.
The aim of this study was to determine and examine the distribution of major frequency MHC II+ cells in the oviduct and vagina of cows during the oestrous and dioestrus phases. Right oviduct (ampulla, isthmus) and vaginal samples taken from a total of twenty seven multiparous cows were used. Tissue samples were processed to obtain both cryostat and paraffin sections. Sections were stained immunocytochemically using StreptABC method using a specific monoclonal antibody to MHC II+ cell population. Intra-epithelial and subepithelial areas along with lamina propria, muscularis mucosae and serosa of both ampulla and isthmus and intra-epithelial/subepithelial areas and mucosae of vagina were examined for the presence of MHC II+ cells. The density of immune positive cells was determined using a subjective scoring system. MHC II+ cells were demonstrated in all areas examined in both oestrus and dioestrus. In oestrus, the density of MHC II+ cells decreased in subepithelial areas (in between the epithelial cells and the basal membrane) of isthmus, whereas the density of immune positive cells was increased in muscularis mucosae of isthmus (P < 0.05), lamina propria and muscularis mucosae of ampulla (P < 0.05) as well as in the mucosae of vagina (P <or= 0.005). This study indicates that the density of MHC II+ cells observed in the oviduct and vagina increases in the majority of areas examined due to the effect of oestrogen.


Recent advances in light-regulated non-radical polymerisations.
Light is one of the non-invasive stimuli which can be used in the spatiotemporal control of chemical reactions. Over the past decade, light has found wide applications in polymer science such as polymer synthesis, release of small molecules from polymers and polymeric photosensors etc. Reviews on light-regulated polymerisations have predominately focused on the free radical process. However, the marriage of light to non-radical polymerisations, e.g. ionic, ring-opening, metathesis, step-growth and supramolecular photopolymerisations, has also spurred tremendous research interest to develop materials. These kinds of non-radical photopolymerisations, compared to the free radical approach, are advantageous in overcoming oxygen inhibition, accessing novel polymer structures and fabricating degradable and dynamic polymers. The relevant light-regulation techniques involved in these polymerisations are usually based on photolinking reactions and photoactivation of latent species. These species produce initiators, catalysts or monomers upon light irradiation to manipulate polymer formation. These techniques have been successfully implemented to adapt conditional polymerisations under light, discover novel polymerisation methods and precisely control polymer structures. This review aims to highlight the recent progress in light-regulated non-radical polymerisations in the development of polymerisation techniques as well as the applications in materials science, emphasising the remaining challenges and promising perspective in the relevant fields.


Large vesicovaginal fistula in women with pelvic organ prolapse: the role of colpocleisis revisited.
Successful repair of large vesicovaginal fistulas poses a significant challenge in surgically unfit older women with pelvic organ prolapse. Two women, at ages of 85 and 93, referred for involuntary urine loss were found to have neglected pessaries resulting in large vesicovaginal fistulas. After the removal of the pessary, fistula repair and LeFort colpocleisis were done with success. At 12 months postoperatively, the patients were free of leakage and prolapse. For frail, elderly women with large vesicovaginal fistula and pelvic organ prolapse, addition of LeFort colpocleisis to the repair provides an effective treatment for both.


Predicting the stiffness and strength of human femurs with real metastatic tumors.
Predicting patient specific risk of fracture in femurs with metastatic tumors and the need for surgical intervention are of major clinical importance. Recent patient-specific high-order finite element methods (p-FEMs) based on CT-scans demonstrated accurate results for healthy femurs, so that their application to metastatic affected femurs is considered herein. Radiographs of fresh frozen proximal femur specimens from donors that died of cancer were examined, and seven pairs with metastatic tumor were identified. These were CT-scanned, instrumented by strain-gauges and loaded in stance position at three inclination angles. Finally the femurs were loaded until fracture that usually occurred at the neck. Histopathology was performed to determine whether metastatic tumors are present at fractured surfaces. Following each experiment p-FE models were created based on the CT-scans mimicking the mechanical experiments. The predicted displacements, strains and yield loads were compared to experimental observations. The predicted strains and displacements showed an excellent agreement with the experimental observations with a linear regression slope of 0.95 and a coefficient of regression R(2)=0.967. A good correlation was obtained between the predicted yield load and the experimental observed yield, with a linear regression slope of 0.80 and a coefficient of regression R(2)=0.78. CT-based patient-specific p-FE models of femurs with real metastatic tumors were demonstrated to predict the mechanical response very well. A simplified yield criterion based on the computation of principal strains was also demonstrated to predict the yield force in most of the cases, especially for femurs that failed at small loads. In view of the limited capabilities to predict risk of fracture in femurs with metastatic tumors used nowadays, the p-FE methodology validated herein may be very valuable in making clinical decisions.


Depigmentation of Melanin-containing Tissues Using Hypochlorous Acid to Enhance Hematoxylin-eosin and Immunohistochemical Staining.
Pathologists diagnose diseases by observing the histologic and cellular morphology microscopically. However, the high pigmentation in melanin-containing tumors can hide the tumor cell structures, making diagnosing challenging. Previously, hydrogen peroxide and potassium permanganate were utilized for melanin bleaching with several limitations. For instance, hydrogen peroxide has a weak bleaching ability, and the process is time-consuming (12 h). Meanwhile, potassium permanganate affects the antigenicity of antigens and is unsuitable for immunohistochemical (IHC) staining. In this study, the hypochlorous acid (HClO) solution was applied to hematoxylin-eosin and IHC staining of melanin tissue sections. The study discovered that 1% HClO could completely bleach melanin particles in tumor tissues in a short period (19.95 ± 2.53 min) without compromising the hematoxylin-eosin staining. In addition, 2% HClO was utilized for bleaching at room temperature for 61.17 ± 4.32 minutes after the tissue was incubated with 3,3'-diaminobenzidine in IHC staining. This treatment effectively removed melanin without negatively impacting 3,3'-diaminobenzidine signal expression, thus ensuring that the sections met the necessary diagnostic requirements. Therefore, this method could facilitate pathologists in disease diagnosis of melanin-containing tissues.


Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain.
Transient receptor potential vanilloid type 1 (TRPV1) has been shown to play an important role in visceral hypersensitivity. A significant proportion of patients with inflammatory bowel disease (IBD) continue to complain of abdominal pain despite their disease being otherwise quiescent. We investigated TRPV1-immunoreactive fibres in rectosigmoid biopsies taken from such patients with correlation to abdominal pain severity. Rectosigmoid biopsies were collected from 20 patients with quiescent IBD fulfilling Rome II criteria for irritable bowel syndrome (IBS), from 20 asymptomatic patients with quiescent IBD and from 28 controls. Abdominal pain scores were recorded using a validated questionnaire. TRPV1- and neuronal marker protein gene product 9.5 (PGP 9.5)-expressing nerve fibres, and lymphocytes (CD3 and CD4) were quantified, following immunohistochemistry with specific antibodies. The biopsy findings were related to abdominal pain scores. A significant 3.9-fold increase in median number of TRPV1-immunoreactive fibres was found in biopsies from patients with quiescent IBD with IBS symptoms when compared with controls (p<0.0001) and a 5-fold increase when compared with the asymptomatic quiescent IBD group (p=0.0003). In the IBD with IBS symptoms group, the total nerve fibres (PGP 9.5) did not differ from those in the asymptomatic IBD group (p=0.10) or the control group (p=0.33) and neither did the CD3 lymphocyte (asymptomatic IBD group p=0.17; controls p=0.88) or CD4 lymphocyte (asymptomatic IBD group p=0.39; controls p=0.97) counts. In stepwise multivariate linear regression analysis, only TRPV1-immunoreactive nerve fibres (R(2)=0.8; p<0.0001) were significantly related to the abdominal pain score. Increased TRPV1 nerve fibres are seen in quiescent IBD with IBS-like symptoms together with a correlation to pain severity. TRPV1 may contribute to the pathophysiology of ongoing pain and visceral hypersensitivity in this group of patients, providing a potential therapeutic target.


Brain Responses to Letters and Speech Sounds and Their Correlations With Cognitive Skills Related to Reading in Children.
Letter-speech sound (LSS) integration is crucial for initial stages of reading acquisition. However, the relationship between cortical organization for supporting LSS integration, including unimodal and multimodal processes, and reading skills in early readers remains unclear. In the present study, we measured brain responses to Finnish letters and speech sounds from 29 typically developing Finnish children in a child-friendly audiovisual integration experiment using magnetoencephalography. Brain source activations in response to auditory, visual and audiovisual stimuli as well as audiovisual integration response were correlated with reading skills and cognitive skills predictive of reading development after controlling for the effect of age. Regression analysis showed that from the brain measures, the auditory late response around 400 ms showed the largest association with phonological processing and rapid automatized naming abilities. In addition, audiovisual integration effect was most pronounced in the left and right temporoparietal regions and the activities in several of these temporoparietal regions correlated with reading and writing skills. Our findings indicated the important role of temporoparietal regions in the early phase of learning to read and their unique contribution to reading skills.


Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APPswe Alzheimer's Disease Mouse Model.
The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APPswe mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R-/-/APPswe, to perform cognition studies and to assess, by immunoblotting Aβ and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R-/-/APPswe mice do not have the characteristic memory impairment of 12-month-old APPswe mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer's disease (AD)-related features, such as amyloid beta (Aβ) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3β and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks.


[Morphology of coronaviruses from different species of monkeys in the Sukhumi nursery].
The ultrastructure of coronaviruses from 46 out of 111 monkeys examined (baboons, macaques, green monkeys, langurs) was studied by negative staining in homogenates of different parts of the intestinal tract, pancreatic gland, liver, kidneys, lungs, heart, and brain. Because of marked pleomorphism of coronaviruses it is suggested that morphological variants of the viruses may be distinguished. No relationship between pleomorphism of virus particles and species differences of monkeys and their organ pathology was established. Morphological signs distinguishing simian coronaviruses from those of man were noted.


Activation of human monocyte tumoricidal activity by C-reactive protein.
We examined the effect of purified human C-reactive protein (CRP) on induction of human peripheral blood monocyte (Mo)-mediated cytotoxicity (CTX) and oxidative metabolism. Exposure of Mo to acute phase serum levels of CRP in vitro resulted in dose-dependent expression of CTX against human tumor cell lines. Nonneoplastic human fibroblasts and glial cells were not affected by CRP-exposed Mo, and treatment of Mo monolayers with anti-Leu 11b (a natural killer marker) and complement did not abrogate or diminish CTX. Tumoricidal activity was observed after 20-44 h of Mo exposure to CRP, and after 48-72 h of coculture with radiolabeled target tumor cells. Mo exposed to CRP for 48 h also demonstrated elevated superoxide anion production when challenged with phorbol myristate acetate. Unlike CTX induced by lipopolysaccharide, CRP-induced CTX was completely inhibited by preincubation of CRP with phosphorylcholine, a CRP ligand, at a concentration of 5.5 molecules phosphorylcholine per molecule CRP. Further, when Mo medium (which contained 5% human AB serum) was preincubated with immobilized CRP, exposure of Mo to CRP in such medium did not result in CTX. In contrast, LPS-induced CTX was not affected. CRP-induced Mo CTX was observed, however, when Mo were exposed to CRP in medium preincubated with phosphorylcholine-treated immobilized CRP, suggesting that an active serum component which complexed with CRP was not removed. These findings indicate that one of the functions of the acute phase protein, CRP, may be to active Mo and that the process may require a CRP-binding serum component.


Health systems challenges in cervical cancer prevention program in Malawi.
Cervical cancer remains the leading cause of cancer death among women in sub-Saharan Africa. In Malawi, very few women have undergone screening and the incidence of cervical cancer is on the increase as is the case in most developing countries. We aimed at exploring and documenting health system gaps responsible for the poor performance of the cervical cancer prevention program in Malawi. The study was carried out in 14 randomly selected districts of the 29 districts of Malawi. All cervical cancer service providers in these districts were invited to participate. Two semi-structured questionnaires were used, one for the district cervical cancer coordinators and the other for the service providers. The themes of both questionnaires were based on World Health Organization (WHO) health system frameworks. A checklist was also developed to audit medical supplies and equipment in the cervical cancer screening facilities. The two questionnaires together with the medical supplies and equipment checklist were piloted in Chikwawa district before being used as data collection tools in the study. Quantitative data were analyzed using STATA and qualitative in NVIVO. Forty-one service providers from 21 health facilities and 9 district coordinators participated in the study. Our findings show numerous health system challenges mainly in areas of health workforce and essential medical products and technologies. Seven out of the 21 health facilities provided both screening and treatment. RESULTS showed challenges in the management of the cervical cancer program at district level; inadequate service providers who are poorly supervised; lack of basic equipment and stock-outs of basic medical supplies in some health facilities; and inadequate funding of the program. In most of the health facilities, services providers were not aware of the policy which govern their work and that they did not have standards and guidelines for cervical cancer screening and treatment. Numerous health system challenges are prevailing in the cervical cancer prevention program in Malawi. These challenges need to be addressed if the health system is to improve on the coverage of cervical cancer screening and treatment.


Seizures in patients with glioma treated with phenytoin and levetiracetam.
Second-generation antiepileptic drugs (AEDs) are increasingly used in the care of patients with glioma. There is little data on how this practice compares with the use of traditional AEDs in this population. This noninferiority analysis compares seizure outcomes and side effects in patients with glioma treated with phenytoin and levetiracetam monotherapy. The authors retrospectively reviewed the records of 500 consecutive patients with glioma who were treated in clinical trials from 2001 to 2008 at 3 Mayo Clinic campuses. To be eligible for the study, these patients had to have had at least 1 clinical seizure and to have undergone follow-up for at least 6 months. Seizure outcomes, defined by the occurrence of a second seizure, time to second seizure, and seizure frequency, along with AED side effects, were compared between cohorts treated with phenytoin or levetiracetam Seventy-six patients were identified, 25 treated with phenytoin and 51 with levetiracetam. Sixty-four percent of the patients had a Grade 4 astrocytoma. There was no difference in seizure outcome between the phenytoin and levetiracetam groups when comparing time to second seizure (p=0.584), second seizure rates (p=0.561), and average seizures per month (p=0.776). When adjusting for age, sex, type of seizure, type of glioma, and dosage using univariate and multivariate models, there were no differences between the treatment groups and none of these covariates were statistically significant for explaining the second seizure rates between treatment groups (all p values>0.05). The incidence of side effects in the levetiracetam group was 6% versus 20% in the phenytoin group (p=0.106). Additionally, 36% of the patients in the phenytoin group had dose adjustments unrelated to breakthrough seizures compared with only 10% in the levetiracetam group (p=0.010) In this study, patients with glioma treated with levetiracetam and phenytoin had similar seizure control. Patients treated with levetiracetam experienced fewer side effects and required fewer nonseizure-related dose adjustments than patients treated with phenytoin. Levetiracetam is a safe, effective, and preferred alternative for seizure management in patients with glioma.


Degradation of melanin by Aspergillus fumigatus.
A strain of Aspergillus fumigatus from composted coffee and garden wastes utilized natural deproteinized insect, banana, hair, octopus, and synthetic tyrosine and dopa melanins as sole sources of carbon. With a sucrose supplement, degradation was essentially complete after 50 days in Czapek medium pH 6.5 at 30 degrees C. The catabolic rate differed for each substrate pigment, as did the molecular weight distribution of products accumulating in the medium. After incubation with L-[U-14C]melanin, over 50% was recovered in a dark fungal pigment, the remainder appearing as cell protein, chitin, lipid, CO2, and polar metabolites. When grown on melanin, the normally pale mycelia darkened with the production of a fungal allomelanin, with infrared spectrum and alkali fusion products differing from those of the substrate pigment. Isotope distribution in amino acids for A. fumigatus grown on labeled melanin supplemented with sucrose suggested separate pools for synthesis of cell proteins and melanoproteins. Deposition of allomelanin increased resistance of conidia, sterigma, and conidiophores to lytic carbohydrases as judged by scanning electron microscopy.


Coach Burnout in Relation to Perfectionistic Cognitions and Self-Presentation.
Coaching athletes is highly rewarding yet stressful, especially at the elite level where media, fans, and sponsors can contribute to an environment that, if not well-managed by the coach, can lead to burnout. Coaches who display perfectionistic tendencies, such as striving for flawlessness, may be particularly vulnerable-even more so if they are overly critical of themselves and have a tendency to ruminate over their performance, or if they are attempting to convey an image of faultlessness, or both. A total of 272 coaches completed a battery of inventories assessing burnout, perfectionistic thoughts, and the tendency for perfectionistic self-presentation. All variables correlated significantly: coaches with higher scores on exhaustion scored higher both on perfectionistic thoughts and self-presentation. However, when three subscales of perfectionistic self-presentation were considered separately, lower and nonsignificant correlations emerged. We believe that this can be explained by the heterogeneous group of coaches participating in this study. Whereas all coaches may at times ruminate privately-self-oriented perfectionism-about their perceived failure to perform to expectations, not all may feel the pressure to present themselves to others as faultless-a more socially prescribed perfectionism. This finding warrants further investigation, preferably comparing coaches at different levels of public scrutiny.


Exponential Stability of Almost Periodic Solutions for Memristor-Based Neural Networks with Distributed Leakage Delays.
In this letter, we deal with a class of memristor-based neural networks with distributed leakage delays. By applying a new Lyapunov function method, we obtain some sufficient conditions that ensure the existence, uniqueness, and global exponential stability of almost periodic solutions of neural networks. We apply the results of this solution to prove the existence and stability of periodic solutions for this delayed neural network with periodic coefficients. We then provide an example to illustrate the effectiveness of the theoretical results. Our results are completely new and complement the previous studies Chen, Zeng, and Jiang ( 2014 ) and Jiang, Zeng, and Chen ( 2015 ).


