CD40 mediates retinal inflammation and neurovascular degeneration.
Retinopathies are major causes of visual impairment. We used a model of ischemic retinopathy to examine the role of CD40 in the pathogenesis of retinal injury. Retinal inflammation, loss of ganglion cells, and capillary degeneration were markedly attenuated in ischemic retinas of CD40(-/-) mice. Up-regulation of NOS2 and COX2 after retinal ischemia were blunted in CD40(-/-) mice. NOS2-COX-2 up-regulation in ischemic retinas from wild-type mice was at least in part explained by recruitment of NOS2(+)COX-2(+) leukocytes. Up-regulation of KC/CXCL1 and ICAM-1 also required CD40. Retinal endothelial and Muller cells expressed CD40. Stimulation of these cells through CD40 caused ICAM-1 up-regulation and KC/CXCL1 production. Bone marrow transplant experiments revealed that leukocyte infiltration, ganglion cell loss, and up-regulation of proinflammatory molecules after retinal ischemia were dependent on CD40 expression in the retina and not peripheral blood leukocytes. These studies identified CD40 as a regulator of retinal inflammation and neurovascular degeneration. They support a model in which CD40 stimulation of endothelial and Muller cells triggers adhesion molecule up-regulation and chemokine production, promoting the recruitment of leukocytes that express NOS2/COX-2, molecules linked to neurovascular degeneration.


Protease-Triggered, Integrin-Targeted Cellular Uptake of Recombinant Protein Micelles.
Targeting nanoparticles for drug delivery has great potential for improving efficacy and reducing side effects from systemic toxicity. New developments in the assembly of materials afford the opportunity to expose cryptic targeting domains in tissue-specific microenvironments in which certain proteases are expressed. Here, recombinant proteins are designed to combine the responsiveness to environmental proteases with specific targeting. Materials made recombinantly allow complete control over amino acid sequence, in which each molecule is identically functionalized. Previously, oleosin, a naturally occurring plant protein that acts as a surfactant, has been engineered to self-assemble into spherical micelles-a useful structure for drug delivery. To make oleosins that are locally activated to bind receptors, oleosin is genetically modified to incorporate the integrin-binding motif RGDS just behind a domain cleavable by thrombin. The resulting modified oleosin self-assembles into spherical micelles in aqueous environments, with the RGDS motif protected by the thrombin-cleavable domain. Upon the addition of thrombin, the RGDS is exposed and the binding of the spherical micelles to breast cancer cells is increased fourfold.


Method for preparing cultures of central neurons: cytochemical and immunochemical studies.
We report a simplified method for culturing fetal central nervous system cells predominantly inducing neurons that grow, differentiate, and live in vitro for as long as 10 weeks. These central nervous system cells form a confluent cell culture in which about 80% of the cells are fully differentiated neurons producing interconnecting axons and dendrite processes and live upon a sparse underlying population of fibrillary and protoplasmic astrocytes, oligodendrocytes, and fibroblasts. Morphological and cytochemical characteristics of these cell types, based on immunofluorescent cell specific markers and silver staining of neurons, are presented.


Modulation of cellular gene expression in B lymphoma cells following in vitro infection by Epstein-Barr virus (EBV).
In vitro infection of EBV-negative lymphoma cell lines with immortalizing strains of Epstein-Barr virus induces the cell-surface expression of B-cell markers, such as the EBV receptor/CR2 (CD21) and the CD23 antigen. The non-immortalizing EBV variant, P3HRI, which carries a deletion encompassing the EBV nuclear antigen 2 (EBNA2) gene, fails to induce any such expression. We show here that the EBV-mediated up-regulation of cell-surface expression of these molecules is associated with an increased level of the specific steady-state RNA corresponding to these 2 genes. These results suggest that the role of EBNA2 in B-cell growth and immortalization may be related to its role in transactivation of cellular genes. In order to identify other cellular genes whose expression may be modulated by EBV, we analyzed the level of transcription of a set of genes possibly involved in Burkitt's lymphoma pathogenesis. The level of the c-myc oncogene transcript was not significantly affected by in vitro EBV infection. The c-fgr oncogene, thought to be specifically activated in EBV-infected cells, was found to be expressed in some EBV-negative lymphoma cells and also to be activated by both non-immortalizing and immortalizing strains of EBV. The expression of vimentin, the major 56-kDa polypeptide of mesenchymal cell intermediate filaments, was altered by all EBV isolates, in either a negative or a positive way, depending on the cell line. Expression of lymphocyte-function-associated antigens, LFA-1 alpha/beta (CD11 a/18) and LFA-3 (CD58), involved in intercellular adhesion and the T-cytotoxic pathway, were differentially regulated by EBV; a crucial observation was the activation by immortalizing EBV isolates of LFA-1 beta chain (CD18) and of LFA-3 (CD58). The EBV-and possibly EBNA2-associated modulation of cellular genes, such as CR2 (CD21), CD23 and LFAs, probably represents key events for EBV-induced B-cell proliferation, and also for in vivo immune control of EBV-infected B cells.


Origin of Dual-Peak Phosphorescence and Ultralong Lifetime of 4,6-Diethoxy-2-carbazolyl-1,3,5-triazine.
Recently, ultralong phosphorescence lifetime has been observed in 4,6-diethoxy-2-carbazolyl-1,3,5-triazine, and H-aggregation induced stabilization of the T1 state was suggested as its source. The response theory calculations demonstrate that the Davydov stabilization of the T1 state of the dimer is marginal with respect to the monomer and the corresponding transition moments are virtually the same. Moreover, the calculated radiative rate constant is far from the experimental value, indicating that the ultralong lifetime is not likely to be of electronic origin only. Our calculations reveal that the dual-peak emission from the T1 state is due to strong vibronic coupling between the T1 and S0 states along selected normal modes. Interestingly, the calculated vibronic radiative rate constant of the dimer (2.33 × 10-3 s-1) is comparable to the experimental value (4.7 × 10-3 s-1), supporting the notion that vibronic contributions to the transition moment are responsible for the ultralong lifetime observed in the bulk system.


[Hemolytic anemia in the malfunction of a mitral bioprosthesis].
Valvular cardiac prosthesis have dramatically altered the prognosis of patients with valvular cardiac disease; however, they are not free of complications. Prosthesis disfunction and problems related to anticoagulation are the more common, but hemolytic anemia should also be considered. In this case, hemolytic anemia appears as the major complication of a mitral bioprosthesis; the decision concerning the presentation of this case report rests upon its rarity and peculiar circumstances of appearance. A brief revision of the diagnostic work-up is also made.


Computer image analysis of brain CT images for discriminating hypodense cerebral lesions in children.
A computer software system was designed for the automatic discrimination of focal oedemas from local glioses in brain CT examinations. Image analysis methods were applied to the images of 77 CT examinations of children with focal oedemas (42) or local glioses (35). Textural features derived from the co-occurrence matrix of the lesion's image and a neural network classifier (the multilayer perceptron) were employed for the design of the system. Best classification accuracy (89.6%) was achieved by two textural features (contrast-difference entropy), one hidden layer and three hidden nodes of the classifier. The proposed software system provides new textural information and may be of value to the radiologist in differentiating focal oedemas from local glioses, especially in small lesions, where other radiological criteria are not evident.


Frailty index and risk of cardiovascular diseases: a mendelian randomization study.
Previous epidemiological evidence has suggested that frailty status might be associated with cardiovascular diseases (CVDs). However, the exact causality remains unestablished. In this study, we employed Mendelian randomization and sought to investigate the potential causality in association of frailty index (FI) with cardiovascular outcomes [coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF)]. Independent single nucleotide polymorphisms (SNPs) at genome-wide significance for FI were obtained from a recent genome-wide association study (GWAS) meta-analysis of European descent (n=175,226). The association of these SNPs with CVDs was examined in summary statistics from corresponding GWASs of European descent (CAD: 184,305 cases and 60,801 controls; MI: 184,305 cases and 43,676 controls; AF: 1,030,836 cases and 60,620 controls; and HF: 977,323 cases and 47,309 controls). Replication analyses were performed using GWAS datasets from FinnGen. In the meta-analysis of inverse-variance weighted estimates from different data sources, genetically determined higher FI conferred an odds ratio (OR) of 1.46 [95% confidence interval (CI): 1.13 to 1.87; P=0.003] for CAD, 1.62 (95% CI: 1.21 to 2.17, P=0.001) for MI, and 1.46 (95% CI: 1.24 to 1.72; P=4.89×10-6) for HF. However, FI failed to be potentially influential on AF risk (OR, 1.43; 95% CI: 0.93 to 1.66; P=0.107). Several complementary analyses also received broadly concordant results. We have provided genetic evidence of a causal association between FI and the risk of CAD, MI, and HF. Further studies are warranted to clarify whether FI is causally related to AF risk.


Structural design and preparation of Ti3C2Tx MXene/polymer composites for absorption-dominated electromagnetic interference shielding.
Electromagnetic interference (EMI) is a pervasive and harmful phenomenon in modern society that affects the functionality and reliability of electronic devices and poses a threat to human health. To address this issue, EMI-shielding materials with high absorption performance have attracted considerable attention. Among various candidates, two-dimensional MXenes are promising materials for EMI shielding due to their high conductivity and tunable surface chemistry. Moreover, by incorporating magnetic and conductive fillers into MXene/polymer composites, the EMI shielding performance can be further improved through structural design and impedance matching. Herein, we provide a comprehensive review of the recent progress in MXene/polymer composites for absorption-dominated EMI shielding applications. We summarize the fabrication methods and EMI shielding mechanisms of different composite structures, such as homogeneous, multilayer, segregated, porous, and hybrid structures. We also analyze the advantages and disadvantages of these structures in terms of EMI shielding effectiveness and the absorption ratio. Furthermore, we discuss the roles of magnetic and conductive fillers in modulating the electrical properties and EMI shielding performance of the composites. We also introduce the methods for evaluating the EMI shielding performance of the materials and emphasize the electromagnetic parameters and challenges. Finally, we provide insights and suggestions for the future development of MXene/polymer composites for EMI shielding applications.


