Main active components of Ilex rotunda Thunb. protect against ulcerative colitis by restoring the intestinal mucosal barrier and modulating the cytokine-cytokine interaction pathways.
Ilex rotunda Thunb. (IR) is widely used for gastrointestinal diseases by Yao physician, and it has a better clinical curative effect on ulcerative colitis (UC). However, the main active components and mechanism of IR in the treatment of UC remain to be clarified. To investigate the main active components and mechanism of IR in the treatment of UC. Ten biological active components of IR were quantified by UPLC-MS/MS. In vitro, Caco2 cell monolayers were stimulated by lipopolysaccharide, and were treated with 10 biologically active components individually to investigate the protective role of the components of IR in mucosal barrier damage. In vivo, a mouse model of UC was induced by dextran sulfate sodium and administered with the candidate active components of IR. On day 8, the serum and colon tissue were collected for histological and molecular analysis to investigate the main active components and mechanism of IR. Ziyuglycoside I, ziyuglycoside II, syringin, and pedunculoside in IR reduced phenol red transmission of the monolayer, and inhibited the protein expression of oncostatin M and oncostatin M receptor in Caco2 cells. Notably, ziyuglycoside II and syringin decreased the transepithelial electrical resistance of the monolayer, and promoted the protein expression of Occludin, Claudin-1 and zonula occludens-1 (ZO-1) in Caco2 cells. In vivo, ziyuglycoside II and syringin improved the symptoms of UC mice, including body weight, disease activity score, shortening of colon length, damaging of acidic mucus layer, histopathological changes, and protein expression of Occludin, Claudin-1, and ZO-1. Pedunculoside reduced the neutrophils and inflammatory response in the UC mice. Moreover, when the combination of ziyuglycoside II, syringin and pedunculoside was used for the treatment of UC, syringin and pedunculoside enhanced the therapeutic effect of ziyuglycoside II. Finally, RNA sequencing and RT-qPCR analysis revealed that ziyuglycoside II + syringin + pedunculoside and IR coregulated up to 42.7% of genes, and mainly reduced the overexpression of C-X-C motif ligand 1(CXCL1), oncostatin M receptor (OSMR), interleukin 1 receptor type I (IL1R1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), C-X-C motif chemokine 13 (CXCL13), oncostatin M (OSM), and interleukin 6 (IL-6) in the cytokine-cytokine interaction pathways. The combination of ziyuglycoside II, syringin, and pedunculoside protects against UC by modulating the intestinal mucosal barrier and inhibiting the cytokine-cytokine interaction pathways, and the effect is relatively equivalent to that of the water extract of Ilex rotunda Thunb.


PLCL/Silk fibroin based antibacterial nano wound dressing encapsulating oregano essential oil: Fabrication, characterization and biological evaluation.
The use of natural biocompatible drugs is highly desirable in wound dressing compared to synthetic chemicals. Oregano essential oil (OEO) is a promising natural compound with marked antibacterial, antioxidant and anti-inflammatory activities. The topical delivery of OEO may result in lower therapeutic efficacy and irritation to the skin. Moreover, OEO is a volatile compound results in instability as well. To overcome these drawbacks, we successfully encapsulated OEO in Poly (L-lactide-co-caprolactone) (PLCL)/ Silk fibroin (SF) nanofibers membrane (NF) and achieved the encapsulation efficiency (%) up to 59.14 ± 0.58. The fabricated membranes were undergone through physicochemical as well as biological evaluation. SEM characterization revealed that OEO could be successfully encapsulated maintaining a smooth profile of nanofibers. The biocompatibility of the NF membrane was confirmed by cytotoxicity assay. Antibacterial results indicated that OEO containing nanofibrous membranes are highly active against both gram-positive and gram-negative bacteria. The result revealed that 5% is the optimized concentration of OEO capable to completely inhibit bacterial growth. Moreover, the NF membranes were evaluated for their in vivo wound healing potential. The results confirmed that OEO containing NF membrane is not only capable to accelerate the wound contraction but also enhances the quality of wound healing confirmed through histology analysis. H&E and Masson's trichrome staining indicated the neo-epithelialization, granulation tissue formation, angiogenesis, and collagen deposition in a group treated with PLCL/SF/5% OEO. Based on the physicochemical and biological evaluation, PLCL/SF/5% OEO NF membrane can be considered as a potential wound dressing candidate.


A case of subdural hemorrhage due to ruptured cerebral aneurysm presenting with atypical imaging features.
Acute subdural hemorrhage caused by ruptured cerebral aneurysms is rare. Herein, we report an atypical case of subdural hemorrhage caused by ruptured anterior communicating artery aneurysm in a 49-year-old woman. Computed tomography revealed subarachnoid, intracerebral, and subdural hemorrhages. After the treatment with endovascular coiling significantly decreased the patient's subdural hemorrhage. However, the subdural hemorrhage revealed and became iso-attenuation compared with the white matter on the 11th day, and hypo-attenuation on the 19th day. On the 33rd day, this subdural hemorrhage completely resolved after discontinuation of dual antiplatelet therapy. Due to rapid changes in the radiologic features of SDH, frequent computed tomography scans at least once a week may be needed especially in patients who receive antiplatelet therapy during the vasospasm phase.


Nomograms for postsurgical extrahepatic recurrence prediction of hepatocellular carcinoma based on presurgical circulating tumor cell status and clinicopathological factors.
Extrahepatic recurrence (EHR) is one of the major reasons for the poor prognosis of hepatocellular carcinoma (HCC). The present study aimed to develop and assess the performance of predictive models by using a combination of presurgical circulating tumor cell (CTCs) data and clinicopathological features to screen patients at high risk of EHR to achieve precise decision-making. A total of 227 patients with recurrent HCC and preoperative CTC data from January 2014 to August 2019 were enrolled. All patients were randomly assigned to one of two cohorts: development or validation. Two preoperative and postoperative nomogram models for EHR prediction were developed and multi-dimensionally validated. Patients with EHR had generally lower recurrence-free survival (p < 0.001), and overall survival (p < 0.001), and significantly higher CTC counts (epithelial CTCs, epithelial/mesenchymal hybrid CTCs, and mesenchymal CTCs count, all p < 0.05) than those without EHR. Univariate and multivariate analyses revealed that EHR was associated with four risk factors in the development cohort: total CTC count (p = 0.014), tumor size (p = 0.028), node number (p = 0.045), and microvascular invasion (p = 0.035). These factors were incorporated into two nomogram models (preoperative and postoperative), which reliably predicted EHR through multidimensional verification (e.g., calibration plot, receiver operating characteristic analysis, decision curve analysis, and clinical impact curve analysis) in the development and validation cohorts, respectively. With threshold of scores of 100.3 and 176.8 before and after surgery respectively, both nomograms were able to stratify patients into two distinct prognostic subgroups (all p < 0.05). The present study proposed two nomogram models integrating presurgical CTC counts and clinicopathological risks and showed relatively good predictive performance of EHR, which may be beneficial to the clinical practice of HCC recurrence. Further multicenter studies are needed to assess its general applicability.


Modulation of nitrate reductase activity in rice seedlings under aluminium toxicity and water stress: role of osmolytes as enzyme protectant.
Nitrate reductase (NR) activity in the presence of Mg2+ (NR act) representing the non-phosphorylated NR state and the activity in the presence of EDTA (NR max) representing maximum NR activity was measured in roots and shoots of 15 d grown aluminium and water stressed rice seedlings to examine changes in NR activation state due to these stresses. Seedlings subjected to a moderate water stress level of -0.5 MPa for 24 h or grown in presence of 80 microM Al3+showed decreased level of NR max but resulted in higher NR act and NR activation state. However, seedlings grown in presence of a higher level of 160 microM Al3+ showed a decline in NR act as well as NR max. With a higher water stress Level of -2.0MPa a marked decline in the levels of both NR act and NR max was observed, whereas NR activation state remained almost unaltered with severe water stress. NR activity appeared to be sensitive to H2O2, PEG-6000, NaCl and various metal salts. Incorporation of these components in the enzyme assay medium led to decreased affinity of enzyme towards its substrate with increase in Km and decrease in Vmax values. Addition of each of the osmolytes i.e. 1 mol/L proline, 1 mol/L glycine betaine or 1 mol/L sucrose in the enzyme assay medium caused a considerable protection to the enzyme against the damaging effects of stressful components. An enhanced level of proline and glycine betaine was observed in Al-stressed seedlings and sucrose in Al as well as water stressed seedlings. Results suggest that Al toxicity and water stress decrease total amount of functional NR in rice seedlings and the osmolytes proline, glycine betaine and sucrose appear to have a direct protective action on enzyme NR under stressful conditions


IGF2BP3 drives gallbladder cancer progression by m6A-modified CLDN4 and inducing macrophage immunosuppressive polarization.
N6-methyladenosine (m6A) is an emerging epigenetic modification, which plays a crucial role in the development of cancer. Nevertheless, the underlying mechanism of m6A-associated proteins and m6A modification in gallbladder cancer remains largely unknown. The Gene Expression Omnibus database and tissue microarray were used to identify the key m6A-related gene in gallbladder cancer. The function and mechanism of IGF2BP3 were further investigated by knockdown and overexpression techniques in vitro and in vivo. We found that IGF2BP3 was elevated and correlated with poor prognosis in gallbladder cancer, which can be used as an independent prognostic factor for gallbladder cancer. IGF2BP3 accelerated the proliferation, invasion and migration of gallbladder cancer cells in vitro and in vivo. Mechanistically, IGF2BP3 interacted with and augmented the stability of CLDN4 mRNA by m6A modification. Enhancement of CLDN4 reversed the inhibitory effect of IGF2BP3 deficiency on gallbladder cancer. Furthermore, we demonstrated that IGF2BP3 promotes the activation of NF-κB signaling pathway by up-regulation of CLDN4. Overexpression of IGF2BP3 in gallbladder cancer cells obviously promoted the polarization of immunosuppressive phenotype in macrophages. Besides, Gallbladder cancer cells-derived IGF2BP3 up-regulated the levels of STAT3 in M2 macrophages, and promoted M2 polarization. We manifested IGF2BP3 promotes the aggressive phenotype of gallbladder cancer by stabilizing CLDN4 mRNA in an m6A-dependent manner and induces macrophage immunosuppressive polarization, which might offer a new theoretical basis for against gallbladder cancer.