Fracture patterns in adult onset type 1 diabetes and associated risk factors - A nationwide cohort study.
This study aimed to determine the hazard ratios (HR) for various fracture sites and identify associated risk factors in a cohort of relatively healthy adult people with newly diagnosed type 1 diabetes (T1D). The study utilized data from the UK Clinical Practice Research Datalink GOLD (1987-2017). Participants included people aged 20 and above with a T1D diagnosis code (n = 3281) and a new prescription for insulin. Controls without diabetes were matched based on sex, year of birth, and practice. Cox regression analysis was conducted to estimate HRs for any fracture, major osteoporotic fractures (MOFs), and peripheral fractures (lower-arm and lower-leg) in people with T1D compared to controls. Risk factors for T1D were examined and included sex, age, diabetic complications, medication usage, Charlson comorbidity index (CCI), hypoglycemia, previous fractures, falls, and alcohol consumption. Furthermore, T1D was stratified by duration of disease and presence of microvascular complications. The proportion of any fracture was higher in T1D (10.8 %) than controls (7.3). Fully adjusted HRs for any fracture (HR: 1.43, CI95%: 1.17-1.74), MOFs (HR: 1.46, CI95%: 1.04-2.05), and lower-leg fractures (HR: 1.37, CI95%: 1.01-1.85) were statistically significantly increased in people with T1D compared to controls. The primary risk factor across all fracture sites in T1D was a previous fracture. Additional risk factors at different sites included previous falls (HR: 1.64, CI95%: 1.17-2.31), antidepressant use (HR: 1.34, CI95%: 1.02-1.76), and anxiolytic use (HR: 1.54, CI95%: 1.08-2.29) for any fracture; being female (HR: 1.65, CI95%: 1.14-2.38) for MOFs; the presence of retinopathy (HR: 1.47, CI95%: 1.02-2.11) and previous falls (HR: 2.04, CI95%: 1.16-3.59) for lower-arm and lower-leg fractures, respectively. Lipid-lowering medication use decreased the risk of MOFs (HR: 0.66, CI95%: 0.44-0.99). Stratification of T1D by disease duration showed that the relative risk of any fracture in T1D did not increase with longer diabetes duration (0-4 years: HR: 1.52, CI95%: 1.23-1.87; 5-9 years: HR: 1.30, CI95%: 0.99-1.71; <10 years: HR: 1.07, CI95%: 0.74-1.55). Similar patterns were observed for other fracture sites. Moreover, the occurrence of microvascular complications in T1D was linked to a heightened risk of fractures in comparison to controls. However, when considering the T1D cohort independently, the association was not statistically significant. In a cohort of relatively healthy and newly diagnosed people with T1D HRs for any fracture, MOFs, and lower-leg fractures compared to controls were increased. A previous fracture was the most consistent risk factor for a subsequent fracture, whereas retinopathy was the only diabetes related one. We postulate a potential initial fracture risk, succeeded by a subsequent risk reduction, which might potentially increase in later years due to the accumulation of complications and other factors.


Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene.
Inheritable isolated central hypothyroidism (ICH) due to mutations of TSH beta gene has been reported in few patients. For this reason the diagnostic criteria are vague. The disorder is usually characterized by undetectable TSH levels, although low/normal serum TSH, depending on TSH measurement methods, has been documented in some patients. Here we report an Egyptian girl with ICH due to a novel nonsense mutation of the TSH beta gene (Q49X). She was referred at 75 days of age for severe clinical signs of hypothyroidism, whose central origin was documented by normal serum TSH, low free T(4) and free T(3) levels, impaired TSH response to TRH, absence of (99)Tc thyroidal uptake, and antithyroid autoantibodies. Ultrasound revealed a hypoplastic thyroid, whereas magnetic resonance imaging showed a hyperplastic pituitary. All other pituitary hormones, including PRL, were normally secreted. A diagnosis of idiopathic ICH was made, and substitutive L-T(4) treatment was started at 81 days of age. At the age of 7 yr the patient had normal thyroid hormone levels, but was severely mentally retarded. Interestingly, the sella computed tomography scan had completely normalized. At 8 yr of age the patient was reinvestigated after 6-week L-T(4) withdrawal. TSH values were highly variable depending on the measurement method used, whereas extremely high levels of circulating free glycoprotein alpha-subunit were recorded. Despite the fact that mutant TSH beta lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity. In conclusion, high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and, possibly, hyperplastic pituitary gland are the hallmark of ICH due to mutations of the TSH beta gene.


A Multidisciplinary Intervention Utilizing Virtual Communication Tools to Reduce Health Disparities: A Pilot Randomized Controlled Trial.
Advances in technology are likely to provide new approaches to address healthcare disparities for high-risk populations. This study explores the feasibility of a new approach to health disparities research using a multidisciplinary intervention and advanced communication technology to improve patient access to care and chronic disease management. A high-risk cohort of uninsured, poorly-controlled diabetic patients was identified then randomized pre-consent with stratification by geographic region to receive either the intervention or usual care. Prior to enrollment, participants were screened for readiness to make a behavioral change. The primary outcome was the feasibility of protocol implementation, and secondary outcomes included the use of patient-centered medical home (PCMH) services and markers of chronic disease control. The intervention included a standardized needs assessment, individualized care plan, intensive management by a multidisciplinary team, including health coach-facilitated virtual visits, and the use of a cloud-based glucose monitoring system. One-hundred twenty-seven high-risk, potentially eligible participants were randomized. Sixty-one met eligibility criteria after an in-depth review. Due to limited resources and time for the pilot, we only attempted to contact 36 participants. Of these, we successfully reached 20 (32%) by phone and conducted a readiness to change screen. Ten participants screened in as ready to change and were enrolled, while the remaining 10 were not ready to change. Eight enrolled participants completed the final three-month follow-up. Intervention feasibility was demonstrated through successful implementation of 13 out of 14 health coach-facilitated virtual visits, and 100% of participants indicated that they would recommend the intervention to a friend. Protocol feasibility was demonstrated as eight of 10 participants completed the entire study protocol. At the end of the three-month intervention, participants had a median of nine total documented contacts with PCMH providers compared to four in the control group. Three intervention and two control participants had controlled diabetes (hemoglobin A1C <9%). Multidisciplinary care that utilizes health coach-facilitated virtual visits is an intervention that could increase access to intensive primary care services in a vulnerable population. The methods tested are feasible and should be tested in a pragmatic randomized controlled trial to evaluate the impact on patient-relevant outcomes across multiple chronic diseases.


Short-term effects of the 2008 Great Recession on the health of the Italian population: an ecological study.
To report on the effects on health that the 2008 Great Recession is producing in Italy, by comparing the consistency of Italian data with general observations reported in the scientific literature, and by pointing out consequences on the rates of all-cause mortality, cardiovascular mortality, male suicidal behaviours, daytime alcohol drinking and traffic fatalities. This is an ecological study in which MEDLINE, PsycINFO and PubMed were searched for the literature with combinations of the following keywords: economic recession, financial crisis, unemployment, health, suicide and mental health. Data from two Italian government agencies (Italian Institute of Statistics, ISTAT, and Italian Agency of Drugs, AIFA) in the years from 2000 to 2010 were obtained and analysed, by producing models of multiple linear regressions. After the recession onset, all-cause mortality remained stable, and was not associated with the economic fluctuations. Differently, cardiovascular mortality was associated with the rate of unemployment, and showed a significant increase in 2010. Alcohol consumption increased in 2009, the year with the worst real GDP decrease (-5.1 %). Though the total rate of suicide was not associated with the economic situation, male completed and attempted suicides due to financial crisis were significantly associated with the rate of unemployment and the real GDP. The increasing diffusion of antidepressants was not associated with a lowering of the rate of suicide. The data on the Italian situation here discussed are sufficiently reliable to conclude that a link exists between the ongoing economic recession and health and mental health of Italians. Further research is needed to understand more in detail and with stronger reliability such link, to support primary and secondary preventive interventions and orient the development of effective sociopolitical interventions.


Heat shock induction of HIV production from chronically infected promonocytic and T cell lines.
HIV infection is associated with a long period of clinical latency before the development of symptoms and HIV-related disease. Two chronically HIV-infected cell lines, U1 (promonocytic) and ACH-2 (T-lymphocytic) have been developed as models for studying the mechanisms governing viral latency and the reactivation of virus expression. We have previously shown that a variety of physiologic stimuli, including cytokines and cell stress, can up-regulate HIV expression from these cell lines. In this study we demonstrate that heat shock can also up-regulate the production of virus from both ACH-2 and U1 cells. Heat induction of virus appears to be mediated at the transcriptional level as established in long terminal repeat-chloramphenicol acetyl transferase transient transfection experiments with the use of U937 cells. This inductive effect in part requires the NF-kappa B-binding region of the HIV-long terminal repeat. Furthermore, although physiologic levels of heat are not sufficient to directly induce virus production from these cells, these temperatures are able to synergistically enhance virus production in U1 cells stimulated with IL-6 and granulocyte macrophage-CSF. In contrast, the inductive effect of other cytokines (i.e., TNF-alpha) was not affected by heat stimulation. These in vitro observations suggest that the hyperthermia associated with opportunistic infections, particularly in conjunction with certain cytokines that are released during immune reactions, may play a role in the in vivo induction of HIV expression in infected cells.