In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes.
To investigate the enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. Six compounds, namely rhodamine B, sodium-fluorescein, fluorescein isothiocyanate (FITC) dextrans of 4, 10, 20 and 40 kDa were selected as model drugs. Permeation studies were performed using excised cornea of rabbits by a Franz-type diffusion apparatus. The safety of borneol was assessed on the basis of corneal hydration level and Draize eye test. The application of 0.2% borneol to the cornea increased the apparent permeability coefficient by 1.82-(P<0.05), 2.49-(P<0.05), 4.18-(P<0.05) and 1.11-fold (not significant) for rhodamine B, sodium-fluorescein, FITC-dextrans of 4 and 10 kDa, respectively. No significant permeability enhancement of FITC dextrans of 10, 20 and 40 kDa with borneol was found compared to control. The permeability coefficient enhanced by 0.2% borneol was linear correlated to the molecular weight of model drugs (R(2)=0.9976). With the 0.05%, 0.1% and 0.2% borneol application, the corneal hydration values were <83% and Draize scores were <4. Borneol may improve the transcorneal penetration of both hydrophilic and lipophilic compounds without causing toxic reactions, especially hydrophilic ones. Furthermore, 0.2% borneol can enhance the permeation of hydrophilic compounds with molecular weight ≤4 kDa. Hence, borneol can be considered as a safe and effective penetration enhancer for ocular drug administration.


[Clinical significance of antinuclear antibodies in progressive systemic sclerosis].
Indirect immunofluorescence (IIF) was used to detect antinuclear antibodies (ANA) in 42 clinical cases. In each case cryostatic rat kidney slices and cultivated HEp-2 cells were used as substrates. Clinical diagnoses were as follow: Progressive Systemic Sclerosis (PSS) 25 cases, of which 8 were acrosclerotic, 8 diffuse, 5 CREST syndrome, 1 overlap PSS + Systemic Lupus Erythematosus (SLE) and 3 PSS + myopathy; Localised scleroderma (morphea): 3 cases; Mixed Connective Tissue Disease (MCTD): 3 cases; "Idiopathic" Raynaud's Disease (RD): 4 cases; Dermatomyositis (DM): 2 cases (1 paraneoplastic); SLE: 1 case; Unclassifiable Connective Tissue Disease (UCTD): 4 cases. The ANA-positive cases identified by the traditional technique were divided according to pattern into 4 categories: homogeneous, peripheral, speckled, nucleolar. In contrast those identified using HEp-2 cells were divided into 9 pattern groups: (nuclear type) centromere, fine speckled, coarse speckled, diffusely grainy, homogeneous: (nucleolar type) speckled, clumpy, homogeneous. The results demonstrated a higher general incidence of positivity with HEp-2 cells and confirmed the close connection between Anticentromere ANA and CREST syndrome. A similarly close connection was noted between MCTD and both nuclear diffusely grainy and nucleolar speckled patterns. A fairly clear connection was also noted between acrosclerotic or diffuse SSP and a fine speckled nuclear pattern. It is felt that ANA tests using IFI on HEp-2 cells should lead to significant progress in the field of diagnosis and prognosis and the study of PSS subsets.


Draft Genome Sequence of Dietzia maris DSM 43672, a Gram-Positive Bacterium of the Mycolata Group.
Here, we report the draft genome sequence of Dietzia maris, known previously as Rhodococcus maris It is 3,505,372 bp in size with a G+C content of 73%. The draft genome sequence will improve our understanding of Dietzia maris related to other mycolata species and constitutes a basic tool for exploring the cell wall proteins.


Life-threatening emphysematous liver abscess associated with poorly controlled diabetes mellitus: a case report.
Emphysematous liver abscesses are defined as liver abscesses accompanied by gas formation. The fatality rate is extremely high at 27%, necessitating prompt intensive care. The patient was a 69-year-old Japanese man with type 2 diabetes. He visited the emergency outpatient department for fever and general malaise that had been ongoing for 2 weeks. Abdominal computed tomography revealed an abscess 5 cm in diameter accompanied by gas formation in the right hepatic lobe. Markedly impaired glucose tolerance was observed with a blood sugar level of 571 mg/dL and a glycated hemoglobin level of 14.6%. The patient underwent emergency percutaneous abscess drainage, and intensive care was subsequently initiated. Klebsiella pneumoniae was detected in both the abscess cavity and blood cultures. The drain was removed 3 weeks later, and the patient was discharged. Emphysematous liver abscesses are often observed in patients with poorly controlled diabetes, and the fatality rate is extremely high. Fever and malaise occasionally mask life-threatening infections in diabetic patients, necessitating careful examination.


Juvenile multiple sclerosis: addressing epidemiology, diagnosis, therapeutic, and prognostic updates along with cognitive dysfunction and quality of life.
Juvenile multiple sclerosis (JMS) is a rare but significant subtype of multiple sclerosis (MS) that affects a small percentage of patients under the age of 10 and 3-5% of all MS patients. Despite its rarity, JMS poses unique challenges in terms of diagnosis, treatment, and management, as it can significantly impact a child or adolescent's physical, cognitive, and emotional development. JMS presents with a varying spectrum of signs and symptoms such as coordination difficulties and permanent cognitive dysfunctions and may include atypical clinical features such as seizures, acute disseminated encephalomyelitis, and optic neuritis, making diagnostic evaluations challenging. Whilst the biology of JMS shares similarities with adult-onset MS, there exist notable distinctions in disease progression, clinical manifestations, and ultimate prognoses. The International Pediatric MS Study Group (IPMSSG) was founded in 2005 to improve understanding of JMS, but there remains a lack of knowledge and guidelines on the management of this condition. This review summarizes the current knowledge on JMS, including its epidemiology, clinical presentations, diagnostic challenges, current treatment options, and outcomes. Current treatment options for JMS include disease-modifying therapies, but JMS can also result in impaired quality of life and psychiatric comorbidity, highlighting the need for comprehensive care for affected children. Through gathering and analyzing scattered studies and recent updates on JMS, the authors aim to address the gaps in current knowledge on JMS and provide an improved understanding of appropriate care for affected children. By doing so, this review hopes to contribute to improving the quality of life and outcomes for JMS patients.


Reflective practice: nursing ethics through story telling.
Reflection is a method of learning and teaching professional maturity through the critical analysis of experience. An illuminative research approach was used over a period of five years in collaboration with students on a palliative care course to investigate the effects of learning moral and ethical reasoning by reliving clinical experiences through story telling. This study concludes that: self-concept is enhanced; communication skills are increased; and insight development is part of learning to reason fairly and ethically, and is achieved through a cathartic process, leading to the conceptualization and discovery of theories of nursing through reflective practice.


Morin, a dietary bioflavonol suppresses monosodium urate crystal-induced inflammation in an animal model of acute gouty arthritis with reference to NLRP3 inflammasome, hypo-xanthine phospho-ribosyl transferase, and inflammatory mediators.
The anti-inflammatory effect of morin, a dietary bioflavanol was explored on monosodium urate (MSU) crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. Morin treatment (30mg/kg b.wt) significantly attenuated the ankle swelling and the levels of lipid peroxidation, nitric oxide, serum pro-inflammatory cytokines (tumor necrosis factor (TNF) -α, interleukin (IL)-1β, and IL-6), monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2), and articular elastase along with an increased anti-oxidant status (catalase (CAT) and superoxide dismutase (SOD)) in the joint homogenate of MSU crystal-induced rats. Histological assessment revealed that morin limited the diffusion of joint space, synovial hyperplasia, and inflammatory cell infiltrations. The mRNA expression of NLRP3 (nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain containing 3) inflammasome, caspase-1, pro-inflammatory cytokines, MCP-1, inflammatory enzymes (inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)), and nuclear factor-kappa B (NF-κB) p65 was found downregulated and HPRT (hypo-xanthine phospho-ribosyl transferase) mRNA expression was upregulated in morin treated MSU crystal-induced rats. In addition, morin treatment reduced the protein expression of NF-κB p65, p-NF-κB p65, iNOS, COX-2, and TNF-α. The results clearly demonstrated that morin exert a potent anti-inflammatory effect on MSU crystal-induced inflammation in rats.


Polystyrene nanoplastics induce haematotoxicity with cell oxeiptosis and senescence involved in C57BL/6J mice.
Nanoplastics (NPs) has become a worrying serious environmental problem. However, the toxicological effects and mechanisms of NPs on hematopoiesis are still unknown. To this end, male C57BL/6J mice were directly exposed to the serial concentration gradient of polystyrene NPs (PSNPs, 0, 30, 60, and 120 μg d), respectively, for 42 days by intragastric administration. Results show that PSNPs were clearly visible in bone tissues, meanwhile, induced the count of major blood indicators (WBC, RBC, and LYM) decreased. H&E staining displayed that exposed to PSNPs can cause hematopoietic damage of BM and extramedullary hematopoiesis in spleen. Flow cytometry result show that the proportion of LSK represented a dose-dependent significantly decreased after PSNPs exposure. Further research found that PSNPs can cause the systemic oxidative stress occurs manifested as MDA accumulated. In addition, as the dose of PSNPs increased, the fluorescence intensity of Keap1 and p53 in femur sections gradually increased, meanwhile, the expression of cell oxeiptosis signal pathway Keap1/PGAM5/AIFM1 and the cell senescence signal pathway p53/p21 was all increased, markedly. Overall, our study demonstrated that PSNPs exposure caused oxidative stress, potentially resulting in cell oxeiptosis and senescence to develop haematotoxicity in C57BL/6J mice.


A Meta-analysis and Economic Evaluation of Neonicotinoid Seed Treatments and Other Prophylactic Insecticides in Indiana Maize From 2000-2015 With IPM Recommendations.
Corn rootworm remains the key pest of maize in the United States. It is managed largely by Bt corn hybrids, along with soil insecticides and neonicotinoid seed treatments (NSTs), the latter of which are applied to virtually all conventionally (non-Bt) produced maize. Frequently, more than one of these pest-management approaches is employed at the same time. To determine the utility and relative contributions of these various approaches, a meta-analysis was conducted on plant health and pest damage metrics from 15 yr of insecticide efficacy trials conducted on Indiana maize to compare the pest-protection potential of NSTs to that of other insecticides and Bt hybrids. The probability of recovering the insecticide cost associated with each treatment was also calculated when possible. With the exception of early-season plant health (stand counts), in which the NSTs performed better than all other insecticides, the vast majority of insecticides performed similarly in all plant health metrics, including yield. Furthermore, all tested insecticides (including NSTs) reported a high probability (>80%) of recovering treatment costs. Given the similarity in performance and probability of recovering treatment costs, we suggest NSTs be optional for producers, so that they can be incorporated into an insecticide rotation when managing for corn rootworm, the primary Indiana corn pest. This approach could simultaneously reduce costs to growers, lower the likelihood of nontarget effects, and reduce the risk of pests evolving resistance to the neonicotinoid insecticides.