Robust water-fat separation based on deep learning model exploring multi-echo nature of mGRE.
To design a new deep learning network for fast and accurate water-fat separation by exploring the correlations between multiple echoes in multi-echo gradient-recalled echo (mGRE) sequence and evaluate the generalization capabilities of the network for different echo times, field inhomogeneities, and imaging regions. A new multi-echo bidirectional convolutional residual network (MEBCRN) was designed to separate water and fat images in a fast and accurate manner for the mGRE data. This new MEBCRN network contains 2 main modules, the first 1 is the feature extraction module, which learns the correlations between consecutive echoes, and the other one is the water-fat separation module that processes the feature information extracted from the feature extraction module. The multi-layer feature fusion (MLFF) mechanism and residual structure were adopted in the water-fat separation module to increase separation accuracy and robustness. Moreover, we trained the network using in vivo abdomen images and tested it on the abdomen, knee, and wrist images. The results showed that the proposed network could separate water and fat images accurately. The comparison of the proposed network and other deep learning methods shows the advantage in both quantitative metrics and robustness for different TEs, field inhomogeneities, and images acquired for various imaging regions. The proposed network could learn the correlations between consecutive echoes and separate water and fat images effectively. The deep learning method has certain generalization capabilities for TEs and field inhomogeneity. Although the network was trained only in vivo abdomen images, it could be applied for different imaging regions.


Optimal ex vivo expansion of neutrophils from PBSC CD34+ cells by a combination of SCF, Flt3-L and G-CSF and its inhibition by further addition of TPO.
Autologous mobilised peripheral blood stem cell (PBSC) transplantation is now a standard approach in the treatment of haematological diseases to reconstitute haematopoiesis following myeloablative chemotherapy. However, there remains a period of severe neutropenia and thrombocytopenia before haematopoietic reconstitution is achieved. Ex vivo expanded PBSC have been employed as an adjunct to unmanipulated HSC transplantation, but have tended to be produced using complex cytokine mixtures aimed at multilineage (neutrophil and megakaryocyte) progenitor expansion. These have been reported to reduce or abrogate neutropenia but have little major effect on thrombocytopenia. Selective megakaryocyte expansion has been to date ineffective in reducing thrombocytopenia. This study was implemented to evaluate neutrophil specific rather than multilineage ex vivo expansion of PBSC for specifically focusing on reduction or abrogation of neutropenia. CD34+ cells (PBSC) were enriched from peripheral blood mononuclear cells following G-CSF-mobilisation and cultured with different permutations of cytokines to determine optimal cytokine combinations and doses for expansion and functional differentiation and maturation of neutrophils and their progenitors. Results were assessed by cell number, morphology, phenotype and function. A simple cytokine combination, SCF + Flt3-L + G-CSF, synergised to optimally expand and mature neutrophil progenitors assessed by cell number, phenotype, morphology and function (superoxide respiratory burst measured by chemiluminescence). G-CSF appears mandatory for functional maturation. Addition of other commonly employed cytokines, IL-3 and IL-6, had no demonstrable additive effect on numbers or function compared to this optimal combination. Addition of TPO, commonly included in multilineage progenitor expansion for development of megakaryocytes, reduced the maturation of neutrophil progenitors as assessed by number, morphology and function (respiratory burst activity). Given that platelet transfusion support is available for autologous PBSC transplantation but granulocyte transfusion is generally lacking, and that multilineage expanded PBSC do not reduce thrombocytopenia, we suggest that instead of multilineage expansion selective neutrophil expansion based on this relatively simple cytokine combination might be prioritized for development for clinical use as an adjunct to unmanipulated PBSC transplantation to reduce or abrogate post-transplant neutropenia.


Surgical intervention for acute intestinal ischemia: experience in a community teaching hospital.
The aim of this study was to evaluate the current management of acute mesenteric ischemia secondary to thrombotic or embolic occlusion of visceral vessels in a community teaching hospital. Between October 1997 and July 2000, a review of all hospital discharges revealed 83 patients with a discharge diagnosis of "acute vascular insufficiency-intestine." Among these 83 patients, 22 cases of acute mesenteric ischemia were confirmed. Management of these 22 patients was divided into 2 groups for analysis. In Group A, 14 patients were aggressively treated with visceral angiography (n=10), visceral artery bypass (n=8), visceral embolectomy (n=4), and bowel resection (n=7). In 8 of 14 of these patients, surgical intervention occurred in less than 24 hours from presentation. In Group B, 8 patients were managed with supportive care because of advanced age (mean age = 86 +/- 7 years), comorbid conditions, or patient and family preference. Postoperative morbidity in Group A consisted of cardiac events (n=3), pulmonary insufficiency (n=5), and prolonged gastrointestinal tract dysfunction (n=3). Twelve of 14 patients in Group A survived and were discharged, whereas only 2 of 8 patients in Group B survived and were discharged from the hospital. Although the literature suggests that there can be a significant delay in the diagnosis and treatment of acute mesenteric ischemia, the early recognition and aggressive treatment of acute mesenteric ischemia resulted in a good survival rate. Supportive management of very elderly and debilitated patients needs to be considered on a case-by-case basis. Although the outlook for such patients is dismal, survivors are possible as demonstrated by this series.


Patient classification in neuropsychological research.
In a number of papers we have been concerned with the type of inferences that are legitimate in "experiments of nature" where the experimenter does not and cannot control the modifications to the cognitive system that are introduced by brain damage. We have argued that in such cases very restrictive conditions must be met in order to be able to draw valid inferences about the structure of normal cognitive mechanisms. Two consequences of these conditions are (1) patient classification into syndrome types (e.g., phonological dysgraphia, agrammatism, and so forth) can play no useful role in research concerned with issues about the structure of normal cognitive functioning or its dissolution under conditions of brain damage; and (2) only single-patient studies allow valid inferences about the structure of cognitive mechanisms from the analysis of impaired performance. Zurif, Gardner, and Brownell (1989, Brain and Cognition, 10, 237-255) have taken exception to our conclusions and propose to show the limitations of our arguments. In this paper we respond to their criticisms.


[Current overview of cartilage regeneration procedures].
Cartilage is an avascular, alymphatic and non-innervated tissue with limited intrinsic repair potential. The high prevalence of cartilage defects and their tremendous clinical importance are a challenge for all treating physicians. This article provides the reader with an overview about current cartilage treatment options and their clinical outcome. Microfracture is still considered the gold standard in the treatment of small cartilage lesions. Small osteochondral defects can be effectively treated with the autologous osteochondral transplantation system. Larger cartilage defects are successfully treated by autologous membrane-induced chondrogenesis (AMIC) or by membrane-assisted autologous chondrocyte implantation (MACI). Despite limitations of current cartilage repair strategies, such procedures can result in short- and mid-term clinical improvement of the patients. Further developments and clinical studies are necessary to improve the long-term outcome following cartilage repair.


CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia.
Expression of the catalytic subunit of the telomerase enzyme hTERT is essential for prolonging the replicative lifespan and is the rate-limiting step in cellular immortalization and carcinogenesis. Because hTERT expression is positively correlated with telomerase activity, its regulation is suggested as the major determinant of enzymatic activity. The hTERT promoter region contains two CpG islands, which are known to be target sites for de novo DNA methylation. To elucidate the impact of this epigenetic mechanism on telomerase activity, we analyzed the degree of hTERT promoter methylation in 30 patients with B-cell chronic lymphocytic leukemia. hTERT promoter methylation was assessed using a methylation-specific competitive polymerase chain reaction assay. The assay is based on digestion of genomic DNA with a methylation-sensitive restriction enzyme before amplification with an internal standard. Patients exhibiting high telomerase activity showed significantly less methylation of the hTERT promoter core domain than patients with low enzyme activity. In addition, telomerase activity was significantly associated with telomere length and overall survival. Our data show that the degree of CpG island methylation of the hTERT promoter exhibits an impact on telomerase activity in a subgroup of patients with B-cell chronic lymphocytic leukemia and therefore is assumed to play a role in regulating hTERT gene expression in these patients.