Are solo infections of the diphyllobothriidean cestode Schistocephalus solidus more virulent than multiple infections?
We performed a long-term natural experiment investigating the impact of the diphyllobotriidean cestode Schistocephalus solidus on the body condition and clutch size (CS) of threespine stickleback Gasterosteus aculeatus, its second intermediate host, and the growth of larval parasites in host fish. We tested the hypothesis that single S. solidus infections were more virulent than multiple infections. We also asked whether the metrics of mean and total parasite mass (proxies for individual and total volume, respectively) were consistent with predictions of the resource constraints or the life history strategy (LHS) hypothesis for the growth of, hence exploitation by, larval helminths in intermediate hosts. The samples were drawn from Walby Lake, Alaska in eight of 11 years. Host body condition and CS (egg number per spawning bout) decreased significantly with intensity after adjustments for host size and parasite index. Thus, infections have an increasingly negative impact on measures of host fitness with greater intensity, in contrast to the hypothesis that single infections are more harmful than multiple infections. We also found that mean parasite mass decreased with intensity while total parasite mass increased with intensity as predicted by the LHS hypothesis.


Anal high-risk human papillomavirus infection and high-grade anal intraepithelial neoplasia detected in women and heterosexual men infected with human immunodeficiency virus.
Although anal high-risk human papillomavirus (HR-HPV) infection and anal cytological abnormalities are highly prevalent among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM), there are insufficient data on these abnormalities among HIV-infected heterosexual men (HSM) and women. In this study, we evaluated the prevalence of anal HR-HPV, cytological abnormalities, and performance of these screening tests in detecting high-grade anal intraepithelial neoplasia (AIN2+) among our cohort of HIV-infected MSM and non-MSM (HSM and women). A single-center, retrospective cohort study was conducted with HIV-infected individuals who underwent anal cancer screening with anal cytology and HR-HPV testing from January 2011 to January 31, 2013. Screening of 221 HIV-infected individuals for both HR-HPV and anal cytology showed the presence of HR-HPV in 54% (abnormal anal cytology 48%) of MSM, 28% (abnormal anal cytology 28%) of HSM, and 27% (abnormal anal cytology 34%) of women. Among 117 (53%) individuals with abnormal results (HR-HPV-positive and/or cytology was atypical squamous cells of undetermined significance or above), 67 underwent high resolution anoscopy. Of these 67 individuals, 22 individuals had AIN2+ (17 MSM, four women, and one HSM). HR-HPV correlated better with AIN2+ than with anal cytology on biopsy in both MSM (r=0.29 versus r=0.10; P=0.05 versus P=0.49) and non-MSM (r=0.36 versus r=-0.34; P=0.08 versus P=0.09). Given the presence of AIN2+ in screened HIV-infected HSM and women, routine anal cancer screening in all HIV-infected individuals should be considered. HR-HPV merits further evaluation for anal cancer screening among non-MSM.


LULU operators and discrete pulse transform for multi-dimensional arrays.
The LULU operators for sequences, that is L(n), U(n) and their compositions, are extended to multidimensional arrays in a way which preserves their essential properties, e.g., consistent separation, total variation and shape preservation. The power of the operators is demonstrated by deriving the discrete pulse transform (DPT), which is a hierarchical decomposition of the input array into pulses. Similar to its 1-D counterpart this transform satisfies a basic consistency property.


Preliminary Effectiveness of Group Interpersonal Psychotherapy for Young Kenyan Mothers With HIV and Depression: A Pilot Trial.
The authors adopted a task-sharing strategy in which lay health workers delivered group interpersonal psychotherapy (IPT-G) in primary care clinics in Nairobi, Kenya, to young mothers with HIV and depression. The study examined the acceptability, feasibility, and effectiveness of IPT-G in improving depression and antiretroviral therapy adherence. Twenty-four mothers (ages 18-24 years and 6-12 weeks postpartum) participated. The women were randomly assigned to IPT-G or to a waitlist. Eight lay providers administered the IPT-G sessions across 8 weeks. The primary outcome was pre- to postintervention change in depression scores as measured on the Edinburgh Postnatal Depression Scale. The secondary outcome was antiretroviral therapy adherence. All waitlist participants subsequently received the intervention, and a secondary outcome, within-group analysis, was conducted and included those participants. Participants' median age was 23.0 years, 17 (71%) lived with a partner, and 19 (79%) had fewer than two children. The intervention group had a mean±SD depression score of 15.9±4.3 at baseline and 6.8±7.0 postintervention. For the waitlist control group, the mean score was 17.3±5.9 at baseline and 13.2±6.6 at the first follow-up. Waitlist participants had significantly greater mean depression scores than did intervention group participants at the first follow-up (after the intervention group's 8-week IPT-G) (β=6.42, 95% confidence interval=1.17 to 11.66, p=0.017). No difference was observed between groups in antiretroviral therapy adherence. This study provides preliminary evidence that IPT-G led by community health workers may have benefits for postpartum depression among young mothers with HIV.


Differential depression of staphylococcal plasmid and chromosomal penicillinase genes by a class of unlinked chromosomal mutations (R2-).
We described previously a class of mutations (phenotypic designation R2(-)) in Staphylococcus aureus that were unlinked to penicillinase genes but nevertheless imposed constitutive synthesis of this enzyme upon wild-type plasmids. The plasmids affected by these mutations have been found to possess the same maintenance-compatibility type (I) and to form penicillinase of serotype A. Three plasmids that had a different maintenance-compatibility type (II) and formed penicillinase of serotype C were only slightly derepressed in R2(-) mutants. Three chromosomal penicillinase genes were variably derepressed, the range extending from negligible to nearly complete derepression. The differences in degree of derepression among the three types of penicillinase linkage groups were tentatively ascribed to position effects.


Trapping of the beta-adrenergic receptor in the hormone-induced state.
Isoproterenol and other agonists readily dissociate from the beta-adrenergic receptor in turkey erythrocyte membranes. However, when a low concentration of deoxycholate is added, the receptor locks the prebound agonist; i.e., the rate of dissociation of the prebound agonist decreases drastically. The dissociation of prebound antagonists is slightly increased by deoxycholate. Locking, which is thus agonist specific, occurs in the cold, is reversed when detergent is removed from the membranes, and appears not to require the guanyl nucleotide binding protein of the adenylate cyclase system. It is suggested that this induced fit of a receptor to an agonist represents the specific conformational response that normally propagates in the receptor molecule in its interaction with the next component along the pathway of signal transmission.


Ecological Assessment of Autonomy in Instrumental Activities of Daily Living in Dementia Patients by the Means of an Automatic Video Monitoring System.
Currently, the assessment of autonomy and functional ability involves clinical rating scales. However, scales are often limited in their ability to provide objective and sensitive information. By contrast, information and communication technologies may overcome these limitations by capturing more fully functional as well as cognitive disturbances associated with Alzheimer disease (AD). We investigated the quantitative assessment of autonomy in dementia patients based not only on gait analysis but also on the participant performance on instrumental activities of daily living (IADL) automatically recognized by a video event monitoring system (EMS). Three groups of participants (healthy controls, mild cognitive impairment, and AD patients) had to carry out a standardized scenario consisting of physical tasks (single and dual task) and several IADL such as preparing a pillbox or making a phone call while being recorded. After, video sensor data were processed by an EMS that automatically extracts kinematic parameters of the participants' gait and recognizes their carried out activities. These parameters were then used for the assessment of the participants' performance levels, here referred as autonomy. Autonomy assessment was approached as classification task using artificial intelligence methods that takes as input the parameters extracted by the EMS, here referred as behavioral profile. Activities were accurately recognized by the EMS with high precision. The most accurately recognized activities were "prepare medication" with 93% and "using phone" with 89% precision. The diagnostic group classifier obtained a precision of 73.46% when combining the analyses of physical tasks with IADL. In a further analysis, the created autonomy group classifier which obtained a precision of 83.67% when combining physical tasks and IADL. Results suggest that it is possible to quantitatively assess IADL functioning supported by an EMS and that even based on the extracted data the groups could be classified with high accuracy. This means that the use of such technologies may provide clinicians with diagnostic relevant information to improve autonomy assessment in real time decreasing observer biases.


Arabidopsis N-MYC DOWNREGULATED-LIKE1, a positive regulator of auxin transport in a G protein-mediated pathway.
Root architecture results from coordinated cell division and expansion in spatially distinct cells of the root and is established and maintained by gradients of auxin and nutrients such as sugars. Auxin is transported acropetally through the root within the central stele and then, upon reaching the root apex, auxin is transported basipetally through the outer cortical and epidermal cells. The two Gbetagamma dimers of the Arabidopsis thaliana heterotrimeric G protein complex are differentially localized to the central and cortical tissues of the Arabidopsis roots. A null mutation in either the single beta (AGB1) or the two gamma (AGG1 and AGG2) subunits confers phenotypes that disrupt the proper architecture of Arabidopsis roots and are consistent with altered auxin transport. Here, we describe an evolutionarily conserved interaction between AGB1/AGG dimers and a protein designated N-MYC DOWNREGULATED-LIKE1 (NDL1). The Arabidopsis genome encodes two homologs of NDL1 (NDL2 and NDL3), which also interact with AGB1/AGG1 and AGB1/AGG2 dimers. We show that NDL proteins act in a signaling pathway that modulates root auxin transport and auxin gradients in part by affecting the levels of at least two auxin transport facilitators. Reduction of NDL family gene expression and overexpression of NDL1 alter root architecture, auxin transport, and auxin maxima. AGB1, auxin, and sugars are required for NDL1 protein stability in regions of the root where auxin gradients are established; thus, the signaling mechanism contains feedback loops.