Treatment of acute posttraumatic stress disorder with brief cognitive behavioral therapy: a randomized controlled trial.
The purpose of this study was to evaluate the efficacy of brief cognitive behavioral therapy for patients with acute posttraumatic stress disorder (PTSD) resulting from various types of psychological trauma. The authors randomly assigned 143 patients with acute PTSD (irrespective of the time criterion), within 3 months after experiencing a traumatic incident, to either brief cognitive behavioral therapy (N=79) or a waiting list comparison group (N=64). Cognitive behavioral therapy consisted of four weekly sessions containing education, relaxation exercises, imaginal exposure, in vivo exposure, and cognitive restructuring. Main outcome measure was PTSD score measured by structured interview; secondary outcomes were anxiety and depression measured by questionnaire. Assessments took place before the intervention and 1 week and 4 months after the intervention. Symptoms of PTSD, anxiety, and depression decreased in both groups over time. One week after the intervention, the cognitive behavioral therapy group had significantly fewer symptoms of PTSD than the comparison group, but this difference was smaller and no longer significant 4 months after the intervention. Similar results were found for anxiety and depression scores. Subgroup analyses showed that cognitive behavioral therapy led to significantly lower PTSD scores at 4 months in patients with baseline comorbid major depression and in patients who were included within the first month after the traumatic incident both at 1 week and at 4 months. Brief early cognitive behavioral therapy accelerated recovery from symptoms of acute PTSD but did not influence long-term results. Brief early cognitive behavioral therapy showed enhanced efficacy in patients with baseline comorbid depression and patients who were included within 1 month after their traumatic experience.


Impact of the maze operation combined with left-sided valve surgery on the change in tricuspid regurgitation over time.
Atrial fibrillation (AF) has been reported to be a predisposing factor for the progression of TR in patients with previous mitral or combined mitral/aortic valve surgery. We hypothesized that the maze operation (MAZE) can prevent the progression of tricuspid regurgitation (TR) in these patients. We analyzed 170 patients (age, 45.5+/-10.9 years) who had undergone mitral or combined mitral/aortic valve surgery. On the basis of preoperative rhythm, patients were divided into 3 groups; GrI was composed of 44 patients with sinus rhythm, GrII of 48 who had undergone MAZE, and GrIII of 78 with AF who had not undergone MAZE. Echocardiographic examinations were performed before, immediately after, and 92.2+/-17.2 (range, 50 to 131) months after surgery. Preoperative and immediate postoperative clinical and echocardiographic parameters were similar among the groups. Insignificant TR at the immediate postoperative examination worsened with time in 7.3% of GrI (3 of 41), 12.8% of GrII (6 of 47), and 38.8% of GrIII (26 of 67) patients at the final examination (P=0.63 for GrI versus GrII, P=0.001 for GrI versus GrIII, P=0.005 for GrII versus GrIII). The incidence of significant TR at the final echocardiographic examination was higher in GrIII (39.7%) compared with GrI (9.1%) and GrII (14.6%) (P=0.001 for GrI versus GrIII, P=0.005 for GrII versus GrIII), whereas GrI and GrII did not show any difference (P=0.63). By multivariate analysis, the only factor identified to prevent TR progression was the group factor (GrI and GrII versus GrIII, P=0.002 and P=0.005, respectively). In a subgroup analysis of GrII according to the presence or absence of atrial mechanical activity, the absence of atrial mechanical activity was identified as an independent parameter for the progression of TR (P=0.001). AF predisposes patients undergoing mitral valve surgery to the progression of TR, which can be prevented by MAZE. This additional benefit of MAZE is largely dependent on the restoration and maintenance of atrial mechanical function.


Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3.
The breakdown of the intestinal epithelial barrier and subsequent increase in intestinal permeability can lead to systemic inflammatory diseases and multiple-organ failure. Nutrition impacts the intestinal barrier, with dietary components such as gluten increasing permeability. Artificial sweeteners are increasingly consumed by the general public in a range of foods and drinks. The sweet taste receptor (T1R3) is activated by artificial sweeteners and has been identified in the intestine to play a role in incretin release and glucose transport; however, T1R3 has not been previously linked to intestinal permeability. Here, the intestinal epithelial cell line, Caco-2, was used to study the effect of commonly-consumed artificial sweeteners, sucralose, aspartame and saccharin, on permeability. At high concentrations, aspartame and saccharin were found to induce apoptosis and cell death in intestinal epithelial cells, while at low concentrations, sucralose and aspartame increased epithelial barrier permeability and down-regulated claudin 3 at the cell surface. T1R3 knockdown was found to attenuate these effects of artificial sweeteners. Aspartame induced reactive oxygen species (ROS) production to cause permeability and claudin 3 internalization, while sweetener-induced permeability and oxidative stress was rescued by the overexpression of claudin 3. Taken together, our findings demonstrate that the artificial sweeteners sucralose, aspartame, and saccharin exert a range of negative effects on the intestinal epithelium through the sweet taste receptor T1R3.


Equilibrium distributions of dipalmitoyl phosphatidylcholine and dilauroyl phosphatidylcholine in a mixed lipid bilayer: atomistic semigrand canonical ensemble simulations.
Conventional molecular dynamics (MD) simulations are seriously limited by the slow rate of diffusive mixing in their ability to predict lateral distributions of different lipid types within mixed-lipid bilayers using atomistic models. A method to overcome this limitation, using configuration-bias Monte Carlo (MC) "mutation" moves to transform lipids from one type to another in dynamic equilibrium, is demonstrated in binary fluid-phase mixtures of lipids whose tails differ in length by four carbons. The hybrid MC-MD method operates within a semigrand canonical ensemble, so that an equilibrium composition of the mixture is determined by a constant difference in chemical potential (Delta(mu)) chosen for the components. Within several nanoseconds, bilayer structures initiated as pure dipalmitoyl phosphatidylcholine (DPPC) or pure dilauroyl phosphatidylcholine (DLPC) converge to a common composition and structure in independent simulations conducted at the same Delta(mu). Trends in bilayer thickness, area per lipid, density distributions across the bilayer, and order parameters have been investigated at three mixture compositions and compared with results from the pure bilayers at 323 K. The mixtures showed a moderate increase in DPPC acyl tail sites crossing the bilayer midplane relative to pure DPPC. Correlations between lateral positions of the two lipid types within or across the bilayer were found to be weak or absent. While the lateral distribution is consistent with nearly ideal mixing, the dependence of composition on Delta(mu) indicates a positive excess free energy of mixing.


Dynamic imaging of the temperature field within an energetic composite using phosphor thermography.
An improved understanding of energy localization ("hot spots") is needed to improve the safety and performance of explosives. We propose a technique to visualize and quantify the properties of a dynamic hot spot from within an energetic composite subjected to ultrasonic mechanical excitation. The composite is composed of an optically transparent binder and a countable number of octahydro 1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) crystals. The evolving temperature field is measured by observing the luminescence from embedded phosphor particles and subsequent application of the intensity ratio method. The spatial temperature precision is less than 2% of the measured absolute temperature in the temperature regime of interest (23°C-220°C). The temperature field is mapped from within an HMX-binder composite under periodic mechanical excitation.


Waves of Change: National Trends in Surgical Management of Male Stress Incontinence.
To determine the trend in surgical management of male stress urinary incontinence (SUI) in the context of the rate of radical prostatectomy (RP) as reported by a national database. Traditionally, the artificial urinary sphincter (AUS) has been the gold standard, but the male sling represents a newer and popular alternative. Refinements in prostate surgery may reduce the incidence and degree of subsequent SUI. A retrospective cross-sectional analysis was performed using the National Inpatient Survey database, which captures discharge data from inpatient and overnight admissions. Cases were identified by their International Classification of Diseases, Ninth Revision procedure codes. We queried the codes 58.93 (implantation of AUS), 59.4 (suprapubic sling operation), 59.5 (retropubic urethral suspension), and 59.6 (paraurethral suspension). We also queried 60.5 (RP) for comparison. Data were collected from January 2000 to December 2012 and weighted to a national average using National Inpatient Survey guidelines. A total of 32,416 anti-incontinence operations (20,790 AUS and 11,625 sling procedures) were performed over the study period. There was a significant downward trend in the total number of incontinence procedures (F(1,11) = 6.15, P = .03). However, when stratifying the data by procedure type, only AUS placement demonstrated a significant decline (F(1,11) = 21.70, P <.01), whereas sling procedures significantly increased (F(1,11) = 12.95, P <.01). There was no significant change in the annual incidence of RP. Inpatient surgery for male SUI is decreasing overall. Placement of the AUS declined significantly, whereas sling placement became more common. Future study will determine the etiology of these trends.


Effect of Intrinsic Disorder and Self-Association on the Translational Diffusion of Proteins: The Case of α-Casein.
Translational diffusion is the major mode of macromolecular transport in leaving organisms, and therefore it is vital to many biological and biotechnological processes. Although translational diffusion of proteins has received considerable theoretical and experimental scrutiny, much of that attention has been directed toward the description of globular proteins. The translational diffusion of intrinsically disordered proteins (IDPs), however, is much less studied. Here, we use a pulsed-gradient nuclear magnetic resonance technique (PFG NMR) to investigate the translational diffusion of a disordered protein in a wide range of concentrations using α-casein that belongs to the class of natively disordered proteins as an example.


Nanocapsules of therapeutic proteins with enhanced stability and long blood circulation for hyperuricemia management.
Among a broad spectrum of medical treatments, protein therapeutics holds tremendous opportunities for the treatment of metabolic disorders, cancer, autoimmune diseases and etc. Broad adaption of protein therapeutics, however, still remain challenging, not only because of poor protein stability, but they also experience fast clearance after administrated and elicit immune responses, resulting in undesirable biodistribution and short blood residence time. In this study, we demonstrate a novel protein delivery method via encapsulating therapeutic proteins within thin shells of poly(N-vinylpyrrolidone) (PVP), which leads to significantly improved protein stability, reduced macrophage uptake, prolonged circulation time and reduced immunogenicity. Exemplified with urate oxidase (UOx), the enzyme used for hyperuricemia treatment, as-formed UOx nanocapsules, n(UOx), exhibits enhanced stability, more significant therapeutic effects, and a more than 10-fold improvement in circulation time when compared with native UOx. This technology not only demonstrates the use of UOx nanocapsules for hyperuricemia management, but also provides a general approach for a broad spectrum of therapeutic proteins for in vivo applications.