The nonlinear contribution of nitrous oxide at sub-MAC concentrations to enflurane MAC in rats.
The presumed linear relationship describing the contribution of nitrous oxide (N2O) to the enflurane requirement necessary to achieve a 1.0 MAC level of anesthesia was tested in rats (N = 84). Each rat received one of six different concentrations of N2O, and enflurane was adjusted to attain 1.0 MAC with the use of a standard tail clamp method. The resultant group MAC anesthetic concentrations were Group I-N2O = 0.0%, enflurane = 2.30%; Group II-N2O = 10.4%, enflurane = 2.19%; Group III-N2O = 30.7%, enflurane = 1.85%; Group IV-N2O = 61.8%, enflurane = 1.75%; Group V-N2O = 70.9%, enflurane = 1.56%; and Group VI-N2O = 80.3%, enflurane = 1.54%. Increasing the N2O concentration from 0-10%, from 30-60%, or 70-80% did not significantly decrease the enflurane requirement; however, increasing the N2O concentration from 10-30% or 60-70% produced a significant decrease (P less than 0.05) in the concentration of enflurane required for 1.0 MAC of anesthesia. Thus, in rats, increasing the concentration of N2O in sub-MAC ranges did not produce a linear decrease in the enflurane concentration required to add up to 1.0 MAC of anesthesia. These results are consistent with a dose-dependent interaction between N2O and the excitatory properties of enflurane; this interaction could represent synergism at low concentrations or antagonism at higher concentration of N2O.


Efficacy of growth hormone replacement on anthropometric outcomes, obesity, and lipids in children with optic nerve hypoplasia and growth hormone deficiency.
Hypopituitarism and obesity are causes of major lifelong morbidity in patients with optic nerve hypoplasia (ONH). Growth hormone deficiency (GHD) affects the majority of children with ONH, though the degree of deficiency and variability of early growth patterns range from early severe retardation to normal initial growth. The utility of early GH replacement for improving anthropometric, body composition, and lipid outcomes in patients with ONH and GHD, especially those with normal initial height velocity, is unknown. This study examines the effects of GH replacement in a cohort of children with ONH and GHD. Controlled clinical trial from 2005-2014. The study included 17 children with ONH and untreated GHD. Those meeting criteria for growth deceleration were assigned to treatment with recombinant human growth hormone (n = 5) while those with normal height velocity were randomized either to treatment (n = 5) or to observation (no intervention, n = 7). Study duration was 3 years. Primary outcome measures included stature, weight, weight-for-stature, and BMI standard deviation score (SDS) at study completion. Subjects on GH, irrespective of entry growth trajectory, grew more on average in stature than controls by a difference of 0.98 SDS by study end; this effect persisted after adjusting for baseline overweight status. Treatment had an effect on weight SDS only after adjusting for initial overweight status, resulting in an average increase of 0.83 SDS more than controls. Subjects who were overweight at the outset experienced greater gains in both weight and stature SDS. Treatment had no statistically significant impact on weight-for-stature or BMI SDS. A reduction in body fat percentage was observed in those treated, both before (-6.1 %) and after (-4.3 %) adjustment for initial overweight status. Early GH replacement has a positive effect on short-term statural outcomes in children with ONH and GHD, even in those exhibiting normal initial linear growth. Results were less conclusive regarding treatment effects on body composition and lipids.


Using human-centred design to tackle COVID-19 vaccine hesitancy for children and youth: a protocol for a mixed-methods study in Montreal, Canada.
To successfully combat COVID-19 vaccine hesitancy and increase uptake, research has demonstrated that interventions are most effective when tailored to meet local needs through active engagement and co-development with communities. This mixed-methods project uses a human-centred design (HCD) approach to understand local perspectives of COVID-19 vaccine hesitancy and develop strategies to enhance vaccine confidence for children and adolescents. Project ECHO (Étude Communautaire sur l'Hésitation vaccinale contre la COVID-19) combines population-based surveys of parents and adolescents with community-based participatory action research to design and pilot strategies to enhance COVID-19 vaccine confidence in two underserved and ethnoculturally diverse neighbourhoods of Montreal, Canada. Two surveys conducted 6 months apart through primary and secondary schools are used to monitor vaccine acceptance and its social determinants among children and youth. Analyses of survey data include descriptive and inferential statistical approaches. Community-led design teams of parents and youth from the two participating neighbourhoods, supported by academic researchers, design thinking experts and community partners, use an HCD approach to: (1) gather data to understand COVID-19 vaccine decision-making among parents and youth in their community and frame a design challenge (inspiration phase); (2) develop an intervention to address the design challenge (ideation phase) and (3) pilot the intervention (implementation phase). Strategies to evaluate the community-led interventions will be co-developed during the implementation phase. This study has been approved by the research ethics boards of the Sainte-Justine University Hospital Centre and the University of Montreal. Community design teams will be involved in the dissemination of findings and the design of knowledge translation initiatives that foster dialogue related to COVID-19 vaccination for children and adolescents among community, school and public health stakeholders. Findings will be disseminated through peer-reviewed publications, conference presentations, community forums, policy briefs, and social media content.


Anti-inflammatory effects of CGP 47969A, a novel inhibitor of proinflammatory cytokine synthesis, in rabbit immune colitis.
Proinflammatory cytokines such as interleukin (IL) 1, IL-8, and tumor necrosis factor (TNF) have been implicated as primary mediators of intestinal inflammation. The aim of the present study was to determine the effects of a novel cytokine antagonist (CGP 47969A) in a rabbit model of acute colitis. Colitis was induced using the formalin-immune complex technique. Animals were pretreated intrarectally with CGP 47969A (30, 10, or 3 mg/kg), hydrocortisone (0.8 mg/kg), or vehicle (4 mL saline) 2 hours before the induction of colitis and twice daily thereafter until death 48 hours after the induction of colitis. The severity of inflammation of colonic tissue was assessed using histological analysis and myeloperoxidase activity assay, and IL-1 alpha, IL-8, TNF-alpha, and IL-1 receptor antagonist levels were determined. Compared with vehicle, CGP 47969A (10 mg/kg) significantly reduced the acute inflammatory index by 58%, edema by 67%, necrosis by 99%, and myeloperoxidase activity by 49% (all P < 0.02) with efficacy similar to that of steroids. These effects were associated with a significant inhibition of colonic IL-1 alpha and IL-8 by 56% and 90%, respectively (p < 0.01). Administration of CGP 47969A reduces inflammation and tissue damage in rabbit immune complex colitis through mechanisms involving the inhibition of mucosal proinflammatory cytokines.


Development of a chromatographic fingerprint for the chloroform extracts of Ganoderma lucidum by HPLC and LC-MS.
A new high-performance liquid chromatographic (HPLC) fingerprinting method was developed for the quality control of Ganoderma lucidum. Twenty-nine batches obtained from three different origins in China were used to establish the fingerprint. The constituents of these samples were separated with a Kromasil C(18) column (250 mm x 4.6 mm, 5 microm) by linear gradient elution using water-acetic acid (100:0.1, v/v) and acetonitrile as mobile phase components at a flow rate of 0.8 ml/min and detector wavelength at 254 nm. Mean chromatograms and correlation coefficients of samples were calculated by the software "Similarity Evaluation System for Chromatographic Fingerprint of TCM". There were 19 common peaks in this fingerprint. Eleven of these common peaks were tentatively identified with reference to literature data based on their liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS) and UV data. This profile was then successfully used to identify and assess the differences among samples from various origins with the aid of similarity analysis. The diverse similarities among different samples indicated that the quality of G. lucidum was not stable and the products from different areas were inconsistent. All results showed that the developed fingerprint assay was specific and could further serve for quality identification and comprehensive evaluation of G. lucidum.


Rosacea Patients Are at Higher Risk for Obstructive Sleep Apnea: Automated Retrospective Research.
Using big data science we employ NLP and a novel interface the BMI Investigator to answer clinically meaninful questions. The use case presented is the association between Rosacea and Obstructive Sleep Apnea.


The effect of heat on skin permeability.
Although the effects of long exposure (>>1s) to moderate temperatures (< or =100 degrees C) have been well characterized, recent studies suggest that shorter exposure (<1s) to higher temperatures (>100 degrees C) can dramatically increase skin permeability. Previous studies suggest that by keeping exposures short, thermal damage can be localized to the stratum corneum without damaging deeper tissue. Initial clinical trials have progressed to Phase II (see http://clinicaltrials.gov), which indicates the procedure can be safe. Because the effect of heating under these conditions has received little systematic or mechanistic study, we heated full-thickness skin, epidermis and stratum corneum samples from human and porcine cadavers to temperatures ranging from 100 to 315 degrees C for times ranging from 100ms to 5s. Tissue samples were analyzed using skin permeability measurements, differential scanning calorimetry, thermomechanical analysis, thermal gravimetric analysis, brightfield and confocal microscopy, and histology. Skin permeability was shown to be a very strong function of temperature and a less strong function of the duration of heating. At optimal conditions used in this study, transdermal delivery of calcein was increased up to 760-fold by rapidly heating the skin at high temperature. More specifically, skin permeability was increased (I) by a few fold after heating to approximately 100-150 degrees C, (II) by one to two orders of magnitude after heating to approximately 150-250 degrees C and (III) by three orders of magnitude after heating above 300 degrees C. These permeability changes were attributed to (I) disordering of stratum corneum lipid structure, (II) disruption of stratum corneum keratin network structure and (III) decomposition and vaporization of keratin to create micron-scale holes in the stratum corneum, respectively. We conclude that heating the skin with short, high temperature pulses can increase skin permeability by orders of magnitude due to structural disruption and removal of stratum corneum.