Cannabis use following bariatric surgery is associated with anxiety and maladaptive eating.
There are limited data regarding the association of cannabis use with outcomes after bariatric surgery. As such, it is challenging to know how to counsel patients using cannabis. The purpose of this study was to examine whether postsurgical cannabis use was associated with psychiatric symptoms and maladaptive eating among individuals up to 4 years after bariatric surgery. Single health system. All patients who underwent bariatric surgery over a 4-year period were invited to participate. Participants (N = 765) completed questionnaires online regarding postsurgical cannabis use, psychiatric symptoms, and maladaptive eating. Any cannabis use after bariatric surgery was associated with increased likelihood of having elevated symptoms of anxiety (odds ratio [OR] = 1.88, P = .003; 37.8% versus 24.4%), increased likelihood of grazing behaviors (OR = 1.77, P = .01; 71.2% versus 58.2%), and higher scores for eating in response to depression (P = .01; 12.13 versus 10.75). Weekly cannabis use was associated with loss of control eating (OR = 1.81, P = .04; 37.2% versus 24.7%), binge eating (OR = 2.16, P = .03; 20.0% versus 10.4%), and night eating behaviors (OR = 2.11, P = .01; 40.0% versus 24.0%). Cannabis use was not associated with depression (P > .05). Cannabis use after bariatric surgery was associated with anxiety symptoms and engaging in maladaptive eating behaviors. Frequent cannabis use (i.e., ≥1 per week) was associated with additional types of maladaptive eating. Clinicians involved in presurgical and postsurgical care may want to counsel patients currently using cannabis, especially those who are engaging in frequent use.


Deciding without data: clinical decision-making in pediatric orthopedic surgery.
Identifying when and how often decisions are made based on high-quality evidence can inform the development of evidence-based treatment plans and care pathways, which have been shown to improve quality of care and patient safety. Evidence to guide decision-making, national guidelines and clinical pathways for many conditions in pediatric orthopedic surgery are limited. This study investigated decision-making rationale and quantified the evidence supporting decisions made by pediatric orthopedic surgeons in an outpatient clinic. We recorded decisions made by eight pediatric orthopedic surgeons in an outpatient clinic and the surgeon's reported rationale behind the decisions. Surgeons categorized the rationale for each decision as one or a combination of 12 possibilities (e.g. 'Experience/anecdote,' 'First principles,' 'Trained to do it,' 'Arbitrary/instinct,' 'General study,' 'Specific study'). Out of 1150 total decisions, the most frequent decisions were follow-up scheduling, followed by bracing prescription/removal. The most common decision rationales were 'First principles' (n = 310, 27.0%) and 'Experience/anecdote' (n = 253, 22.0%). Only 17.8% of decisions were attributed to scientific studies, with 7.3% based on studies specific to the decision. As high as 34.6% of surgical intervention decisions were based on scientific studies, while only 10.4% of follow-up scheduling decisions were made with studies in mind. Decision category was significantly associated with a basis in scientific studies: surgical intervention and medication prescription decisions were more likely to be based on scientific studies than all other decisions. With increasing emphasis on high value, evidence-based care, understanding the rationale behind physician decision-making can educate physicians, identify common decisions without supporting evidence and help create clinical care pathways in pediatric orthopedic surgery. Decisions based on evidence or consensus between surgeons can inform pathways and national guidelines that minimize unwarranted variation in care and waste. Decision support tools and aids could also be implemented to guide these decisions.


Molecular Biology and Pathological Process of an Infectious Bronchitis Virus with Enteric Tropism in Commercial Broilers.
Infectious bronchitis virus (IBV) induces respiratory and urogenital disease in chickens. Although IBV replicates in the gastrointestinal tract, enteric lesions are uncommon. We have reported a case of runting-stunting syndrome in commercial broilers from which an IBV variant was isolated from the intestines. The isolate, CalEnt, demonstrated an enteric tissue tropism in chicken embryos and SPF chickens experimentally. Here, we determined the full genome of CalEnt and compared it to other IBV strains, in addition to comparing the pathobiology of CalEnt and M41 in commercial broilers. Despite the high whole-genome identity to other IBV strains, CalEnt is rather unique in its nucleotide composition. The S gene phylogenetic analyses showed great similarity between CalEnt and Cal 99. Clinically, vent staining was slightly more frequent in CalEnt-infected birds than those challenged with M41. Furthermore, IBV IHC detection was more evident and the viral shedding in feces was overall higher with the CalEnt challenge compared with M41. Despite underlying intestinal lesions caused by coccidiosis and salmonellosis vaccination, microscopic lesions in CalEnt-infected chickens were more severe than in M41-infected chickens or controls, supporting the enteric tropism of CalEnt. Further studies in SPF chickens are needed to determine the pathogenesis of the virus, its molecular mechanisms for the enteric tropism, and its influence in intestinal health.


Subretinal gene therapy of mice with Bardet-Biedl syndrome type 1.
To study safety and efficacy of subretinal adeno-associated virus (AAV) vector AAV-Bbs1 injection for treatment of a mouse model of Bardet-Biedl syndrome type 1 (BBS1). Constructs containing a wild-type (WT) Bbs1 gene with and without a FLAG tag in AAV2/5 vectors were generated. Viral genomes were delivered by subretinal injection to right eyes and sham injections to left eyes at postnatal day 30 (P30) to P60. Transgene expression and BBSome reconstitution were evaluated by immunohistochemistry and Western blotting following sucrose gradient ultracentrifugation. Retinal function was analyzed by electroretinogram (ERG) and structure by optical coherence tomography (OCT). Histology and immunohistochemistry were performed on selected eyes. Expression of FLAG-tagged Bbs1 was demonstrated in photoreceptor cells using antibody directed against the FLAG tag. Coinjection of AAV-GFP demonstrated transduction of 24% to 32% of the retina. Western blotting demonstrated BBS1 protein expression and reconstitution of the BBSome. ERG dark-adapted bright flash b-wave amplitudes were higher in AAV-Bbs1-injected eyes than in sham-injected fellow eyes in more than 50% of 19 animals. Anti-rhodopsin staining demonstrated improved localization of rhodopsin in AAV-Bbs1-treated eyes. WT retinas injected with AAV-Bbs1 with or without a FLAG tag showed outer retinal degeneration on ERG, OCT, and histology. In a knock-in model of BBS1, subretinal delivery of AAV-Bbs1 rescues BBSome formation and rhodopsin localization, and shows a trend toward improved ERG. BBS is challenging to treat with gene therapy due to the stoichiometry of the BBSome protein complex and overexpression toxicity.


[Results of surgical treatment of benign non-epithelial tumors and cysts of the esophagus].
Based on questionnaires, roentgenological and esophagotonokimographic studies the authors present an analysis of the results of surgical therapy in 33 patients showing benign non-epithelial neoplasms of the esophagus. Comparative data on the frequency and character of pathological signs appearing prior to and after surgery are reported. The necessity of a differential approach to formulating indications to surgical treatment of benign esophageal tumors and cysts is emphasized, since serious functional disorders arising postoperatively should be warranted by the rationality of a surgical intervention.


Pressurized carbon dioxide as a potential tool for decellularization of pulmonary arteries for transplant purposes.
Vascular bio-scaffolds produced from decellularized tissue offer a promising material for treatment of several types of cardiovascular diseases. These materials have the potential to maintain the functional properties of the extracellular matrix (ECM), and allow for growth and remodeling in vivo. The most commonly used methods for decellularization are based on chemicals and enzymes combinations, which often damage the ECM and cause cytotoxic effects in vivo. Mild methods involving pressurized CO2-ethanol (EtOH)-based fluids, in a supercritical or near supercritical state, have been studied for decellularization of cardiovascular tissue, but results are controversial. Moreover, data are lacking on the amount and type of lipids remaining in the tissue. Here we show that pressurized CO2-EtOH-H2O fluids (average molar composition, ΧCO2 0.91) yielded close to complete removal of lipids from porcine pulmonary arteries, including a notably decrease of pro-inflammatory fatty acids. Pressurized CO2-limonene fluids (ΧCO2 0.88) and neat supercritical CO2 (scCO2) achieved the removal of 90% of triacylglycerides. Moreover, treatment of tissue with pressurized CO2-limonene followed by enzyme treatment, resulted in efficient DNA removal. The structure of elastic fibers was preserved after pressurized treatment, regardless solvent composition. In conclusion, pressurized CO2-ethanol fluids offer an efficient tool for delipidation in bio-scaffold production, while pressurized CO2-limonene fluids facilitate subsequent enzymatic removal of DNA.