Complementation of multiple sulfatase deficiency in somatic cell hybrids.
Multiple sulfatase deficiency (MSD) is an inherited disorder characterized by deficient activity of seven different sulfatases. Genetic complementation for steroid sulfatase (STS), arylsulfatase A, and N-acetylgalactosamine 6-SO4 sulfatase was demonstrated in somatic cell hybrids between MSD fibroblasts and mouse cells ( LA9 ) or Chinese hamster cells ( CHW ). In an electrophoretic system that separates human and rodent STS isozymes, enzyme from hybrids migrated as human enzyme. We concluded that the rodent cell complemented the MSD deficiency and allowed normal expression of the STS structural gene. Some MSD- LA9 hybrids showed significant levels of human arylsulfatase A activity, as shown by the immunoprecipitation of active enzyme by human-specific antiserum. Complementation was also suggested for N-acetylgalactosamine 6- sulfatate sulfatase (GalNAc-6S sulfatase) in several MSD- LA9 hybrids by the demonstration of a significant increase in activity (10-fold) over that of the GalNAc-6S sulfatase-deficient parental mouse and MSD cells. Thus, it was possible to demonstrate complementation for more than one sulfatase in a single MSD-rodent hybrid. Normal levels of sulfatase activity in hybrids indicate that the sulfatase structural genes are intact in MSD cells.


Issues in determining financial competence in the elderly.
With the ever-increasing numbers and relative proportion of elderly in the population, physicians are now frequently facing the difficult task of determining the financial competence of vulnerable individuals. The determination of financial competence in the elderly is still a very poorly defined issue. In this paper an attempt is made to clarify the existing law and the physician's legal obligations. The Mental Health Act, Powers of Attorney Act and Mental Incompetency Act, as they relate to a patient's financial competence, are reviewed. The difficulties in the clinical application of these laws are illustrated by two reports of patients referred to the geriatric psychiatry service of Sunnybrook Medical Centre, University of Toronto. Some general principles and practical guidelines are proposed to help physicians deal more effectively with this issue.


Health Technology Assessment of CEM Pulpotomy in Permanent Molars with Irreversible Pulpitis.
Teeth with irreversible pulpitis usually undergo root canal therapy (RCT). This treatment modality is often considered disadvantageous as it removes vital pulp tissue and weakens the tooth structure. A relatively new concept has risen which suggests vital pulp therapy (VPT) for irreversible pulpitis. VPT with calcium enriched mixture (VPT/CEM) has demonstrated favorable treatment outcomes when treating permanent molars with irreversible pulpitis. This study aims to compare patient related factors, safety and organizational consideration as parts of health technology assessment (HTA) of the new VPT/CEM biotechnology when compared with RCT. Patient related factors were assessed by looking at short- and long-term clinical success; safety related factors were evaluated by a specialist committee and discussion board involved in formulating healthcare policies. Organizational evaluation was performed and the social implications were assessed by estimating the costs, availability, accessibility and acceptability. The impact of VPT/CEM biotechnology was assessed by investigating the incidence of irreversible pulpitis and the effect of this treatment on reducing the burden of disease. VPT/CEM biotechnology was deemed feasible and acceptable like RCT; however, it was more successful, accessible, affordable, available and also safer than RCT. When considering socioeconomic implications on oral health status and oral health-related quality of life of VPT/CEM, the novel biotechnology can be more effective and more efficient than RCT in mature permanent molars with irreversible pulpitis.


Role of topology in electrical properties of bacterio-rhodopsin and rat olfactory receptor I7.
We report on electrical properties of the two sensing proteins: bacteriorhodopsin and rat olfactory receptor OR-I7. As relevant transport parameters we consider the small-signal impedance spectrum and the static current-voltage characteristics. Calculations are compared with available experimental results and the model predictability is tested for future perspectives.


High-Performance Magnesium-Carbon Nanofiber Hygroelectric Generator Based on Interface-Mediation-Enhanced Capacitive Discharging Effect.
This study reports the concept of a water/moisture-induced hygroelectric generator based on the direct contact between magnesium (Mg) alloy and oxidized carbon nanofibers (CNFs). This device generates an open-circuit voltage up to 2.65 V within only 10 ms when the unit is placed in contact with liquid water, which is higher than the reduction potential of magnesium. The average peak short-circuit current density is ∼6 mA/cm2, which is among the highest values yet reported for water-induced electricity generators. Our results indicate that galvanic corrosion occurs at the interface between the CNF and Mg electrode, but the device can still generate electricity because of the high contact resistance caused by the work function difference between Mg and CNF and the surface oxidation. The oxidized CNF is shown to absorb water/moisture and get reduced, leading to a capacitive discharging effect to provide enhanced signal amplitude and sensitivity. These devices are found to be highly sensitive to small quantities of water, and their high output voltage and current make them useful for the detection of water vapor in the human breath as well as changes in ambient humidity. The Mg/CNF systems thus provide a new technology for use in the fabrication of self-powered water/moisture sensors and the development of portable electric power generators.


Successful treatment of refractory thrombocytopenia with mycophenolate mofetil in a patient with systemic lupus erythematosus.
While mild thrombocytopenia in systemic lupus erythematosus (SLE) is frequently seen in the context of active disease, severe thrombocytopenia causing significant bleeding is not that common. Corticosteroids are considered the first line therapy for severe thrombocytopenia in SLE. Second-line therapeutic agents or splenectomy have been reported to be effective for patients who fail to respond to steroids or those who require moderate doses of steroids to maintain the platelet counts. Recent randomized controlled studies have shown that mycophenolate mofetil (MMF) is an efficacious and safe therapeutic agent in patients with proliferative forms of lupus nephritis. However, little information has been available regarding the role of MMF in the treatment of immune thrombocytopenia complicated with SLE. Hereby I describe a patient with SLE in whom thrombocytopenia was refractory to corticosteroids, intermittent intravenous cyclophosphamide, azathioprine, cyclosporine, intravenous gamma globulin, danazol, and splenectomy, and whose platelet counts eventually normalized during therapy with MMF. In this patient, thrombocytopenia is initially thought to be associated with active SLE involving major organ. However, after immunosuppressive agents were given, the refractory nature of thrombocytopenia seems to be an isolated phenomenon, independently of SLE activity.


Sonographic evaluation of the endometrium in patients with a history or an appearance of polycystic ovarian syndrome.
The purpose of this study was to assess the incidence and significance of a thick, cystic-appearing endometrium in association with a history or an ovarian appearance of polycystic ovarian syndrome. An Institutional Review Board-approved, retrospective medical record review of sonographic studies from January 1, 1998, to December 31, 2005, found 245 patients with clinical features, a characteristic sonographic appearance of the ovaries, hormonal abnormalities, or a history of polycystic ovarian syndrome. The sonographic thickness and appearance of the endometrium (homogeneous or heterogeneous) and histologic findings on biopsy were obtained. Two hundred twenty-seven patients had a homogeneous endometrium in the range of 1 to 17 mm (mean +/- SD, 6.4 +/- 3.1 mm); 18 patients had a heterogeneous endometrium in the range of 4 to 23 mm (mean, 13.2 +/- 5.6 mm). Of the 18 patients with a heterogeneous endometrium, 9 also had a sonographic finding of tiny cystic foci within the endometrium. Of these, 5 had endometrial biopsy, resulting in 2 cases of a proliferative endometrium and 1 case each of simple hyperplasia, hyperplasia with atypia, and scant tissue. No cases of hyperplasia were present in the patients with a homogeneous endometrium. A heterogeneous cystic endometrium is associated with the prolonged proliferative phase from chronic anovulation as well as endometrial hyperplasia.


Production of Recombinant Antimicrobial Polymeric Protein Beta Casein-E 50-52 and Its Antimicrobial Synergistic Effects Assessment with Thymol.
Accelerating emergence of antimicrobial resistance among food pathogens and consumers' increasing demands for preservative-free foods are two contemporary challenging aspects within the food industry. Antimicrobial packaging and the use of natural preservatives are promising solutions. In the present study, we used beta-casein-one of the primary self-assembly proteins in milk with a high polymeric film production capability-as a fusion partner for the recombinant expression of E 50-52 antimicrobial peptide in Escherichia coli. The pET21a-BCN-E 50-52 construct was transformed to E. coli BL21 (DE3), and protein expression was induced under optimized conditions. Purified protein obtained from nickel affinity chromatography was refolded under optimized dialysis circumstances and concentrated to 1600 µg/mL fusion protein by ultrafiltration. Antimicrobial activities of recombinant BCN-E 50-52 performed against Escherichia coli, Salmonella typhimurium, Listeria monocytogenes, Staphylococcus aureus, Aspergillus flavus, and Candida albicans. Subsequently, the synergistic effects of BCN-E 50-52 and thymol were assayed. Results of checkerboard tests showed strong synergistic activity between two compounds. Time-kill and growth kinetic studies indicated a sharp reduction of cell viability during the first period of exposure, and SEM (scanning electron microscope) results validated the severe destructive effects of BCN E 50-52 and thymol in combination on bacterial cells.


Mortality and complications after stoma closure.
This study was undertaken to evaluate factors contributing to hospital mortality and complications of stoma closure. Retrospective cohort study. Department of Surgery of a 2500-bed university hospital. Consecutive eligible patients who underwent stoma closure were selected from a local registry containing 30 219 patients. The medical records of 587 adult patients were reviewed according to a predefined extraction form. Patients with additional, unrelated surgical interventions or younger than 18 years were excluded. Follow-up was complete for all included patients. The primary outcome variable was 30-day mortality; the secondary outcome variable was presence of surgery-related complications within 30 days. We analyzed 533 patients with stoma closure between 1993 and 2001. The overall stoma closure-related mortality rate was 3% (15 patients); the overall stoma closure-related surgical complications rate was 20% (107 patients). Wound infections (9%) and anastomotic leakage (5%) were the most common surgical complications. Age was the only significant risk factor for survival (P = .02). Use of a soft silicone drain for intraperitoneal drainage (odds ratio, 1.62 [95% confidence interval, 1.07-2.45]; P = .03) was the only significant risk factor for complications. In patients with carcinoma as the primary disease (odds ratio, 0.61 [95% confidence interval, 0.40 to 0.93]; P = .02), we observed significantly fewer complications. We found considerable mortality and complications after stoma closure. Apart from age, we could not identify any predictor for mortality in patients with stoma closure. Randomized studies are needed to determine whether certain types of drains influence outcome.