Heat generation during ablation of porcine skin with erbium:YAG laser vs a novel picosecond infrared laser.
Despite significant advances in surgery, most surgical tools remain basic. Lasers provide a means of precise surgical ablation, but their clinical use has remained limited because of undesired thermal, ionizing, or acoustic stress effects leading to tissue injury. A novel ultrafast, nonionizing, picosecond infrared laser (PIRL) system has recently been developed and is capable, in theory, of ablation with negligible thermal or acoustic stress effects. To measure and compare heat generation by means of thermography during ablation of ex vivo porcine skin by conventional microsecond-pulsed erbium:YAG (Er:YAG) laser and picosecond infrared laser (PIRL). This study was conducted in an optics laboratory and used a pretest-posttest experimental design comparing 2 methods of laser ablation of tissue with each sample acting as its own control. Ex vivo porcine skin was ablated in a 5-mm line pattern with both Er:YAG laser and PIRL at fluence levels marginally above ablation threshold (2 J/cm² and 0.6 J/cm², respectively). Peaks and maxima of skin temperature rises were determined using a thermography camera. Means of peak temperature rises were compared using the paired sample t test. Ablation craters were assessed by means of digital microscopy. RESULTS Mean peak rise in skin surface temperature for the Er:YAG laser and PIRL was 15.0°C and 1.68°C, respectively (P < .001). Maximum peak rise in skin surface temperature was 18.85°C for the Er:YAG laser and 2.05°C for the PIRL. Ablation craters were confirmed on digital microscopy. Picosecond infrared laser ablation results in negligible heat generation, considerably less than Er:YAG laser ablation, which confirms the potential of this novel technology in minimizing undesirable thermal injury associated with lasers currently in clinical use.


Self-change in eating disorders: is "spontaneous recovery" possible?
A limited series of community studies including non-treatment-seekers has shown that a considerable number of eating disorder patients do not enter the health care system but can be considered "clinically recovered" (remission of major symptoms) if followed up long enough. The possibility of "spontaneous recovery" (overcoming an eating disorder without professional treatment or formal help) often faces scepticism on the part of professionals. Clearly, self-change is an underestimated pathway to recovery from an eating disorder, but open-minded clinicians can learn a lot from it. Active coping and making use of one's "recovery capital" are key features of self-change even if maintenance of change is associated with social support and positive life changes.


Pigment Loss in Patients with Large Congenital Melanocytic Nevi: Various Clinical Presentations Documented in a Large Series.
The association between vitiligo and congenital melanocytic nevi remains incompletely understood. The objective of this study was to investigate the frequency of depigmentation, including vitiligo, in patients with a large congenital melanocytic nevus (LCMN), which is a rare melanocytic tumor variant. We retrospectively reviewed the files of 92 patients with an LCMN, including photographic documentation regarding the presence of pigment loss on the nevus mass, around the nevus, around the satellites, and elsewhere on the body. Depigmentation was observed in 8 (8.7%) of 92 patients with an LCMN. Depigmented areas within the main nevus mass were observed in six patients, and adjacent or remote vitiligo was observed in four patients. One patient also demonstrated halo depigmentation around some satellite nevi. The coexistence of an LCMN with vitiligo does not appear to be rare and may occur with a spectrum of clinical presentations.


Implementation of a bundle of care to reduce surgical site infections in patients undergoing vascular surgery.
Surgical site infections (SSI's) are associated with severe morbidity, mortality and increased health care costs in vascular surgery. To implement a bundle of care in vascular surgery and measure the effects on the overall and deep-SSI's rates. Prospective, quasi-experimental, cohort study. A prospective surveillance for SSI's after vascular surgery was performed in the Amphia hospital in Breda, from 2009 through 2011. A bundle developed by the Dutch hospital patient safety program (DHPSP) was introduced in 2009. The elements of the bundle were (1) perioperative normothermia, (2) hair removal before surgery, (3) the use of perioperative antibiotic prophylaxis and (4) discipline in the operating room. Bundle compliance was measured every 3 months in a random sample of surgical procedures and this was used for feedback. Bundle compliance improved significantly from an average of 10% in 2009 to 60% in 2011. In total, 720 vascular procedures were performed during the study period and 75 (10.4%) SSI were observed. Deep SSI occurred in 25 (3.5%) patients. Patients with SSI's (28,5±29.3 vs 10.8±11.3, p<0.001) and deep-SSI's (48.3±39.4 vs 11.4±11.8, p<0.001) had a significantly longer length of hospital stay after surgery than patients without an infection. A significantly higher mortality was observed in patients who developed a deep SSI (Adjusted OR: 2.96, 95% confidence interval 1.32-6.63). Multivariate analysis showed a significant and independent decrease of the SSI-rate over time that paralleled the introduction of the bundle. The SSI-rate was 51% lower in 2011 compared to 2009. The implementation of the bundle was associated with improved compliance over time and a 51% reduction of the SSI-rate in vascular procedures. The bundle did not require expensive or potentially harmful interventions and is therefore an important tool to improve patient safety and reduce SSI's in patients undergoing vascular surgery.


Correction: Hydrophobicity of Antifungal β-Peptides Is Associated with Their Cytotoxic Effect on In Vitro Human Colon Caco-2 and Liver HepG2 Cells.
[This corrects the article DOI: 10.1371/journal.pone.0149271.].


The direct use of CT numbers in radiotherapy dosage calculations for inhomogeneous media.
Techniques by which the quantitative anatomical data inherent in a CT scan can be directly used in treatment planning are described. The correction algorithms used in the RAD-8 system, based on an effective path length, have been extended to a pixel-by-pixel approach. By calibrating the X-ray transmission CT scanner in terms of electron densities (electron cm-3) inhomogeneity corrections may be made automatically.


Mechanisms of immediate temperature compensation: experiments with brain synaptosomes from rat and ground squirrel.
Glucose conversion by brain synaptosomes can be regarded as a special case of intrinsic kinetic properties of the enzyme substrate system. Temperature modulation of apparent K(m) for this process can be described with our kinetic model. Using experimental data and the kinetic model, the minimal K(m) value for glucose conversion in ground squirrel synaptosomes was found at the lower temperature (6.5 degrees C), much lower than that for the rat (16.6 degrees C). The inversion temperatures (T(min)) closely coincided with the lowest body temperatures from which the unassisted recovery from hypothermia was demonstrated in both species. This study indicated that thermal modulation of enzyme affinities may have an adaptive role in endotherms that is linked to their tolerance to hypothermia.


Prostate cancer: evaluation of response to treatment, response criteria, and the need for standardization of the reporting of results.
Response criteria and the reporting of results in clinical trials on drug therapy of stage D prostate cancer were evaluated by examination of studies listed in the Index Medicus 1980-1984. During this 5-year period, 70 studies (51 phase II and 16 phase III) were listed, comprising 3184 evaluable patients. Among 346 patients reported as having evaluable disease according to the WHO criteria, 198 had well-defined evaluable disease. A variety of response criteria were used, the NPCP criteria being the most frequent. Only three studies included solely patients with evaluable disease according to the WHO criteria. Reporting of results was often inadequate. The value of the most frequently used response parameters such as acid phosphatase, bone scan, per-rectal ultrasound, CT scan, bone pain and performance status is discussed. A system to standardise the reporting of results is proposed.


Exploring the extent of source imaging: Recent advances in noninvasive electromagnetic brain imaging.
Electrophysiological source imaging (ESI) has been successfully employed in many brain imaging applications during the last 20 years. ESI estimates of underlying brain networks provide millisecond resolution of dynamic brain processes; yet, it remains to be a challenge to further improve the spatial resolution of ESI modality, in particular on its capability of imaging the extent of underlying brain sources. In this review, we discuss the recent developments in signal processing and machine learning that have made it possible to image the extent, i.e. size, of underlying brain sources noninvasively, using scalp electromagnetic measurements from electroencephalogram (EEG) and magnetoencephalogram (MEG) recordings.


α-Cyclodextrin Encapsulation of Bicyclo[1.1.1]pentane Derivatives: A Storable Feedstock for Preparation of [1.1.1]Propellane.
The bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α-cyclodextrin (α-CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3-diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non-polar solvents. The combination of these methodologies enables simple, on-demand preparation of [1.1.1]propellane in various solvents under mild conditions from α-CD capsules containing 1,3-diiodo BCP.