Does smoking increase relapse rates in Graves' disease?
We wondered whether the relapse rate of Graves' hyperthyroidism was increased amongst patients who smoked. To this end, a retrospective analysis of clinical and laboratory data of consecutive patients with Graves' disease was carried out. All patients were treated with thionamide anti-thyroid drugs (ATD) for at least one year and remission was defined as continued and biochemical euthyroidism, at least 6 months after discontinuing ATD. The study comprised 221 subjects with Graves' disease from a hospital-based population over 9 years. We took the following variables into account when assessing contribution to disease relapse: Goiter, Thyroid Associated Ophthalmopathy (TAO), and Time to euthyroidism after starting ATD and interaction between smoking and sex. Smoking had a marginally significant (p=0.081) deleterious effect on the likelihood of remission after ATD treatment for Graves' disease. The effect of smoking was, however, highly significant in males and indeed the deleterious effect on remissions may be restricted to males (odds ratio, 11.1; 95% confidence interval, 1.25 to 98.5). The presence of goiter (odds ratio, 3.8; 95% confidence interval, 2.05 to 7.1) and TAO (odds ratio, 1.8; 95% confidence interval, 0.993 to 3.18) forecasted lower chances of achieving remission. The shorter the time a patient became euthyroid after starting ATD the more likely his disease was to remit. We conclude that cigarette smoking increases the likelihood of Graves' disease recurrence in males treated with anti-thyroid drugs. Thus, smoking appears to be an important risk factor in the pathogenesis and outcome of Graves' disease patients at least in subsets of patients.


Infant feeding effects on early neurocognitive development in Asian children.
Breastfeeding has been shown to enhance global measures of intelligence in children. However, few studies have examined associations between breastfeeding and specific cognitive task performance in the first 2 y of life, particularly in an Asian population. We assessed associations between early infant feeding and detailed measures of cognitive development in the first 2 y of life in healthy Asian children born at term. In a prospective cohort study, neurocognitive testing was performed in 408 healthy children (aged 6, 18, and 24 mo) from uncomplicated pregnancies (i.e., birth weight >2500 and <4000 g, gestational age ≥37 wk, and 5-min Apgar score ≥9). Tests included memory (deferred imitation, relational binding, habituation) and attention tasks (visual expectation, auditory oddball) as well as the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Children were stratified into 3 groups (low, intermediate, and high) on the basis of breastfeeding duration and exclusivity. After potential confounding variables were controlled for, significant associations and dose-response relations were observed for 4 of the 15 tests. Higher breastfeeding exposure was associated with better memory at 6 mo, demonstrated by greater preferential looking toward correctly matched items during early portions of a relational memory task (i.e., relational binding task: P-trend = 0.015 and 0.050 for the first two 1000-ms time bins, respectively). No effects of breastfeeding were observed at 18 mo. At 24 mo, breastfed children were more likely to display sequential memory during a deferred imitation memory task (P-trend = 0.048), and toddlers with more exposure to breastfeeding scored higher in receptive language [+0.93 (0.23, 1.63) and +1.08 (0.10, 2.07) for intermediate- and high-breastfeeding groups, respectively, compared with the low-breastfeeding group], as well as expressive language [+0.58 (-0.06, 1.23) and +1.22 (0.32, 2.12) for intermediate- and high-breastfeeding groups, respectively] assessed via the BSID-III. Our findings suggest small but significant benefits of breastfeeding for some aspects of memory and language development in the first 2 y of life, with significant improvements in only 4 of 15 indicators. Whether the implicated processes confer developmental advantages is unknown and represents an important area for future research. This trial was registered at www.clinicaltrials.gov as NCT01174875.


Most of ADP x glucose linked to starch biosynthesis occurs outside the chloroplast in source leaves.
Sucrose and starch are end products of two segregated gluconeogenic pathways, and their production takes place in the cytosol and chloroplast of green leaves, respectively. According to this view, the plastidial ADP.glucose (ADPG) pyrophosphorylase (AGP) is the sole enzyme catalyzing the synthesis of the starch precursor molecule ADPG. However, a growing body of evidences indicates that starch formation involves the import of cytosolic ADPG to the chloroplast. This evidence is consistent with the idea that synthesis of the ADPG linked to starch biosynthesis takes place in the cytosol by means of sucrose synthase, whereas AGP channels the glucose units derived from the starch breakdown. To test this hypothesis, we first investigated the subcellular localization of ADPG. Toward this end, we constructed transgenic potato plants that expressed the ADPG-cleaving adenosine diphosphate sugar pyrophosphatase (ASPP) from Escherichia coli either in the chloroplast or in the cytosol. Source leaves from plants expressing ASPP in the chloroplast exhibited reduced starch and normal ADPG content as compared with control plants. Most importantly however, leaves from plants expressing ASPP in the cytosol showed a large reduction of the levels of both ADPG and starch, whereas hexose phosphates increased as compared with control plants. No pleiotropic changes in photosynthetic parameters and maximum catalytic activities of enzymes closely linked to starch and sucrose metabolism could be detected in the leaves expressing ASPP in the cytosol. The overall results show that, essentially similar to cereal endosperms, most of the ADPG linked to starch biosynthesis in source leaves occurs in the cytosol.


Second-generation dopamine agonists and recollection impairments in Parkinson's disease.
A selective deficit in the recollection of episodic details is frequently reported in Parkinson's disease (PD). Previous explanations implicate dopamine dysregulation in prefrontal structures on which strategic memory processes rely. However, neuroimaging advancements suggest dopaminergic dysregulation of hippocampally dependent memory processes. Accordingly, dopamine agonists, which target D3 receptors in the hippocampus, may impair hippocampal functioning, causing a more pronounced recollection decline. Recognition memory (RM), familiarity, and recollection were examined in 21 patients with mild-to-moderate PD (Hoehn and Yahr mean: 2.67). Patients were subdivided into two subgroups according to dopamine agonist (pramipexole [PPX] or ropinirole [RPR]), and completed matched versions of an RM test in a medicated and unmedicated condition (termed ON and OFF, respectively). Ten demographically matched healthy volunteers (HVs) also completed both RM tasks in two separate sessions. The PD group (PPX and RPR subgroups combined) showed impairments in RM and recollection, but spared familiarity. When subdivided by dopamine agonist, the PPX subgroup's ON-medication recollection performance was significantly lower than that of both the HVs and RPR subgroup. There was no evidence of decline in OFF-medication recollection or familiarity in either the PPX or RPR subgroups. Recollection in both PD subgroups correlated positively with a composite measure of recall, but not prefrontally dependent measures of cognitive control. These findings suggest that mild-to-moderate PD patients may show relatively preserved recollection and familiarity, but that recollection is selectively disrupted by PPX, but not RPR and that this effect may depend on disrupted hippocampal function rather than impaired pre-frontally dependent executive functions.


Characterization of structural changes in vimentin bearing an epidermolysis bullosa simplex-like mutation using site-directed spin labeling and electron paramagnetic resonance.
Mutations in intermediate filament protein genes are responsible for a number of inherited genetic diseases including skin blistering diseases, corneal opacities, and neurological degenerations. Mutation of the arginine (Arg) residue of the highly conserved LNDR motif has been shown to be causative in inherited disorders in at least four different intermediate filament (IF) proteins found in skin, cornea, and the central nervous system. Thus this residue appears to be broadly important to IF assembly and/or function. While the genetic basis for these diseases has been clearly defined, the inability to determine crystal structure for IFs has precluded a determination of how these mutations affect assembly/structure/function of IFs. To investigate the impact of mutation at this site in IFs, we have mutated the LNDR to LNDS in vimentin, a Type III intermediate filament protein, and have examined the impact of this change on assembly using electron paramagnetic resonance. Compared with wild type vimentin, the mutant shows normal formation of the coiled coil dimer, with a slight reduction in the stability of the dimer in rod domain 1. Probing the dimer-dimer interactions shows the formation of normal dimer centered on residue 191 but a failure of dimerization at residue 348 in rod domain 2. These data point toward a specific stage of assembly at which a common disease-causing mutation in IF proteins interrupts assembly.


Conformational changes, plasma membrane penetration, and infection by human rhinovirus type 2: role of receptors and low pH.
Human rhinovirus type 2 (HRV2) is internalized by members of the low-density lipoprotein (LDL) receptor (LDLR) family. It then progresses into late endosomes, where it undergoes conversion from D- to C-antigenicity at pH < 5.6. Upon uncoating, the viral RNA is transferred into the cytoplasm across the endsosomal membrane. However, C-antigenic particles fail to attach to LDLR; this raised the question of whether the virus remains attached to the receptors and is carried to late compartments or rather falls off at the higher pH in early endosomes. We therefore determined the pH dependence of virus-receptor dissociation and virus conversion to C-antigen under conditions preventing endocytosis. (35)S-HRV2 was attached to HeLa cells at 4 degrees C and incubated in buffers of pH 7.4 to 5.0; levels of native virus and C-antigenic particles remaining cell associated or having been released into the medium were determined by immunoprecipitation. At pH 6.0, HRV2 was readily released from plasma membrane receptors in its native form, whereas at pH < or = 5.4, it was entirely converted to C-antigen, which, however, only dissociated from the surface upon prolonged incubation. The antigenic conversion occurred at the same pH regardless of whether HRV2 was free in solution or bound to its receptors. These data suggest that, in vivo, the virus is no longer bound to its receptors when the antigenic conversion and uncoating occur in more acidic late endosomes. When virus was bound to HeLa cells at 4 degrees C, converted into C-antigen by exposure to pH 5.3, and subsequently warmed to 34 degrees C in the presence of bafilomycin (to prevent endosomal uncoating), viral de novo synthesis was detected. This study demonstrates for the first time that a nonenveloped virus such as HRV2 can infect from the plasma membrane when artificially exposed to low pH. This implies that the viral RNA can gain access to the cytoplasm from the plasma membrane.