Recessive embryonic lethal mutations uncovered in heterozygous condition in silkworm semiconsomic strains.
In this study, we found two embryonic lethal mutations, t04 lethal (l-t04) and m04 lethal (l-m04), in semiconsomic strains T04 and M04, respectively. In these semiconsomic strains, the entire diploid genome, except for one chromosome 4 of the wild silkworm Bombyx mandarina, is substituted with chromosomes of the domesticated silkworm B. mori, and l-t04 and l-m04 mutations are located on B. mandarina-derived chromosome 4. To clarify the cause of the lethalities and the genes responsible for these mutations, positional cloning and CRISPR/Cas9 mediated knockout screening were performed. Finally, genetic complementation tests identified the mutations responsible for the l-t04 and l-m04 as the Bombyx homolog of imaginal discs arrested (Bmida) and TATA box binding protein-associated factor 5 (BmTaf5), respectively. Lethal stages of each knockout mutant indicated the importance of these genes in B. mori late embryogenesis. The lethal mutations responsible for l-t04 and l-m04 were not found in parental strains or wild B. mandarina collected from 39 distinct locations in Japan, indicating that both mutations were independently introduced during or after the development of the semiconsomic strains. We conclude that the recessive embryonic lethality in the T04 and M04 strains is due to deleterious mutations produced in B. mandarina-derived chromosome 4.


Molecular identity and calmodulin-mediated regulation of the taurine transporter in a human retinal pigment epithelial cell line.
The molecular identity and calmodulin-mediated regulation of the taurine transporter were investigated in a human retinal pigment epithelial cell line (HRPE). Reverse transcription-polymerase chain reaction amplification of HRPE cell mRNA using primer specific for a taurine transporter cloned from human placenta yielded a product of expected size (approximately 0.9 kb) which hybridized to the placental cDNA probe under high stringency conditions. The nucleotide sequence of the product was identical to the sequence of the portion of the placental taurine transporter cDNA flanked by the specific primers. The taurine transporter expressed in the HRPE cell line thus appears to be identical to the transporter cloned from the placenta. Treatment of the HRPE cells with a selective calmodulin antagonist CGS 9343 B (CGS) led to a marked decrease in taurine transport activity. This effect could be reproduced with W-7, another calmodulin antagonist. The inhibition caused by CGS occurred rapidly (t1/2 approximately 10 min). Treatment of the cells with CGS did not affect the transport of leucine, and amino acid not recognized by the taurine transporter as a substrate. The CGS-induced inhibition of taurine transport was accompanied by a decrease in the maximal velocity of the transporter with no detectable change in the substrate affinity. The steady state levels of the transporter mRNA however remained unaffected by CGS treatment. It is concluded that the HRPE cell line expressed a taurine transporter identical to the transporter describe in the human placenta and that the function of this transporter is regulated by calmodulin-dependent processes.


Multiple active voltage stabilizations for multi-reflection time-of-flight mass spectrometry.
The performance of a multi-reflection time-of-flight (MR-ToF) mass spectrometer is evaluated under the use of four voltage feedback loops to actively regulate its mirror potentials. Different electronic hardware is characterized to find the most useful configuration for parallel regulation of all of the MR-ToF analyzer's reflecting potentials. The gain in mass resolving power for low-abundance ion species is demonstrated by measuring pairs of molecular isobars of zinc clusters and analyzed in the context of expected flight-time fluctuations. For higher-abundance species, the resolving powers reached in short- and long-term measurements are probed with bismuth-cluster ions, resulting in values up to 500 000 and 200 000, respectively, in the absence of offline corrections. Additionally, feedback-loop regulation is found to be advantageous for changes of experiment cycles in which voltages are switched for, e.g., ion ejection.


Gonadotropins--domestic animals.
The application of RIAs for the gonadotropins to the study of domestic animal reproduction has depended on the availability of sensitive and specific reagents, automated systems for increased throughput and an awareness of the assay errors. Illustrations are given on the measurement of seasonal, surge and episodic changes in LH secretion and the advantages gained by such investigation are outlined.


Classification of Rhinoentomophthoromycosis into Atypical, Early, Intermediate, and Late Disease: A Proposal.
Rhinoentomophthoromycosis, or rhino-facial conidiobolomycosis, is a rare, grossly disfiguring disease due to an infection with entomophthoralean fungi. We report a case of rhinoentomophthoromycosis from Gabon and suggest a staging system, which provides information on the prognosis and duration of antifungal therapy. We present a case of rhinoentomophthoromycosis including the histopathology, mycology, and course of disease. For the suggested staging system, all cases on confirmed rhinoentomophthoromycosis published in the literature without language restriction were eligible. Exclusion criteria were missing data on (i) duration of disease before correct diagnosis, (ii) outcome, and (iii) confirmation of entomophthoralean fungus infection by histopathology and/or mycology. We classified cases into atypical (orbital cellulitis, severe pain, fever, dissemination), early, intermediate, and late disease based on the duration of symptoms before diagnosis. The outcome was evaluated for each stage of disease. The literature search of the Medpilot database was conducted on January 13, 2014, (updated on January 18, 2015). The search yielded 8,333 results including 198 cases from 117 papers; of these, 145 met our inclusion criteria and were included in the final analysis. Median duration of treatment was 4, 3, 4, and 5 months in atypical, early, intermediate, and late disease, respectively. Cure rates were clearly associated with stage of disease and were 57%, 100%, 82%, and 43% in atypical, early, intermediate, and late disease, respectively. We suggest a clinical staging system that underlines the benefit of early case detection and may guide the duration of antifungal treatment. The scientific value of this classification is its capacity to structure and harmonize the clinical and research approach towards rhinoentomophthoromycosis.


Regulated phosphorylation of secretory granule membrane proteins of the rat parotid gland.
An antiserum raised against purified rat parotid secretory granule membrane proteins has been used to identify organelle-specific protein phosphorylation events following stimulation of intact cells from the rat parotid gland. After lobules were prelabeled with [32P]orthophosphate and exposed to secretagogues, phosphoproteins were immunoprecipitated with the granule membrane protein antiserum, separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and visualized by autoradiography. Parallel studies of stimulated amylase release were performed. Isoproterenol treatment of parotid lobules resulted in an increase in the phosphate content of immunoprecipitable 60- and 72-kDa proteins that correlated with amylase release in a time-dependent manner. Forskolin addition mimicked these effects, but only the isoproterenol effects were reversed by propranolol treatment. To confirm the specificity of the antiserum to the secretory granule membrane fraction, subcellular isolation techniques were employed following in situ phosphorylation. The 60- and 72-kDa phosphoproteins were immunoprecipitated from both a particulate fraction and a purified secretory granule fraction. Furthermore, the extraction properties of both species suggest that they are integral membrane proteins. These findings support the possibility that stimulus-regulated secretion may involve phosphorylation of integral membrane proteins of the exocrine secretory granule.


Mechanistic studies on regioselective dephosphorylation of phosphate prodrugs during a facile synthesis of antitumor phosphorylated 2-phenyl-6,7-methylenedioxy-1H-quinolin-4-one.
Phosphorylation of 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxy-1H-quinolin-4-one (1) afforded diphosphate 2. We found that, upon treatment with methanol under mild conditions, 2 can undergo facile and highly regioselective dephosphorylation to give the monophosphate 3, with a phosphate group remaining on the phenyl ring. The details of the dephosphorylation process were postulated and then probed by LC-MS and HPLC analyses. Furthermore, as a preliminary study, the water soluble monophosphate prodrug 4 was tested for antitumor activity against a MCF-7 xenograft nude mice model.


Encapsulation of a quinolone in liposomes. Location and effect on lipid bilayers.
The effect of a new fluoroquinolone on the distearoyl phosphatidylcholine (DSPC) bilayers was examined above and below the phase transition temperature (Tm) of the lipid. It was found by photon correlation spectroscopy that size and polydispersity of the extruded liposomes were unaffected by quinolone. Moreover, fluorescence quenching methods revealed a low fraction (13%) of non-accessible population of drug in the vesicles. This was interpreted in terms of encapsulation efficiency. However, variations in size correlated with decrease in the values of precipitation factor (P). These results reveal the instability of quinoline-DSPC liposomes beyond 5 days.


[Expert consensus on newborn screening for spinal muscular atrophy (2023 edition)].
Spinal muscular atrophy (SMA) is a common degenerative neurological disease characterized by progressive muscle weakness and atrophy. In recent years, disease-modifying therapies have emerged and changed the natural course of SMA, with pre-symptomatic diagnosis and treatment being superior to post symptom treatment. Therefore, in order to standardize and guide the current newborn screening work of SMA, we organized national experts from related fields across the country to reach the following consensus: the SMA newborn screening process and related issues, the SMA post-screening diagnosis process and related issues, and the disease management of screened and confirmed SMA newborns, etc.


[The possibilities of using himantane in the treatment of Parkinson's disease].
The domestic drug himantane has been used as a monotherapy in dosage 25 mg daily during 12 weeks in patients with Parkinson's disease. Patient's state has been assessed using clinical, electromyographic, electroneuromyographic, EEG and psychometric (UPDRS and other scales) methods. The preparation used is well tolerated, induces the significant decrease of movement disorders, i.e. tremor, and exerts a positive effect on emotional and personality disturbances. The clinical changes have been confirmed by electroneuromyographic data and EEG.