Dietary Recommendations in Fracture Healing in Traditional Persian Medicine: A Historical Review of Literature.
Fracture repair is a complex process. An inappropriate diet is a contributing risk factor for fracture nonunion. The aim of this study was to extract dietary recommendations for fracture healing according to traditional Persian medicine (TPM) literature. The contents relevant to diets in fracture healing were selected from main textbooks in TPM like Al Qanon fi Al-teb ( The Canon). Other reference textbooks in traditional medicine were also used for a comprehensive study in this respect. Finally content analysis was used for summarizing and describing the results. Food stuffs are classified in TPM according to their nutritive value, their assimilability, and the quality of achieved chyme. Some light meals like chicken soup are recommended for the early days of fracture and high-nutrient and dense foods such as goat's or sheep's head and nuts are advised in following days for fracture healing acceleration and callus formation. Several recommendations are also provided for pacing the healing process. A comparison of Avicenna and other Persian sage's recommended regimens with the recent evidence revealed the potential positive effects of their regimen for bone healing acceleration. It can shed light on a part of history of orthopedics and add to current knowledge about bone fracture and its management.


Predictors of non-calcified plaque presence and future adverse cardiovascular events in symptomatic rural Appalachian patients with a zero coronary artery calcium score.
Coronary artery calcium (CAC) scoring is a proven predictor for future adverse cardiovascular events (CVE) in asymptomatic individuals. Data is emerging regarding the usefulness of non-calcified plaque (NCP) assessment on cardiac computed tomography (CCT) angiography in symptomatic patients with a zero CAC score for further risk assessment. A retrospective review from January 2019 to January 2022 of 696 symptomatic patients with no known CAD and a zero CAC score identified 181 patients with NCP and 515 patients without NCP by a visual assessment on CCT angiography. The primary endpoint was to identify predictors for NCP presence and adverse CVEs (death, myocardial infarction, or cerebrovascular accident) within two years. Based on logistic regression, age (OR 1.039, 95% CI [1.020-1.058], p < 0.001), diabetes mellitus (OR 2.192, 95% CI [1.307-3.676], p < 0.003), tobacco use (OR 1.748, 95% CI [1.157-2.643], p < 0.008), low-density lipoprotein cholesterol level (OR 1.009, 95% CI [1.003-1.015], p < 0.002), and hypertension (OR 1.613, 95% CI [1.024-2.540], p < 0.039) were found to be predictors of NCP presence. NCP patients had a higher pretest probability for CAD using the Morise risk score (p < 0.001∗), with NCP detection increasing as pretest probability increased from low to high (OR 55.79, 95% CI [24.26-128.26], p < 0.001∗). 457 patients (66%) reached a full two-year period after CCT angiography completion, with NCP patients noted to have shorter follow-up times and higher rates of elective coronary angiography, intervention, and CVEs. The presence of NCP (aOR 2.178, 95% CI [1.025-4.627], p < 0.043) was identified as an independent predictor for future adverse CVEs when adjusted for diabetes mellitus, age, and hypertension. NCP was identified at high rates (26%) in our symptomatic Appalachian population with no known CAD and a zero CAC score. NCP was identified as an independent predictor of future adverse CVEs within two years.


Ectopic lymph node of the orbit simulating a lacrimal gland tumor.
A 47-year-old woman had a tumor in the lacrimal gland region of the orbit for 20 years which was histologically diagnosed as a large lymph node. The ectopic lymph node was probably congenital.


Is aeromedical transport of patients during acute myocardial infarction safe?
The emergence of coronary artery thrombolysis and angioplasty have raised new questions about the transfer of patients with acute myocardial infarction (AMI). Since these modalities are generally limited in their availability, and since the success of thrombolysis is strongly time-dependent, the interfacility transfer of patients during AMI has become more common. Study of a relatively small number of patients indicates that aeromedical helicopter transport can be conducted in a safe manner, and that the outcome of management is of benefit to the patients. Reperfusion events, however, must be anticipated during transport of patients in whom thrombolysis is initiated preflight. Furthermore, initiation of thrombolytic therapy may be problematic if begun in patients with events mimicking AMI, particularly aortic dissection or Prinzmetal's angina.


Multiple endocrine neoplasia presenting as primary amenorrhea: a case report.
Primary amenorrhea is rarely secondary to hyperprolactinemia. This case highlights the importance of obtaining a complete family history to identify patients who may have hyperprolactinemia secondary to multiple endocrine neoplasia type 1 syndrome. A 16-year-old female presented with primary amenorrhea and was noted to have hyperprolactinemia. Her family history revealed an extensive family tree consistent with multiple endocrine neoplasia type 1 syndrome. She was diagnosed subsequently with the syndrome, having both pituitary and parathyroid adenomas. A detailed family history of patients with hyperprolactinemia secondary to a pituitary adenoma may prompt a serum calcium measurement, which may identify patients at risk for development of multiple endocrine neoplasia type 1 syndrome.


Molecular biology of basal and squamous cell carcinomas.
Basal cell carcinomas and Squamous cell carcinomas are the two most common human cancers. The incidence of these two types of cancer is estimated to double within 20 years. Identification of the key molecular events is critical in helping us design novel strategies to treat and to prevent these cancers. For example, identification of hedgehog signaling activation has opened up many opportunities for targeted therapy and prevention of basal cell carcinomas. Significant progress has also been made in our understanding of squamous cell carcinomas of the skin. In this chapter, we will focus on major recent developments in our understanding of basal cell carcinomas and squamous cell carcinomas at the molecular levels and their clinical implications.


Factors associated with local invasion in infective endocarditis: a nested case-control study.
A substantial proportion of infective endocarditis (IE) cases are complicated by local invasion. The purpose of this study was to identify patient and disease characteristics associated with local invasion in surgically treated IE patients. This was a nested case-control study. All episodes of IE for patients admitted to Cleveland Clinic from 1 January 2013 to 30 June 2016 were identified from the Cleveland Clinic IE Registry. Patients ≥18 years of age who underwent surgery for IE were included. Among these, cases were those with local invasion, controls were those without. Local invasion, defined as periannular extension, paravalvular abscess, intracardiac fistula or pseudoaneurysm, was ascertained from the surgical operative note. Associations of selected factors with local invasion were examined in a multivariable logistic regression model. Among 511 patients who met inclusion criteria, 215 had local invasion. Mean age was 56 years; 369 were male. Overall 345 (68%) had aortic valve, 228 (45%) mitral valve, and 66 (13%) tricuspid or pulmonic valve involvement. Aortic valve involvement (OR 6.23, 95% CI 3.55-11.44), bioprosthetic valve (OR 3.88, 95% CI 2.36-6.44), significant paravalvular leak (OR 3.80, 95% CI 1.60-9.89), new atrioventricular nodal block (OR 3.77, 95% CI 1.87-7.90), infection with streptococci other than viridans group streptococci (OR 7.54, 95% CI 2.42-24.87) and presence of central nervous system emboli (OR 1.85, 95% CI 1.13-3.04) were associated with local invasion. Intracardiac and microorganism factors, but not comorbid conditions, are associated with local invasion in IE.


Cyclic adenosine 3', 5'-monophosphate and the mechanism of action of three common anti-inflammatory drugs.
1 The effects of indomethacin, dexamethasone and colchicine on cyclic adenosine 3', 5'-monophosphate (cyclic AMP) concentration in leucocytes during a crystal-induced pleurisy in rats were studied. 2 Each of the drugs significantly increased leucocyte cyclic AMP content within 3 h of the injection of crystals. 3 By 6 h, leucocyte cyclic AMP levels returning toward control levels and could not be sustained at the higher level by an additional administration of the respective anti-inflammatory drug.


Fisher's hypothesis in time-frequency space: a premier using South Africa as a case study.
Fisher hypothesis is universally accepted as an integral portion of monetary theory and practice, and yet the empirical evidence confirming a full Fisher effect remains scarce and the relationship has been challenged on several theoretical grounds referred to as 'puzzles'. Our paper suggests the use of continuous wavelet transforms as a unified analytical framework for confronting the different Fisher puzzles in a harmonious way. Taking South Africa as a case study, we focus on the inflation targeting period of 2002:01-2021:02 and use signal-image conversion tools such as wavelet power spectrum, wavelet coherence spectrum and phase-difference dynamics to extract signal features of nominal interest rates and inflation expectations and further explore their dynamic synchronization across a time-frequency plane/domain. Three unique findings emerge from our study. Firstly, across a time domain a full Fisher effect only holds in the pre-financial crisis period. Secondly, across the frequency spectrums, higher frequency oscillations gradually lose relevance to lower frequency oscillations providing evidence of volatility transfer in the Fisher effect. Lastly, the phase-dynamics indicate a consistent positive synchronization throughout the sample period which is line with the traditional Fisher effect. Overall, these findings highlight the success of the South African Reserve Bank in using inflation targeting to steer the expectations of economic agents under the tenures of the last three governors and provide important lessons for other Central banks.