Multivariate genome-wide analyses of the well-being spectrum.
We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.


Mycobacterium tuberculosis Rv0679c protein sequences involved in host-cell infection: potential TB vaccine candidate antigen.
To date, the function of many hypothetical membrane proteins of Mycobacterium tuberculosis is still unknown and their involvement in pathogen-host interactions has not been yet clearly defined. In this study, the biological activity of peptides derived from the hypothetical membrane protein Rv0679c of M. tuberculosis and their involvement in pathogen-host interactions was assessed. Transcription of the Rv0679c gene was studied in 26 Mycobacterium spp. Strains. Antibodies raised against putative B-cell epitopes of Rv0679c were used in Western blot and immunoelectron microscopy assays. Synthetic peptides spanning the entire length of the protein were tested for their ability to bind to A549 and U937 cells. High-activity binding peptides (HABPs) identified in Rv0679c were tested for their ability to inhibit mycobacterial invasion into cells. The gene encoding Rv0679c was detected in all strains of the M. tuberculosis complex (MTC), but was only transcribed in M. tuberculosis H37Rv, M. tuberculosis H37Ra and M. africanum. Anti-Rv0679c antibodies specifically recognized the protein in M. tuberculosis H37Rv sonicate and showed its localization on mycobacterial surface. Four HABPs inhibited invasion of M. tuberculosis to target cells by up to 75%. The results indicate that Rv0679c HABPs and in particular HABP 30979 could be playing an important role during M. tuberculosis invasion of host cells, and therefore could be interesting research targets for studies aimed at developing strategies to control tuberculosis.


Ultrasound-Guided Serratus Plane Block and Fast-Track Tracheal Extubation in the Operating Room for Thoracic Trauma Patients: A Case Report.
Painful rib fractures may be a factor in trauma patients remaining intubated and being given postoperative mechanical ventilation after emergency surgery. Regional techniques could provide sufficient analgesia in these patients to enable weaning and extubation and thus prevent or minimize complications related to prolonged ventilatory support. We describe a trauma patient with multiple rib fractures requiring an emergency splenectomy for whom an ultrasound-guided serratus plane block provided good quality pain relief for his rib fractures and enabled fast-track extubation in the operating room.


In vivo identification of solar radiation-responsive gene network: role of the p38 stress-dependent kinase.
Solar radiation is one of the most common threats to the skin, with exposure eliciting a specific protective cellular response. To decrypt the underlying mechanism, we used whole genome microarrays (Agilent 44K) to study epidermis gene expression in vivo in skin exposed to simulated solar radiation (SSR). We procured epidermis samples from healthy Caucasian patients, with phototypes II or III, and used two different SSR doses (2 and 4 J/cm(2)), the lower of which corresponded to the minimal erythemal dose. Analyses were carried out five hours after irradiation to identify early gene expression events in the photoprotective response. About 1.5% of genes from the human genome showed significant changes in gene expression. The annotations of these affected genes were assessed. They indicated a strengthening of the inflammation process and up-regulation of the JAK-STAT pathway and other pathways. Parallel to the p53 pathway, the p38 stress-responsive pathway was affected, supporting and mediating p53 function. We used an ex vivo assay with a specific inhibitor of p38 (SB203580) to investigate genes the expression of which was associated with active p38 kinase. We identified new direct p38 target genes and further characterized the role of p38. Our findings provide further insight into the physiological response to UV, including cell-cell interactions and cross-talk effects.


Evaluation of prostate volume in mpMRI: comparison of the recommendations of PI-RADS v2 and PI-RADS v2.1.
We aimed to evaluate the prostate volumes calculated as recommended in the PI-RADS v2 and PI-RADS v2.1 guidelines, intraobserver and interobserver variability, and the agreement between the two measurement methods. Prostate mpMRI examinations of 114 patients were evaluated retrospectively. T2-weighted sequences in the axial and sagittal planes were used for the measurement of the prostate volume. The measurements were performed by two independent observers as recommended in the PI-RADS v2 and PI-RADS v2.1 guidelines. Both observers conducted the measurements twice and the average values were obtained. In order to prevent bias, the observers carried out measurements at one-week intervals. In order to assess intraobserver variability, observers repeated the measurements again at one-week intervals. The prostate volume was calculated using the ellipsoid formula (W×H×L×0.52). Intraclass correlation coefficient (ICC) revealed almost perfect agreement between the first and second observers for the measurements according to both PI-RADS v2 (0.93) and PI-RADS v2.1 (0.96) guidelines. The measurements were repeated by both observers. According to the ICC values, there was excellent agreement between the first and second measurements with respect to both PI-RADS v2 and PI-RADS v2.1 for first (0.94 and 0.96, respectively) and second observer (0.94 and 0.97, respectively). For both observers, the differences had a random, homogeneous distribution, and there was no clear relationship between the differences and mean values. The ellipsoid formula is a reliable method for rapid assessment of prostate volume, with excellent intra- and interobserver agreement and no need for expert training. For the height measurement, the recommendations of the PIRADS v2.1 guideline seem to provide more consistently reproducible results.


Effects of beraprost sodium, a prostacyclin analogue, on diabetic neuropathy in streptozotocin-induced diabetic rats.
The effects of beraprost sodium (BPS), a stable prostacyclin analogue, on motor nerve conduction velocity and nerve blood flow of the sciatic nerve were investigated in streptozotocin-induced diabetic rats, and they were compared with the effects of epalrestat (aldose reductase inhibitor). Treatment with BPS for 4 weeks significantly inhibited the decrease in motor nerve conduction velocity and nerve blood flow dose-dependently, but epalrestat had no effect on nerve blood flow. Morphological changes of the myelinated fibers of the sciatic nerve were observed macroscopically. The mean axonal area and the mean circularity index of diabetic control rats were significantly less than that of normal rats, while after 6 weeks of BPS treatment, these decreases of the axonal area and the circularity index were inhibited. The enlargement of the mean lumen area of microvessels in the diabetic rats was significantly inhibited after 6 weeks of BPS treatment. Additionally, augmentation of the washed platelet aggregation in diabetic rats was significantly normalized by BPS. It was suggested that BPS is effective on diabetic neuropathy via amelioration of the decrease of blood supply to the structure. The effects of BPS on platelets might also contribute to the improvement of neuronal circulatory deficiency.


Human milk oligosaccharides 3'-sialyllactose and 6'-sialyllactose attenuate LPS-induced lung injury by inhibiting STAT1 and NF-κB signaling pathways.
Acute lung injury (ALI) is the leading cause of respiratory diseases induced by uncontrolled inflammation and cell death. Lipopolysaccharide (LPS) is a major trigger of ALI in the progression through macrophage differentiation and the accelerated release of pro-inflammatory cytokines. The present study aimed to investigate the protective effects of human milk oligosaccharides, specifically 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL), on LPS-induced ALI and elucidate their underlying signaling pathways. The inhibitory effects of 3'-SL and 6'-SL on inflammation were evaluated using LPS-treated RAW 264.7 macrophages. To establish the ALI model, mice were treated with 10 mg/kg LPS for 24 h. Histological changes in the lung tissues were assessed using hematoxylin and eosin staining and immunofluorescence. LPS causes thickening of the alveolar wall infiltration of immune cells in lung tissues and increased serum levels of TNF-α, IL-1β, and GM-CSF. However, these effects were significantly alleviated by 100 mg/kg of 3'-SL and 6'-SL. Consistent with the inhibitory effects of 3'-SL and 6'-SL on LPS-induced pro-inflammatory cytokine secretion in serum, 3'-SL and 6'-SL suppressed mRNA expression of TNF-α, IL-1β, MCP-1, iNOS, and COX2 in LPS-induced RAW 264.7 cells. Mechanistically, 3'-SL and 6'-SL abolished LPS-mediated phosphorylation of NF-κB and STAT1. Interestingly, fludarabine treatment, a STAT1 inhibitor, did not affect LPS-mediated NF-κB phosphorylation. In summary, 3'-SL and 6'-SL protect LPS-induced macrophage activation and ALI through the STAT1 and NF-κB signaling pathways.


ST6GalNAcII mediates the invasive properties of breast carcinoma through PI3K/Akt/NF-κB signaling pathway.
Metastasis of tumor cells is the most deadly attribute of breast cancer patients. Aberrant sialylation is closely associated with malignant phenotype of tumor cells, including invasiveness and metastasis. The objective of this study is to clarify the possible role and mechanism of ST6GalNAcII in the metastasis process of breast carcinoma. Real-time PCR, Western blot, and immunohistochemical were used to analyze differential expression of ST6GalNAc II in breast carcinoma cell lines and tissue specimens. PI3K/AKt signaling pathway was also analyzed. The high expression level of ST6GalNAcII was corresponding to invasive phenotype of breast cancer cells both in vitro and in vivo. Further data indicated that manipulation of ST6GalNAcII gene expression led to alter the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway. Blocking the PI3K/Akt pathway resulted in reduced capacity in invasion of MDA-MB-231 cells. ST6GalNAcII elucidated the unusual properties of invasion in breast cancer cell via modulating the PI3K/AKt signaling pathway.