A case of congenital corneal anesthesia with hypopyon in china.
To report a case of congenital corneal anesthesia (CCA) associated with hypopyon and tactile hypoesthesia. Case report. A 3-year-old girl presented with redness and mild photophobia in the left eye accompanied by corneal ulcer, hypopyon, and corneal neovascularization. Corneal sensation was reduced bilaterally. She exhibited an absence of normal response to painful stimuli. She also had extensive ulceration of the lateral borders and tip of the tongue. The left corneal biopsy revealed negative cultures for bacteria and fungi. She was treated with human amniotic membrane transplantation in the left eye. The response to treatment was good. This is the first case of CCA reported in China. CCA is often misdiagnosed as infectious keratitis. Amniotic membrane transplantation is effective in repairing the severe corneal ulcer which may be associated with CCA.


Identifying the challenges of holding comprehensive exams in the Ph.D. programs of Iranian medical universities: A protocol for qualitative research.
The purpose of Ph.D. education is to train students equipped with science in a particular area and familiar with research methods and the most recent foundations of education and research to apply their knowledge, creativity, and innovation in research and scientific areas to meet the needs of the society, extending the frontiers of knowledge in their special field, and reach undetected areas in the world of science, especially health. One component of evaluating Ph.D. students in medical universities is the comprehensive exam that aims to assess Ph.D. students' skills, knowledge, and experiences in both educational and research areas. However, the process sometimes encounters substantial administrative challenges and problems. In this study protocol, we will interview. Ph.D. students, members of the examining committees of comprehensive exams, and educational practitioners involved in the administration of the comprehensive exam in District 7 of Iran's medical universities (Isfahan, Kashan, Yazd, and Shaherekord)) as one of the 10 major districts of medical education in the country (Iran). Thus, the present study will identify the challenges of the comprehensive exam to find ways to eliminate them and offer suitable solutions to increase the effectiveness of the exam. Indeed, what is expected from this study is to help educational practitioners and policymakers in medical universities detect the strengths and weaknesses of administering the comprehensive exam and help educational practitioners and policymakers detect potential alternatives for the present comprehensive exam.


HER2 testing in gastric cancer: molecular morphology and storage time-related changes in archival samples.
Seventy-two archival specimens of advanced gastric adenocarcinoma were analyzed by fluorescence in situ hybridization and immunohistochemistry for HER2 gene status. Gene amplification and concomitant protein overexpression were detected in 15.2% of cases. Intratumor topographical variability of HER2 amplification was observed, indicative of the late involvement of HER gene in gastric tumorigenesis. No significant correlations were found between HER2 status and histopathologic type, grade of differentiation, and Goseki classification of carcinomas, suggesting that HER2 gene is variably linked with the morphogenesis of gastric adenocarcinoma. A significant decrease of the incidence of HER2 amplified carcinomas in function of the duration of the storage of paraffin blocks was observed: 42-33% for tumor specimens paraffin-embedded in 2002-2001; 8.3%, 15.7%, 11.1% for the years 2000, 1999, 1998, respectively; 0% for cases embedded during 1997. According to these results, the reliability of the FISH and immunohistochemical assays decreases after prolonged storage of paraffin-embedded specimens.


An evaluation of postvention following adolescent suicide.
This study sought to evaluate postvention provided to two schools following student suicides. A risk index for suicidal behavior among exposed adolescents was devised. The index clearly differentiated high (n = 272) and low (n = 534) scorers on a range of outcome variables. While two-thirds of students attending postvention counselling had two or more putative risk factors for suicidal behavior, a further 231 uncounselled students had similar risk scores. Counselled students (n = 63) did not differ from matched controls (n = 63) at 8-month follow-up on a range of outcome variables. Measures to improve future postvention are discussed.


Expression of DKK1 in Endometrial Endometrioid Carcinoma and Its Correlation with Wnt/β-catenin Signalling Pathway.
Endometrial cancer is the most prevalent form of cancer affecting female reproductive organs. The most common histologic type, endometrioid carcinoma, accounts for 75-80% of all endometrial cancer cases. Studies on DKK1 expression profiles and their inhibitory role in the Wnt signalling pathway in the genesis and development of endometrial carcinoma are scarce. This study aimed to investigate DKK1 expression in endometrial carcinoma and its correlation with the Wnt/β-catenin pathway. A total of 160 formalin-fixed paraffin-embedded samples were included in this study (50 cases of endometrial atypical hyperplasia, 50 cases of endometrioid endometrial carcinoma, 30 cases of proliferative endometrium and 30 cases of secretory endometrium). The expression patterns of DKK1, E-cadherin, β-catenin and c-Myc in endometrial atypical hyperplasia and carcinoma were investigated and compared with that of proliferative and secretory endometrium. Immunohistochemistry and analysis were performed from July 2018 to June 2020. A decreasing pattern of immunopositivity for DKK1, E-cadherin and β-catenin from proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid carcinoma was found. Increasing c-Myc immunopositivity was noted from proliferative/secretory endometrium to endometrial atypical hyperplasia and endometrioid carcinoma. Moreover, decreasing DKK1 immunopositivity was well correlated with E-cadherin, β-catenin and c-Myc immunopositivity. Decreasing DKK1 positivity from benign endometrium to endometrioid carcinoma suggests a negative regulatory function of DKK1 in endometrioid carcinoma. DKK1 is downregulated in the Wnt signalling pathway in endometrioid endometrial carcinoma. Therefore, DKK1 is promising as a biomarker for screening endometrioid carcinoma. Future studies should examine the reactivation of the DKK1 gene, which may be a valuable strategy for antagonising the Wnt signalling pathway.


Under-the-Radar Dengue Virus Infections in Natural Populations of Aedes aegypti Mosquitoes.
The incidence of locally acquired dengue infections increased during the last decade in the United States, compelling a sustained research effort concerning the dengue mosquito vector, Aedes aegypti, and its microbiome, which has been shown to influence virus transmission success. We examined the "metavirome" of four populations of Aedes aegypti mosquitoes collected in 2016 to 2017 in Manatee County, FL. Unexpectedly, we discovered that dengue virus serotype 4 (DENV4) was circulating in these mosquito populations, representing the first documented case of such a phenomenon in the absence of a local DENV4 human case in this county over a 2-year period. We confirmed that all of the mosquito populations carried the same DENV4 strain, assembled its full genome, validated infection orthogonally by reverse transcriptase PCR, traced the virus origin, estimated the time period of its introduction to the Caribbean region, and explored the viral genetic signatures and mosquito-specific virome associations that potentially mediated DENV4 persistence in mosquitoes. We discuss the significance of prolonged maintenance of the DENV4 infections in A. aegypti that occurred in the absence of a DENV4 human index case in Manatee County with respect to the inability of current surveillance paradigms to detect mosquito vector infections prior to a potential local outbreak.IMPORTANCE Since 1999, dengue outbreaks in the continental United States involving local transmission have occurred only episodically and only in Florida and Texas. In Florida, these episodes appear to be coincident with increased introductions of dengue virus into the region through human travel and migration from countries where the disease is endemic. To date, the U.S. public health response to dengue outbreaks has been largely reactive, and implementation of comprehensive arbovirus surveillance in advance of predictable transmission seasons, which would enable proactive preventative efforts, remains unsupported. The significance of our finding is that it is the first documented report of DENV4 transmission to and maintenance within a local mosquito vector population in the continental United States in the absence of a human case during two consecutive years. Our data suggest that molecular surveillance of mosquito populations in high-risk, high-tourism areas of the United States may enable proactive, targeted vector control before potential arbovirus outbreaks.


Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study.
To evaluate the pharmacokinetics of haloperidol after intranasal administration compared with intravenous and intramuscular administration, and to evaluate systemic and local tolerance of intranasal administration. Randomized, open-label, three-way crossover study. Academic medical center. Four healthy volunteers (two men, two women; aged 24-37 yrs). Each subject received in a randomized order the following three treatments, with a 2-week washout period between treatments: intravenous haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml) infused over 15 minutes, intramuscular haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml), and intranasal haloperidol 2.5 mg (2.5 mg/0.1-ml spray into a single naris). Blood samples were obtained serially and plasma levels determined. Noncompartmental analysis was used to estimate pharmacokinetic parameters. Physical and nasal examinations and adverse-effect profiles were obtained to assess tolerance. Mean (percent coefficient of variation) haloperidol bioavailability after intranasal administration was 63.8% (24.4%) compared with intravenous administration and 48.6% (29.4%) compared with intramuscular administration. Intranasal administration achieved higher peak levels that occurred more quickly compared with intramuscular administration. Median time to maximum concentration was 15 minutes after the intranasal dose compared with 37.5 and 15 minutes after the intramuscular and intravenous doses, respectively. Subjects had mild-to-moderate systemic adverse effects, all related to an extension of haloperidol's pharmacologic actions. Two of the four subjects complained of mild-tomoderate nasal irritation after the intranasal doses. Our results suggest that additional research studies are warranted for further evaluation of intranasal administration of haloperidol. The product provides rapid therapeutic plasma levels and sedation, with only minor and short-lived nasal irritation. These data suggest that intranasal administration of haloperidol, or other antipsychotics with similar potency, could play a role in treating psychiatric emergencies.


Amyloid β Proteoforms Elucidated by Quantitative LC/MS in the 5xFAD Mouse Model of Alzheimer's Disease.
Numerous Aβ proteoforms, identified in the human brain, possess differential neurotoxic and aggregation propensities. These proteoforms contribute in unknown ways to the conformations and resultant pathogenicity of oligomers, protofibrils, and fibrils in Alzheimer's disease (AD) manifestation owing to the lack of molecular-level specificity to the exact chemical composition of underlying protein products with widespread interrogating techniques, like immunoassays. We evaluated Aβ proteoform flux using quantitative top-down mass spectrometry (TDMS) in a well-studied 5xFAD mouse model of age-dependent Aβ-amyloidosis. Though the brain-derived Aβ proteoform landscape is largely occupied by Aβ1-42, 25 different forms of Aβ with differential solubility were identified. These proteoforms fall into three natural groups defined by hierarchical clustering of expression levels in the context of mouse age and proteoform solubility, with each group sharing physiochemical properties associated with either N/C-terminal truncations or both. Overall, the TDMS workflow outlined may hold tremendous potential for investigating proteoform-level relationships between insoluble fibrils and soluble Aβ, including low-molecular-weight oligomers hypothesized to serve as the key drivers of neurotoxicity. Similarly, the workflow may also help to validate the utility of AD-relevant animal models to recapitulate amyloidosis mechanisms or possibly explain disconnects observed in therapeutic efficacy in animal models vs humans.