Macrophage polarization in tumour progression.
Macrophages are a fundamental part of the innate defense mechanisms, which can promote specific immunity by inducing T cell recruitment and activation. Despite this, their presence within the tumour microenvironment has been associated with enhanced tumour progression and shown to promote cancer cell growth and spread, angiogenesis and immunosuppression. This paradoxical role of macrophages in cancer finds an explanation in their functional plasticity, that may result in the polarized expression of either pro- or anti-tumoural functions. Key players in the setting of their phenotype are the microenvironmental signals to which macrophages are exposed, which selectively tune their functions within a functional spectrum encompassing the M1 and M2 extremes. Here, we discuss recent findings suggesting that targeting tumour-associated macrophages (TAMs) polarization may represent a novel therapeutic strategy against cancer.


A novel mitochondrial amidoxime reducing component 2 is a favorable indicator of cancer and suppresses the progression of hepatocellular carcinoma by regulating the expression of p27.
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime reducing component 2 (MARC2) as a newly discovered molybdenum enzyme was downregulated in human HCC tissues and HCC cells. Downregulated MARC2 was significantly associated with clinicopathological characteristics of HCC, such as tumor size, AFP levels, and tumor grade and was an independent risk factor of poor prognosis. Both in vitro and in vivo studies suggested that MARC2 suppressed the progression of HCC by regulating the protein expression level of p27. The Hippo signaling pathway and RNF123 were required for this process. Moreover, MARC2 regulated expression of HNF4A via the Hippo signaling pathway. HNF4A was recruited to the promoter of MARC2 forming a feedback loop. MARC2 levels were downregulated by methylation. We demonstrated the prognostic value of MARC2 in HCC and determined the mechanism by which MARC2 suppressed the progression of HCC in this study. These findings may lead to new therapeutic targets for HCC.


Purification of truncated and mutated Chemotaxis Inhibitory Protein of Staphylococcus aureus--an anti-inflammatory protein.
The Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) binds and blocks the C5a receptor (C5aR) and formyl-peptide receptor (FPR). This way, CHIPS is a potent inhibitor of the immune cell recruitment associated with inflammation. Truncation of the protein and the introduction of mutations, shifts the expression towards the insoluble fraction of Escherichia coli, whereas the wild-type protein can be solubly expressed. A protocol for expression and tag independent purification of biologically active CHIPS variants has been established to enable further characterization of an improved CHIPS variant, called ADC-1004. The CHIPS variants were purified by washing of E. coli inclusion bodies followed by refolding and gel filtration. New techniques were utilized to optimize the purification process. Expression in inclusion bodies was increased by the use of Ultra Yield flasks and optimal refolding conditions were determined by the use of the iFOLD Refolding System 2. The folding and biological activity of the purified proteins were analyzed by circular dichroism (CD) spectroscopy and flow cytometry, respectively, and compared to solubly produced CHIPS(31-113) and wild-type CHIPS(1-121). We show that the CHIPS variants produced in inclusion bodies can be refolded and purified to achieve equal biological activity as solubly produced CHIPS(31-113) and wild-type CHIPS(1-121). The truncation causes minor structural changes while purification from inclusion bodies or the soluble fraction does not further affect the structure.


The aqueous extract of Angelica sinensis, a popular Chinese herb, inhibits wear debris-induced inflammatory osteolysis in mice.
More and more studies have shown Angelica sinensis' (AS) therapeutic action on chronic inflammatory diseases in recent years. We investigated effects of aqueous extract of AS on inflammatory cytokines release and wear debris particles-induced osteolysis. Ultra high molecular weight polyethylene (UHMWPE) particles were used to induce inflammation in RAW264.7 cell and C57BL/J6 mice. AS extract was obtained through a series of purification steps, and divided into high dose group and low dose group during the research of cell culture, tissue culture, and animal treatment. After 72 h culture with optimal particles, supernatants were collected for cytokine analysis. Calvaria were harvested from the mice model after 10 d treatment with the AS extract. Six calvaria of each group were cultured into medium for 72 h for analyzing cytokine generated in vivo. Histologic analyses and micro-computed tomography (micro-CT) scan were used to determine osteoclastogenesis and inflammatory bone resorption. Concentration of tumor necrosis-alpha (TNF-α) and interleukin-1beta (IL-1β) was significantly attenuated by AS extract both in vitro and in vivo. The osteolysis area and the osteoclast numbers were decreased from 0.406 ± 0.0799 to 0.117 ± 0.0103 mm(2), and from 22.7 ± 5.0 to 11.3 ± 1.8, respectively (P < 0.01). Compared with the control group, the protection effects of AS extract was further confirmed with data of the more accurate 3-dimension micro-CT reconstruction. This study suggests a potential resolution of inhibiting wear debris particles-induced inflammatory bone resorption, as well as a possible way of inhibiting aseptic loosening after joint replacement surgery.


Brevican: a key proteoglycan in the perisynaptic extracellular matrix of the brain.
Brevican is a neural proteoglycan implicated in a multitude of physiological and pathophysiological plasticity processes in the brain. It localizes to neuronal surfaces and contributes to the formation of specific types of extracellular matrix like the perineuronal nets or the perisynaptic or axon initial segment-based matrix in mature neuronal tissue. Via a variable degree of chondroitin sulfate attachment, limited proteolytic cleavage by matrix metalloproteinases, differential splicing and Ca(2+)-dependent binding to interaction partners it acts as a regulator in synaptic plasticity, glioma invasion, post-lesion plasticity or Alzheimer's disease. This review briefly summarizes its gene and protein structure, biochemical interactions and neurobiological functions.


Inhibition of benzo[a]pyrene dihydrodiol epoxide mutagenicity by synthetic analogues of ellagic acid.
Dibenzo[b, d]pyran-6-one, hydroxylated and methoxylated derivatives of this ring system, and some other analogues of the natural product ellagic acid have been synthesized and examined as inhibitors of benzo[a]pyrene dihydrodiol epoxide (BPDE) mutagenicity in Salmonella typhimurium strain TA100. Some of these new compounds have inhibitory effectiveness comparable to the natural product. On the basis of our results, we suggest qualitative rules for predicting inhibitory activity of ellagic acid analogues.


Loss of LXN promotes macrophage M2 polarization and PD-L2 expression contributing cancer immune-escape in mice.
Latexin (LXN) plays an important role in tumorigenesis and inflammatory response and as a tumor suppressor in many tumors. However, whether LXN regulates tumorigenesis through immune regulation remains uncertain. Here, we demonstrate that LXN deficiency increases hematopoietic stem cells, as well as affects the proportion of immune cells in the peripheral system. Animal studies show that mice loss of LXN promotes tumor growth in subcutaneous tumor model and AOM/DSS-induced colorectal cancer model. We found that loss of LXN promotes macrophage M2 polarization and PD-L2 expression in macrophage, thus, inhibits the function of T cells. Adoptive transfer of wild-type macrophage rescues the function of T cells in LXN-deficient mice. LXN deficiency in hematopoietic lineage exacerbates colorectal carcinogenesis, and targeted inhibition of PD-L2 ameliorates cancer growth in LXN-deficient mice. Mechanistically, we demonstrate that LXN inhibits STAT3 transcriptional activity by targeting inhibition of JAK1 in macrophages. LXN deficiency enhances PD-L2 expression rather than PD-L1 in macrophages, which lead to inhibition of T cells in tumor microenvironment. Collectively, we define a critical role of LXN/JAK1/STAT3 signal in macrophage and highlights the potential role of LXN in tumor immune-escape by regulating macrophage polarization, as well as the expression of immune checkpoint PD-L2.


Lipid peroxidation and loss of potassium from red blood cells produced by phototoxic quinolones.
Alterations of the cationic permeability of red blood cell membranes induced by the photosensitiser nalidixic acid were demonstrated by evaluating the potassium loss from intact erythrocytes. The results show that an increase in intracellular potassium efflux, precedes the photohemolysis induced by nalidixic acid. The addition of a nonpermeable osmotic solute, such as sucrose, inhibited photohemolysis but not the potassium loss, indicating a colloid osmotic lysis. Lipid peroxidation induced by nalidixic acid and other photosensitiser quinolones (oxolinic acid and rosoxacin) was time irradiation-dependent. Although rosoxacin was the most photoperoxidative, none of the three quinolones studied produced significant lipid peroxidation. However, of the three quinolones studied, only rosoxacin considerably diminished the percentage of the cholesterol extracted from red blood cell membranes. It is postulated that the increased cation permeability induced by nalidixic and oxolinic acids cannot be attributed to cholesterol oxidation nor to lipid peroxidation; a more probable mechanism is photo-oxidation of amino acid residues of the membrane proteins. However, the lysis induced by rosoxacin is caused by photo-oxidation of cholesterol, not excluding other cellular targets.