Methylenedioxy group as determinant of schisandrin in enhancing hepatic mitochondrial glutathione in carbon tetrachloride-intoxicated mice.
As a preliminary approach to exploring whether the methylenedioxy group of the dibenzocyclooctadiene skeleton of schisandrins plays an important role in hepatic mitochondrial-reduced glutathione (GSH) stimulatory activity, we examined the effects of three schisandrins, namely schisandrin A (Sch A), schisandrin B (Sch B), and schisandrin C (Sch C), on carbon tetrachloride (CCl4) hepatotoxicity and hepatic mitochondrial GSH status in mice. Pretreating mice with Sch A at a daily oral dose of 1 mmol/kg for 3 days did not protect against CCl4 hepatotoxicity, whereas pretreatment with Sch B or Sch C at the same dosage regimen produced almost complete protection. The hepatoprotection afforded by Sch B or Sch C pretreatment was associated with significant increases in the hepatic mitochondrial GSH level and glutathione reductase (EC 188.8.131.52) activity. Our results indicate that the methylenedioxy group of the dibenzocyclooctadiene skeleton of schisandrin is an important structural determinant in the stimulation of hepatic mitochondrial GSH, particularly under conditions of CCl4 intoxication.


Berberine Induces Autophagic Cell Death in Acute Lymphoblastic Leukemia by Inactivating AKT/mTORC1 Signaling.
Berberine has been reported to inhibit cancer cell growth by apoptosis induction and exhibits a protective role against cancer progression. The current study aims to investigate the effects of berberine on acute lymphoblastic leukemia (ALL) and the mechanism beyond apoptosis. Cell viability was determined in ALL cell lines EU-6 and SKW-3 using trypan blue staining. Cell autophagy was determined by immunofluorescence and Western blot. ALL xenograft mice were established to investigate the anti-tumor effects of BBR. The molecular mechanism was explored in ALL cell lines using siRNA and signaling inhibitors. Herein, we show that berberine treatment significantly inhibits ALL cell viability and promotes cell death by inducing autophagy in a dose-dependent manner. Moreover, berberine significantly alleviates the aggressive pathological condition in ALL xenograft mice. Mechanistic studies exhibit that berberine induces autophagic death in ALL cells by inactivating AKT/mTORC1 signaling. Chemically targeting AKT/mTORC1 signaling controls berberine-induced cell autophagy in vitro, and blockade of autophagic process blunts berberine-alleviated pathological condition in vivo. In conclusion, our study reveals that berberine could induce ALL cell autophagic death by inactivating AKT/mTORC1 signaling that could be used to develop small molecule drug for ALL treatment.


Medical Leaders Identify Personal Characteristics and Experiences that Contribute to Leadership Success in Medicine.
This article was migrated. The article was marked as recommended. Introduction: The approach of medical educators to preparing learners for leadership reflects the emphasis leadership theories once placed on experiential learning. But, contemporary theories now also show a renewed interest in the role of personal characteristics in effective leadership. This shift raises questions explored here: What characteristics mark top medical leaders? What experiences nurture those characteristics? Method: In a 2015 qualitative study, 48 University of Missouri-Kansas City (UMKC) medical graduates who met criteria for outstanding leadership participated in semi-structured interviews. Investigators applied directed content-analysis to their responses. Then, using iterative open-coding, investigators identified personal characteristics leaders said contributed to their leadership, clustered them into types, and counted the number of leaders who spoke to each type. Next, they coded and categorized experiences leaders discussed and counted the number of leaders who mentioned each type of experience. Finally, they identified leaders' comments about which types of experiences helped develop which types of characteristics. Results: Most leadersmentioned four types of characteristics: openness to new ideas/opportunities/astute risk-taking; intense motivation/active involvement/commitment; people-orientation; and capability/competence/ intelligence. Many discussed two additional types: self-awareness and service-orientation. Leaders said these types of experiences nurtured their characteristics: family traditions, high-school co-curricular activities, participation in medical school learning communities plus interaction with role models/mentors and authentic opportunities to practice leadership, innovation, and excellence throughout their education and in the workplace. Conclusions: Medical leaders' views of the role of personal characteristics in outstanding leadership and the power of educational and workplace experiences, especially informal ones, to mold those characteristics have enriched understanding how to prepare tomorrow's leaders.


Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise.
Rahimi, R. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. J Strength Cond Res 25(12): 3448-3455, 2011-Creatine (Cr), or methyl guanidine-acetic acid, can be either ingested from exogenous sources, such as fish or meat, or produced endogenously by the body, primarily in the liver. It is used as an ergogenic aid to improve muscle mass, strength, and endurance. Heretofore, Cr's positive therapeutic benefits in various oxidative stress-associated diseases have been reported in the literature and, recently, Cr has also been shown to exert direct antioxidant effects. Therefore, the purpose of this study was to investigate the effects of an acute bout of resistance exercise (RE) on oxidative stress response and oxidative DNA damage in male athletes and whether supplementation with Cr could negate any observed differences. Twenty-seven resistance-trained men were randomly divided into a Cr supplementation group (the Cr group [21.6 ± 3.6 years], taking 4 × 5 g Cr monohydrate per day) or a placebo (PL) supplementation group (the PL group [21.2 ± 3.2 years], taking 4 × 5 g maltodextrin per day). A double-blind research design was employed for a 7-day supplementation period. Before and after the seventh day of supplementation, the subjects performed an RE protocol (7 sets of 4 exercises using 60-90 1 repetition maximum) in the flat pyramid loading pattern. Blood and urine samples taken before, immediately, and 24-hour postexercise were analyzed for plasma malondialdehyde (MDA) and urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) excretion. Before the supplementation period, a significant increase in the urinary 8-OHdG excretion and plasma MDA levels was observed after RE. The Cr supplementation induces a significant increase in athletics performance, and it attenuated the changes observed in the urinary 8-OHdG excretion and plasma MDA. These results indicate that Cr supplementation reduced oxidative DNA damage and lipid peroxidation induced by a single bout of RE.


High sulfur content in corn dried distillers grains with solubles protects against oxidized lipids by increasing sulfur-containing antioxidants in nursery pigs.
Some sources of corn dried distillers grains with solubles (DDGS) contain relatively high amounts of oxidized lipids produced from PUFA peroxidation during the production process. These oxidized lipids may impair metabolic oxidation status of pigs. The objective of this study was to understand the effects of feeding corn-soybean meal diets (CON) or diets containing 30% highly oxidized DDGS with 1 of 3 levels of supplemental vitamin E (dl-α-tocopheryl acetate), none, the 1998 NRC level (11 IU/kg), and 10x the 1998 NRC level (110 IU/kg), on oxidative status of nursery pigs. The DDGS source used in this study contained the greatest thiobarbituric acid reactive substances (TBARS) value, peroxide value, and total S content (5.2 ng/mg oil, 84.1 mEq/kg oil, and 0.95%, respectively) relative to 30 other DDGS sources sampled (mean values = 1.8 ng/mg oil, 11.5 mEq/kg oil, and 0.50%, respectively). Barrows (n = 54) were housed in pens and fed the experimental diets for 8 wk after weaning and transferred to individual metabolism cages for collection of feces, urine, blood, and liver samples. Total S content was greater in DDGS diets than in CON (0.39 vs. 0.19%). Dietary inclusion of 30% DDGS improved apparent total tract digestibility of S (86.8 vs. 84.6%; P < 0.001) and S retained (2.94 vs. 2.07 g/d; P < 0.01) compared with CON. Although pigs were fed highly oxidized DDGS in this study, serum TBARS were similar between DDGS and CON treatments. There was an interaction between DDGS and dietary vitamin E level for serum concentrations of α-tocopherol. Serum α-tocopherol concentrations were greater (P < 0.001) in pigs fed DDGS diets than those fed CON when dl-α-tocopheryl acetate was not provided or provided at the NRC level but were similar when dl-α-tocopheryl acetate was supplemented at the 10x NRC level. Pigs fed DDGS diets had greater serum concentrations of S-containing AA, particularly Met (P < 0.001) and taurine (P = 0.002), compared with those fed CON. Liver glutathione concentration was greater in pigs fed DDGS diets than CON (56.3 vs. 41.8 nmol/g). Dietary inclusion of DDGS (P < 0.001) and vitamin E (P = 0.03) increased enzyme activity of glutathione peroxidase. The elevated concentrations of S-containing antioxidants (Met, taurine, and glutathione) in vivo may protect pigs against oxidative stress when feeding highly oxidized DDGS. Therefore, the increased S content in DDGS may be beneficial, and increasing concentrations of vitamin E in diets may not be necessary to protect pigs against metabolic oxidative stress when feeding high S and highly peroxidized DDGS.