Restructuring the Art of Health by Pharmacists: Formulation Designs with Oral Vehicles--Teaching Pharmacy Students.
Compounding pharmacists, responsible for appropriate preparation of medications, coordinate with other professionals to reach optimal therapeutic options for patients. This review summarizes proprietary oral vehicles or suspensions focusing on available information or updated data from suppliers. Research has advanced methods with revised applications, cutting-edge safety considerations, beyond-use dating provisions for technical assistance, and evidence to review and teach pharmacy students the opportunities in the choices of an oral vehicle. Current marketing, competitive, and scientific trends necessitate that manufacturers shift further to research of product or integrated product mixes to sustain their independence in pharmacies.


Electrical impedance measurements of root canal length.
Electronic methods are now widely used during endodontic treatment for the assessment of root canal length. These commonly measure the electrical resistance or impedance between the root canal and the buccal mucosa. A number of studies have been undertaken to determine the accuracy of commercially available instruments. The aims of this investigation were to determine the electrical impedance characteristics of the root canal and periapical tissues in vivo, measure the changes relative to the distance of an endodontic instrument from the apical constriction and propose an equivalent circuit modelling the periapical tissues. The length of the root canals of 20 previously untreated teeth were determined using radiographic and electronic methods. Minimal canal preparation was carried out and measurements were made with a size 10 K-Flex file. A microprocessor-controlled LCR analyser was used to measure the electrical impedance characteristics of each root canal. The instrument measured the series and parallel resistive (RS, RP) and capacitance (CS, CP) component of the tissues at two test frequencies, 100 Hz and 1 kHz. Measurements were made for each root canal when the diagnostic file was placed at the apical constriction and repeated when the file was withdrawn to -0.5, -1.0, -1.5, -2.0 and -5.0 mm from the foramen. Readings were taken for each canal after the canal had been dried with paper points, and flooded first with deionised water and then with sodium hypochlorite. The root canals were then prepared, cleaned and obturated using standard endodontic procedures. The LCR analyser selected the series resistance component as the major measurement parameter. There was a clear increase in series resistance (RS) with increasing distance from the radiographic apex for dry canals and those containing deionised water and sodium hypochlorite. The mean resistance for dry canals was markedly higher than for those containing fluid, ranging from 22.19 k omega to 92.07 k omega in comparison with 9.32 k omega to 12.10 k omega for deionised water and from 7.46 k omega to 8.92 k omega for canals containing sodium hypochlorite. There was a marked change in the series and parallel resistive component with distance from the apex, suggesting a complex relationship between the impedance of the smear layer and bulk dentine. The impedance characteristics of a root canal were a complex electrical network comprising resistive and capacitive series and parallel elements.


Practice patterns for extended venous thromboembolism chemoprophylaxis among urologic oncologists after radical cystectomy.
Extended outpatient chemoprophylaxis (ECP) following radical cystectomy (RC) for bladder cancer is proven to reduce rates of venous thromboembolism (VTE). While ECP is commonly performed with enoxaparin, its cost-effectiveness and adherence rate has been called into question. Data from orthopedic literature suggest that ECP with direct oral anticoagulants (DOACs) may be as effective in VTE prevention as enoxaparin in patients undergoing joint surgery. Our goal is to determine how urologic oncologists employ ECP following RC. Members of the Society of Urologic Oncology were surveyed on practice patterns for the use of ECP after RC. Specific questions were asked regarding the use of inpatient and outpatient VTE prophylaxis, as well as perceived barriers to DOACs and enoxaparin. There were 121 of 878 (13.8%) respondents and the majority were in academic practices (83%). Most respondents had at least 5 years of experience and performed greater than 10 cystectomies annually. Almost all participants utilized inpatient (97%) and extended (80%) chemoprophylaxis for VTE prevention. Of those who elected for ECP, almost all (96%) used enoxaparin. Only 3 respondents (3%) prescribed oral agents such as rivaroxaban (2) or warfarin (1). Among those using enoxaparin, financial-specific barriers to treatment such as lack of insurance coverage (38%), inability to afford the medication (51%), and need for additional insurance authorization (44%) were reported. Poor patient adherence and refusal to perform injections were reported by 20% and 18% of respondents, respectively. Among the 23 physicians who did not use ECP, cost (39%) and delivery method (26%) were cited as barriers to treatment. The majority of surveyed urologic oncologists are prescribing subcutaneous enoxaparin ECP following RC. Poor patient adherence due to self-injections and financial barriers were frequently reported and represent a possible opportunity for the use of oral anticoagulants in the post-operative setting. These data will be used in the development of a proposed clinical trial of a DOAC in the post-RC setting.


Asynchronous pheochromocytoma in childhood.
A case of asynchronous pheochromocytoma in a 13-year-old boy is reported. Two years elapsed between excision of the right adrenal gland and the appearance of another tumour in the contralateral gland. Selective central venous sampling for plasma catecholamine measurement and adrenal phlebography were of diagnostic value. Excision of the tumour with partial adrenalectomy was the preferred surgical treatment in the remaining contralateral adrenal; no clinical or biochemical abnormalities were observed 2 years after removal of the second pheochromocytoma. This case stresses the importance of a closer follow-up in children for early detection of a second pheochromocytoma.


Assessment of serum apolipoprotein B and apolipoprotein A-1 and their ratio in healthy full term small for gestational age newborns.
Programmed changes in growth restricted fetuses can increase the risk of adulthood diseases due to elevated serum cholesterol and apolipoprotein-B (Apo-B) concentrations. Increasing evidence demonstrated the role of apoB/apoA-I ratio as a strong risk factor for cardiovascular diseases. To determine the concentration of cord blood lipoproteins and apolipoproteins as well as their correlation with birth weight. This cross-sectional study was conducted in a teaching institution in central India. Healthy full-term newborns, born out of normal vaginal deliveries, were recruited. Cases include term small for gestational age (SGA) babies while term appropriate for gestational age (AGA) babies were taken as controls. Their umbilical venous blood was collected and sent for biochemical analysis. Out of 126 healthy newborns, 66 were cases and 60 were controls. Mean values of serum triglyceride (141.56±69.67 mg/dl vs. 113.67±33.38 mg/dl; p < 0.006; 95% CI = 8.31 to 47.46) and serum apo-B/apo-A-1 ratio (0.67±0.28 vs. 0.55±0.20; p < 0.007; 95% CI = 0.033 to 0.206) were significantly high and that of serum high density cholesterol (35.84±10.42 mg/dl vs. 40.73±11.70 mg/dl; p < 0.014; 95% CI = -8.79 to -0.98) and Apo-A1 [87.59±12.44 mg/dl vs. 101.87±35.07 mg/dl; p = 0.002; 95% CI = -23.39 to -5.16) were significantly low in SGA newborns. Serum cholesterol, very low-density cholesterol rlow-density cholesterol rand Apo-B did not show any significant difference. Among SGA newborns significant negative correlation was seen between birth weight and apo-B/apo-A1 and serum triglyceride, while birth weight and serum apo-A1 level showed significant positive correlation. There was no statistically significant correlation between birth weight and other parameters. These findings further support the association of prenatal factors with lipid profile rand can serve as starting point for studying lipid transport system changes during early life in Indian population.


Salmonella-mediated delivery of RNase P-based ribozymes for inhibition of viral gene expression and replication in human cells.
A fundamental challenge in gene therapy is to develop approaches for delivering nucleic acid-based gene interfering agents, such as small interfering RNAs and ribozymes, to the appropriate cells in a way that is tissue/cell specific, efficient, and safe. Using human cytomegalovirus (HCMV) infection of differentiated macrophages as the model, we showed that Salmonella can efficiently deliver RNase P-based ribozyme sequence in specific human cells, leading to substantial ribozyme expression and effective inhibition of viral infection. We constructed a functional RNase P ribozyme (M1GS RNA) that targets the overlapping mRNA region of two HCMV capsid proteins, the capsid scaffolding protein (CSP) and assemblin, which are essential for viral capsid formation. Substantial expression of ribozymes was observed in human differentiated macrophages that were treated with attenuated Salmonella strains carrying the ribozyme sequence constructs. A reduction of 87-90% in viral CSP expression and a reduction of about 5,000-fold in viral growth were observed in cells that were treated with Salmonella carrying the sequence of the functional ribozyme but not with those carrying the sequence of a control ribozyme that contained mutations abolishing the catalytic activity. To our knowledge, this study showed for the first time that ribozymes expressed following targeted gene transfer with Salmonella-based vectors are highly active and specific in blocking viral infection. Moreover, these results demonstrate the feasibility to develop Salmonella-mediated gene transfer of RNase P ribozymes as an effective approach for gene-targeting applications.


Sludge quality after 10-20 years of treatment in reed bed systems.
The effect on the environment of the operation of sludge treatment in reed beds (STRB) system is seen as quite limited compared to traditional sludge treatment systems such as mechanical dewatering, drying and incineration with their accompanying use of chemicals and energy consumption. There are several STRB systems in Denmark receiving sludge from urban wastewater treatment plants. Stabilization and mineralization of the sludge in the STRB systems occur during a period between 10 and 20 years, where after the basins are emptied and the sludge residue typically is spread on agricultural land. In the present study, the sludge residue quality after treatment periods of 10-20 years from four Danish STRBs is presented. After reduction, dewatering and mineralization of the feed sludge (dry solid content of 0.5-3 %) in the STRB systems, the sludge residue achieved up to 26 % dry solid, depending on the sludge quality and dimensioning of the STRB system. The concentration of heavy metals and hazardous organic compounds in the sludge residue that are listed in the Danish and EU legislation for farmland application of sludge was below the limit values. The nitrogen and phosphorus concentrations as an average in the sludge residue were 28 and 36 g/kg dry solid (DS), respectively. In addition, mineralization on average across the four STRB systems removed up to 27 % of the organic solids in the sludge. The investigation showed that the sludge residue qualities of the four STRBs after a full treatment period all complied with the Danish and European Union legal limits for agricultural land disposal.