Cuff-leak test combined with interventional bronchoscopy benefits early extubation for patients who received tarp surgery.
This study explored the performance characteristics of a cuff-leak test (CLT) combined with interventional fiberoptic bronchoscopy (FBS) for evaluating whether early nasoendotracheal extubation was possible for patients who had received transoral atlantoaxial reduction plate (TARP) internal fixation surgery. 318 patients who underwent surgery were retrospectively analyzed (between January 2006 and December 2012). Extubation was performed by conventional approach (CA group, until December 2008) and improved approach (IA group, from January 2009) including CLT and an interventional FBS procedure. The extubation success within 1-3 days after surgery, incidence of postextubation stridor and tracheal reintubation were examined. More IA-treated patients experienced extubation during the first 2 days than those CA-treated, median extubation time was 3 (2, 3) days in the CA group and 2 (1, 2) days in the IA group (all P < 0.01). The incidence of stridor and reintubation was 5.69 and 0.57 % in IA and 11.98 and 4.93 % in CA, respectively (both P < 0.05). For the CLT-positive patients in the IA group that remained intubated until day 3-4, interventional FBS was applied for safe extubation and achieved 100 % success. Early extubation through IA is safe and interventional FBS assists successful extubation for CLT-positive patients who underwent TARP surgery.


Endoplasmic reticulum-mitochondrial calcium transport contributes to soft extracellular matrix-triggered mitochondrial dynamics and mitophagy in breast carcinoma cells.
Although mitochondrial morphology and function are considered to be closely related to matrix stiffness-driven tumor progression, it remains poorly understood how extracellular matrix (ECM) stiffness affects mitochondrial dynamics and mitophagy. Here, we found that soft substrate triggered calcium transport by increasing endoplasmic reticulum (ER) calcium release and mitochondrial (MITO) calcium uptake. ER-MITO calcium transport promoted the recruitment of dynamin-related protein 1 (Drp1) to mitochondria and phosphorylation at the serine 616 site, which induced mitochondrial fragmentation and Parkin/PINK1-mediated mitophagy. Furthermore, in vivo experiments demonstrated that soft ECM enhanced calcium levels in tumor tissue, Drp1 activity was required for soft ECM-induced mitochondrial dynamics impairment, and inhibition of Drp1 activity enhanced soft ECM-induced tumor necrosis. In conclusion, we revealed a new mechanism whereby ER-MITO calcium transport regulated mitochondrial dynamics and mitophagy through Drp1 translocation in response to soft substrates. These findings provide valuable insights into ECM stiffness as a potential target for antitumor therapy. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and mitochondrial dynamics by using polyacrylamide (PAA) substrates to simulate the stages of breast cancer or BAPN to reduce tumor tissue stiffness. The results elucidated that soft substrate triggered the recruitment of DRP1 and subsequent mitochondrial fission and mitophagy by ER-MITO calcium transport. Furthermore, mitophagy partly attenuated soft ECM-mediated tumor tissue necrosis and contributed to tumor survival in vivo. Our discoveries revealed the molecular mechanisms by which mechanical stimulation regulates mitochondrial dynamics, providing valuable insights into ECM stiffness as a target for anti-tumor approaches, which could be beneficial for both biomechanics research and clinical applications.


Metalloporphyrins inactivate caspase-3 and -8.
Activation of caspases represents one of the earliest biochemical indicators for apoptotic cell death. Therefore, measurement of caspase activity is a widely used and generally accepted method to determine apoptosis in a wide range of in vivo and in vitro settings. Numerous publications characterize the role of the heme-catabolizing enzyme heme oxygenase-1 (HO-1) in regulating apoptotic processes. Different metalloporphyrins representing inducers and inhibitors of this enzyme are often used, followed by assessment of apoptotic cell death. In the present work, we found that caspase-3-like activity, as well as activity of caspase-8 measured in either Fas (CD95) ligand-treated Jurkat T-lymphocytes or by the use of recombinant caspase-3 or -8, was inhibited by different metalloporphyrins (cobalt(III) protoporphyrin IX, tin and zinc(II) protoporphyrin-IX). Moreover, employing the mouse model of Fas-induced liver apoptosis these properties of porphyrins could also be demonstrated in vivo. The metalloporphyrins were shown to inhibit caspase-3-mediated PARP cleavage. Molecular modeling studies demonstrated that porphyrins can occupy the active site of caspase-3 in an energetically favorable manner and in a binding mode similar to that of known inhibitors. The data shown here introduce metalloporphyrins as direct inhibitors of caspase activity. This finding points to the need for careful employment of metalloporphyrins as modulators of HO-1.


Ketamine-snorting associated cystitis.
Ketamine hydrochloride, commonly used as a pediatric anesthetic agent, is an N-methyl-D-aspartic (NMDA) acid receptor antagonist with rapid onset and short duration of action. It produces a cataleptic-like state where the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. It has emerged as an increasingly popular choice among young drug users, especially within dance club venues. Cases of bladder dysfunction among recreational ketamine users were reported since Shahani et al first reported nine cases of ketamine-associated ulcerative cystitis in 2007. We report on four patients who had history of ketamine abuse, presenting with dysuria, fluctuating lower urinary tract symptoms (LUTS), lower abdominal or perineal pain, and impaired functional bladder capacities. Urinalysis showed pyuria and microhematuria. Urine culture was sterile. Bladder ulceration with severe diffuse hemorrhage and low bladder capacity were noted under anesthetized cystoscopic examination. Transurethral bladder mucosa biopsy was consistent with chronic cystitis. Cessation of ketamine abuse was the milestone of treatment, followed by the administration of mucosal protective agents, such as pentosan polysulphate or hyaluronic acid. Suprapubic pain was improved in three patients during follow-up. However, the outcome of treatment depends on the severity of the disease process, similar to that of interstitial cystitis (IC).


Liver Fibrosis Scores Are Associated With Resting and Exercise Fontan and Pulmonary Artery Wedge Pressures: Insights Into FALD.
Alterations in liver perfusion and venous hypertension have been implicated in the pathophysiology of Fontan-associated liver disease (FALD). However, the correlation between exercise hemodynamics and markers of FALD have not been studied. We performed a retrospective review of 32 consecutive adults undergoing exercise catheterisation at the Mayo Clinic, Minnesota. Invasive hemodynamics were correlated with aspartate transaminase to platelet ratio index (APRI) and the Fibrosis-4 (Fib-4) score, well validated surrogates of liver fibrosis. The mean age was 30.9 ± 7 years. The mean APRI was 0.5 ± 0.2 and the mean Fib-4 score 1.3 ± 0.8. Fib-4 scores correlated with spleen size on abdominal imaging (r = 0.40; P = 0.03). Resting Fontan pressure was 13.9 ± 3.9 mm Hg and pulmonary artery wedge pressure (PAWP) 10.0 ± 3.5 mm Hg. At peak exercise (69.4 ± 23.2 W), Fontan pressures increased to 26.5 ± 6.2 mm Hg and PAWP to 22.4 ± 7.1 mm Hg. APRI and Fib-4 score were directly related to Fontan pressure and PAWP at rest and during exercise, and inversely related to exercise arterial O2 saturation. Fib-4 inversely correlated with O2 delivery indices. Similarly, when categorising patients according to high APRI (> 0.5 vs ≤ 0.5) or Fib-4 score (≥ 1.45 vs < 1.45) according to previously proposed cutoffs for diagnosis of liver fibrosis, those with elevated scores had higher resting and exercise Fontan and PAWP pressure with lower O2 arterial saturation. APRI and Fib-4 score correlated with resting and exercise Fontan pressure and PAWP. In addition, Fib-4 scores were inversely related to O2 delivery indices. These findings support a role played by hepatic venous hypertension and reduced O2 supply in patients with FALD.


Intranodal lymphangiogram: technical aspects and findings.
To report the technical results and imaging findings of intranodal lymphangiogram (INL). we studied four patients (three men, one woman) who had persistent chylous leakage despite conservative treatment after esophageal cancer surgery. Their mean age was 68 years (range 61-74 years). The inguinal or femoral lymph node was punctured under ultrasound guidance using a 60-mm-long, 23-gauge needle. If the lipiodol injected via the needle showed granular nodules on fluoroscopy, lipiodol injection was continued manually at a rate of 1 mL/3 min for INL. If the cisterna chyli was detectable on the lymphangiogram, it was punctured percutaneously via the abdomen by a needle under fluoroscopy, and thoracic duct embolization was performed. INL was successful in all patients. Lymphaticovenous anastomoses at the femoral or pelvic region were confirmed in all four patients. In one case, a different ipsilateral lymph node was punctured because major flow of lipiodol into the veins through a lymphaticovenous anastomosis occurred. Catheter cannulation and embolization were successful for three of the four patients. In unsuccessful procedures, the cisterna chyli was not visualized, and puncture was not possible. INL succeeded in all patients. Lipiodol leaked into the vein through a lymphaticovenous anastomosis at the femoral or pelvic region in all patients.