Reduced α4 subunit expression in α4+- and α4+- /β2+- nicotinic acetylcholine receptors alters α4β2 subtype up-regulation following chronic nicotine treatment.
Genomic analysis has shown many variants in both CHRNA4 and CHRNB2, genes which encode the α4 and β2 subunits of nicotinic ACh receptors (nAChR) respectively. Some variants influence receptor expression, raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic exposure to nicotine increases expression of nAChRs, particularly α4β2-nAChRs, in humans and laboratory animals. Here, we have evaluated whether the initial level of receptor expression affects the increase in expression. Mice differing in expression of α4 and/or β2 nAChR subunits were chronically treated with saline, 0.25, 1.0 or 4.0 mg·kg-1 ·h-1 nicotine. Brain preparations were analysed autoradiographically by [125 I]-epibatidine binding, immunoprecipitation and Western blotting. Immunochemical studies confirmed that most of the [3 H]-epibatidine binding corresponds to α4β2*-nAChR and that increases in binding correspond to increases in α4 and β2 proteins. Consistent with previous reports, the dose-dependent increase in nAChR in wild-type mice following chronic nicotine treatment, measured with any of the methods, reached a maximum. Although receptor expression was reduced by approximately 50% in β2+- mice, the pattern of response to chronic treatment resembled that of wild-type mice. In contrast, both α4+- and α4+- /β2+- exhibited relatively greater up-regulation. Consistent with previous reports, α4β2α5-nAChR did not increase in response to nicotine. These results indicate that mice with reduced expression of the α4 nAChR subunit have a more robust response to chronic nicotine than mice with normal expression of this subunit. This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.


Distinct Mechanisms Underlying Resveratrol-Mediated Protection from Types of Cellular Stress in C6 Glioma Cells.
The polyphenolic phytostilbene, trans-resveratrol, is found in high amounts in several types and tissues of plants, including grapes, and has been proposed to have beneficial effects in the central nervous system due to its activity as an antioxidant. The objective of the present study was to identify the mechanisms underlying the protective effects of resveratrol under conditions of oxidative stress or DNA damage, induced by the extracellularly applied oxidant, tert-butyl hydrogen peroxide, or UV-irradiation, respectively. In C6 glioma cells, a model system for glial cell biology and pharmacology, resveratrol was protective against both types of insult. Prevention of tau protein cleavage and of the formation of neurofibrillary tangles were identified as mechanisms of action of resveratrol-mediated protection in both paradigms of cellular damage. However, depending on the type of insult, resveratrol exerted its protective activity differentially: under conditions of chemically induced oxidative stress, inhibition of caspase activity, while with DNA damage, resveratrol regulated tau phosphorylation at Ser422. Results advance our understanding of resveratrol's complex impact on cellular signaling pathway and contribute to the notion of resveratrol's role as a pleiotropic therapeutic agent.


Resonantly enhanced two photon ionization and zero kinetic energy spectroscopy of jet-cooled 4-aminopyridine.
We report studies of supersonically cooled 4-aminopyridine (4-AP) using two-color resonantly enhanced multiphoton ionization (REMPI) and two-color zero kinetic energy (ZEKE) photoelectron spectroscopy. With the aid of ab initio and density functional calculations, vibrational modes of the first electronically excited state (S1) of the neutral species and those of the cation have been assigned, and the adiabatic ionization potential has been determined to be 62291+/-6 cm(-1). The REMPI spectrum of the S1 state is dominated by ring deformation modes and the inversion mode of the amino group, while the ZEKE spectra demonstrate a strong propensity of Deltav=0, where v is the vibrational quantum number of the intermediate vibronic state from S1. In addition, the ZEKE spectra obtained via different vibrational levels of the S1 state contain four common features, corresponding to the activation of four different vibrational modes of the cation. These observations are explained in terms of the structural changes from the ground state to S1 and further to the cation. The vibrational mode distributions in both the REMPI and the ZEKE spectra, the excitation energy of the S1 state, and the ionization potential of 4-AP, are remarkably similar to those of aniline, suggesting that the electronic activity is centered on the ring.


Human subject research at Armstrong Laboratory, 1973-93: medical and musculoskeletal disqualifications.
The reasons for disqualification of human subjects from 1973-93 at Armstrong Laboratory, formerly the Harry G. Armstrong Aeromedical Research Laboratory (AAMRL), are presented for both sustained and impact acceleration panels. Evaluations for both medical and spinal anomalies were accomplished. The rationale for each disqualification is discussed, demonstrating the variability in each panel physician's clinical judgment in the context of personal bias, the ethical framework surrounding the use of human volunteers, and the existing research milieu.


Supervised exercise training versus usual care in ambulatory patients with left ventricular assist devices: A systematic review.
Implantation of left ventricular assist devices (LVAD) has increased because of improved safety profile and limited availability of heart transplantation. Although supervised exercise training (ET) programs are known to improve exercise capacity and quality of life (QoL) in heart failure (HF) patients, similar data is inconclusive in LVAD patients. Thus, we performed a systematic review on studies that incorporated supervised ET and measured peak oxygen uptake in LVAD patients. A total of 150 patients in exercise and 55 patients in control groups were included from 8 studies selected from our predefined criteria. Our systematic review suggests supervised ET has an inconsistent effect on exercise capacity and QoL when compared to control groups undergoing usual care. A quantitative sub-analysis was performed with 4 studies that provided enough data to compare peak oxygen uptake and QoL at baseline and at follow-up. After at least 6 weeks of training, LVAD patients undergoing supervised ET demonstrated significant improvement in exercise capacity (standardized mean difference [SMD] = 0.735, 95% Confidence Interval-[CI], 0.31-1.15 units of the standard deviation, P = 0.001) and QoL scores (SMD = 1.58, 95% CI 0.97-2.20 units of the standard deviation, P <0.001) when compared to the usual care group, with no serious adverse events with exercise. These results suggest that supervised ET is safe and can improve patient outcomes in LVAD patients when compared to the usual care.


Decrease in infection rate following use of povidone-iodine during transrectal ultrasound guided biopsy of the prostate: a double blind randomized clinical trial.
Infection after transrectal ultrasound (TRUS) guided biopsy of the prostate is a major and potentially life-threatening problem. Using antibiotic premedication can not completely eliminate infection after biopsy. We performed this study to determine the value of using povidone-iodine in prevention of post biopsy infection. Totally, 280 patients who were referred for TRUS guided biopsy of the prostate were divided randomly into two equal groups. The case group received an intrarectal mixture of povidone-iodine and lidocaine gel before performing biopsy, while the control group received only lidocaine gel. Patients were followed up for 30 days for possible signs of infection including fever, chills and dysuria. The mean age in the case group was 68.7 ± 7 years and 68.1 ± 7 years in the control group (P = 0.78). Overall, there were signs and symptoms of infection in 78 patients (27.9%), of which 27 (19.3%) were in the case group, while 51 (36.4%) were in the control group (P = 0.001, OR = 2.4, 95% CI = 1.4-4.1). Simple use of widely available povidone-iodine for cleaning the rectum before TRUS guided prostate biopsy can reduce the infection rate.


Engineered exosomes derived from miR-132-overexpresssing adipose stem cells promoted diabetic wound healing and skin reconstruction.
The tissue reconstruction of diabetic wounds mainly depends on the proliferation and remodelling of cutaneous cells around wounds and the transplantation of random skin flaps, however, the proliferation of cells or survival of skin flaps are difficult due to the severe inflammation and other problems caused by diabetes. The stem cell-derived exosomes loaded with miRNA can be an effective therapeutic strategy for promoting diabetic wound healing. Therefore, in this study, the engineered exosomes derived from miR-132-overexpressing adipose stem cells (miR-132-exo) was obtained for promoting the healing of diabetic wounds and skin flaps. In vitro, the miR-132-exo promoted the proliferation and migration of human umbilical vein endothelial cells (HUVECs). In vivo, streptozotocin (STZ) induced diabetic mice were used to create full-thickness skin wounds and random skin flaps to further investigate the healing effect of miR-132-exo. The results showed miR-132-exo evidently enhanced the survival of skin flaps and promote diabetic wound healing, through reducing local inflammation, promoting angiogenesis and stimulating M2-macrophages polarization mediated by NF-κB signaling pathway. These novel findings demonstrated that engineered miR-132-exo can be a potent therapeutic for treating diabetic wounds and inflammatory-related disease.


MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions.
Natural killer (NK) cells are large granular lymphocytes that promote the antitumor response via communication with other cell types in the tumor microenvironment. Previously, we have shown that NK cells secrete a profile of immune stimulatory factors (e.g., IFNγ, MIP-1α, and TNFα) in response to dual stimulation with the combination of antibody (Ab)-coated tumor cells and cytokines, such as IL12. We now demonstrate that this response is enhanced in the presence of autologous monocytes. Monocyte enhancement of NK cell activity was dependent on cell-to-cell contact as determined by a Transwell assay. It was hypothesized that NK cell effector functions against Ab-coated tumor cells were enhanced via binding of MICA on monocytes to NK cell NKG2D receptors. Strategies to block MICA-NKG2D interactions resulted in reductions in IFNγ production. Depletion of monocytes in vivo resulted in decreased IFNγ production by murine NK cells upon exposure to Ab-coated tumor cells. In mice receiving trastuzumab and IL12 therapy, monocyte depletion resulted in significantly greater tumor growth in comparison to mock-depleted controls (P < 0.05). These data suggest that NK cell-monocyte interactions enhance NK cell antitumor activity in the setting of monoclonal Ab therapy for cancer. Cancer Immunol Res; 5(9); 778-89. ©2017 AACR.


A computational study of vicinal fluorination in 2,3-difluorobutane: implications for conformational control in alkane chains.
A comprehensive conformational analysis of both 2,3-difluorobutane diastereomers is presented based on density functional theory calculations in vacuum and in solution, as well as NMR experiments in solution. While for 1,2-difluoroethane the fluorine gauche effect is clearly the dominant effect determining its conformation, it was found that for 2,3-difluorobutane there is a complex interplay of several effects, which are of similar magnitude but often of opposite sign. As a result, unexpected deviations in dihedral angles, relative conformational energies and populations are observed which cannot be rationalised only by chemical intuition. Furthermore, it was found that it is important to consider the free energies of the various conformers, as these lead to qualitatively different results both in vacuum and in solvent, when compared to calculations based only on the electronic energies. In contrast to expectations, it was found that vicinal syn-difluoride introduction in the butane and by extension, longer hydrocarbon chains, is not expected to lead to an effective stabilisation of the linear conformation. Our findings have implications for the use of the vicinal difluoride motif for conformational control.