Effect of intraoperative blood pressure on incidence of hematoma in breast reduction mammoplasty.
Postoperative hematomas are among the most frequent complications following breast reduction mammoplasty (BRM). Intraoperative hypotension has been implicated in the development of postoperative hematomas following breast reduction. In this study, we performed a retrospective, propensity-matched analysis of patients undergoing primary breast reduction to determine the relationship between intraoperative blood pressure and the development of a postoperative hematoma. A retrospective review of all patients that underwent BRM at a single institution from 2017 to 2019 (n = 563) was conducted. Patients who developed a postoperative hematoma were propensity matched to two controls based on body mass index (BMI) and age. The mean systolic blood pressure (SBP) and average mean arterial pressure (MAP) were recorded for each third of the operation. Data were analyzed using conditional logistic regression. Thirty-two patients that developed postoperative hematomas were propensity matched to 64 controls. There was no difference in baseline SBP, diastolic blood pressures, or prevalence of hypertension between groups. There was no significant difference in average SBP or MAP between groups. The average MAP during the first third of the procedure was found to be lower in patients who developed a hematoma (69 vs. 72 mmHg), which approached significance at p = 0.08. Closed suction drains were used in 53% of the hematoma group and 78% of the control group (p = 0.02). There does not appear to be an association between intraoperative blood pressure and the incidence of hematoma when comparing patients who developed hematomas after BRM to propensity-matched controls.


Incompatible blood-group A determinants in tumoral mucins. Isolation of oligosaccharides having a 2-acetamido-2-deoxy-alpha-D-galactopyranosyl group at the non-reducing end.
Two glycopeptide fractions were obtained from pseudomyxomatous mucins secreted by an ovarian cystadenocarcinoma from a female having blood-group B, and by an appendix tumor from a male having blood-group O. The carbohydrate and amino acid content of these fractions suggests the presence of numerous carbohydrate side-chains linked through O-glycosyl bonds to a peptide core rich in threonine and proline. The two glycopeptide fractions exhibit compatible B- and H-blood-group activities. They are reactive towards Dolichos biflorus lectin and human anti-A agglutinins, and so exhibit an incompatible A activity. Alkali-borohydride degradation of Pronase-digested glycopeptides gave dialyzable oligosaccharides that were purified and shown to possess 2-acetamido-2-deoxygalactitol at the terminal reducing-end. 2-Acetamido-2-deoxyglucose, galactose, fucose, and neuraminic acid were absent, or present, in variable proportions. Four oligosaccharides containing 2-acetamido-2-deoxy-D-galactose residues were reactive towards Dolichos biflorus lectin and human anti-A agglutinins, indicating the presence, at the nonreducing end, of a 2-acetamido-2-deoxy-alpha-D-galactopyranosyl group, responsible for blood-group A activity.


Nail-based reconstruction strategies for Wassel-Flatt type IVh thumb polydactyly with a floating ulnar digit: A preliminary report with 63 thumbs.
To present a surgical regimen based on nail morphology for Wassel-Flatt type IVh thumb polydactyly with a floating ulnar digit. Cases within six years were retrospectively analyzed and followed up for an average of 18 months. Three types of classifications were defined based on nail morphology ‒ ulnar nail dominant type with two subtypes of nail lateral fold symmetric or asymmetric, radial nail dominant type, and equal nail size type. One out of three procedures, on-top plasty (Ⅰ), soft tissue augmentation (Ⅱ), and the combination of the above two (Ⅲ), was performed. The Tada scoring system was used to evaluate the results. Sixty-three thumbs were enrolled, forty-one of better ulnar nail type underwent top transposition, and in cases of asymmetric nail lateral fold subtype, the result of procedure Ⅲ was better than that of procedure Ⅰ, thirteen of the radial nail dominant type and nine of equal nail size type both had procedure Ⅱ. The equal nail size type was the least effective among groups, with an average Tada of four points. Six cases underwent secondary revision surgery. According to the Tada scoring system, the results were excellent in 61, fair in two. Classifications based on the morphology of the nail can guide surgical planning. On-top plasty is suitable for symmetric nail lateral fold subtype. Soft tissue augmentation is ideal for radial nail dominant type and equal nail size type, and the combination of the two procedures is a better option for asymmetric nail lateral fold subtype.


Reinforcement of hydrogel scaffold using oxidized-guar gum incorporated with curcumin-loaded zein nanoparticles to improve biological performance.
Newly, the use of biocompatible injectable hydrogel with appropriate features for application in the tissue engineering area as a perfect wound dressing has been more attracted. For this purpose, the curcumin loaded Zein nanoparticles/aldehyde-modified guar gum/silk fibroin (Cur-NPs/OGG/SF) hydrogel networks were successfully developed to increase the Cur bioavailability during the wound treatment procedure. Fabricated hydrogels were assessed for their morphological, thermal stability, degradation, and mechanical features. By varying the OGG/SF weight ratios, the physicochemical features of hydrogels without or with Cur-loaded Zein NPs were studied. The results showed that with enhancing the OGG content, the degradation behavior of hydrogels were improved. Besides, Cur-NPs/OGG/SF hydrogels increased the cell proliferation without any cytotoxic effect on mouse embryonic fibroblast (NIH-3T3) cells. The Cur-NPs/OGG/SF hydrogel exposed inhibition activity against Bacillus (15.26 ± 1.09 mm) and E. coli (11.54± 1.36 mm) bacteria. These achieved results recommended that the novel developed hydrogel could be suitable for wound healing application.


Evaluation of aptamer and molecularly imprinted polymers as a first hybrid sensor for leptin detection at femtogram levels.
Selective and sensitive determination of macromolecules maintains its importance in diagnosing and determining diseases to protect human health. In this study, a hybrid sensor designed with dual recognition elements consisting of both aptamers (Apt) and molecularly imprinted polymers (MIPs) was carried out for the ultra-sensitive determination of Leptin. Firstly, the screen-printed electrode (SPE) surface was coated with platinum nanospheres (Pt NSs) and gold nanoparticles (Au NPs) to provide immobilization of the Apt[Leptin] complex on the surface. In the next step, the formed polymer layer around the complex using the electropolymerization of orthophenilendiamine (oPD) kept the Apt molecules on the surface more effectively. As expected, a synergistic effect occurred between the formed MIP cavities by removing Leptin from the surface and the embedded Apt molecules to fabricate a hybrid sensor. Under optimal conditions, responses in differential pulse voltammetry (DPV) currents showed a linear response over a wide concentration range from 1.0 fg/mL to 10.0 pg/mL with a limit of detection (LOD) of 0.31 fg/mL for Leptin detection. Moreover, the effectiveness of the hybrid sensor was assessed using real samples, such as human serum and plasma samples, and satisfactory recovery findings (106.2-109.0%) were found.


Role of protein kinase C on the alteration of retinal endothelin-1 in streptozotocin-induced diabetic rats.
Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic retinopathy. The purpose of this study was to investigate the role of PKC on the alteration of retinal endothelin-1 in 2-week streptozotocin (STZ)-induced diabetic rats. The measurement of retinal PKC activities from membranous and cytosolic fractions was conducted by ELISA. Retinal tissues were analysed for the expression of endothelin-1 (ET-1), endothelin-3 (ET-3), endothelin-A (ET-A), and endothelin-B (ET-B) mRNA by means of semi-quantitative RT-PCR. Retinal vasculature isolated by trypsin digest technique was immunostained for ET-1. We followed the alteration of retinal ET-1 after intravitreal injection of a general PKC inhibitor, GF109203X, in 2-week diabetic rats. Retinal PKC specific activities were significantly increased by 37% (P=0.027) in the membranous fraction in diabetic rats compared with normal rats, whereas PKC specific activities in the cytosolic fraction were unchanged. The retina from the diabetic rats showed increased ET-1 mRNA expression after 2 weeks, while no changes were found for ET-3, ET-A and ET-B. ET-1 immunoreactivity was also increased in the retinal vasculature of diabetic rats. Retinal ET-1 expression was decreased after intravitreal injection of GF109203X (10(-5), 10(-6), 10(-7) M) in a dose-dependent manner. The results from this study showed that the enhanced ET-1 expression associated with the activation of PKC has occurred in early diabetes, and PKC inhibitor could reverse the up regulation of ET-1.


Dialysis-associated allergic reactions during continuous renal replacement therapy and hemodialysis: A case report.
Dialyzer reactions are long-appreciated complications of dialysis. Despite advances in dialysis machines and membranes, these life-threatening reactions still occur. It is imperative to recognize potential dialyzer reactions when assessing adverse dialysis events as reexposure to dialytic treatments could be life threatening. We present the case of a 72-year old woman with dialysis-requiring anuric acute kidney injury who experienced acute hypotension and cardiopulmonary arrest during both continuous renal replacement therapy and a subsequent hemodialysis treatment. We concluded that she had an anaphylactic reaction to an unidentified component of the dialysis equipment. Identification, work up, treatment, and reporting of dialyzer reactions are discussed in the context of this case.


Redistribution of P-selectin ligands on neutrophil cell membranes and the formation of platelet-neutrophil complex induced by hemodialysis membranes.
The formation of platelet-neutrophil microaggregates and successive activation of neutrophils are closely related to hemodialysis-associated complications. The microaggregate is mediated primarily by the interaction between P-selectin (CD62P) expressed on activated platelets and P-selectin glycoprotein ligand-1 (PSGL-1, CD162) expressed on neutrophils. We previously reported that the clustered distribution of PSGL-1 on the cell membranes of chemokine-treated neutrophils caused upregulation of the microaggregate formation. In this study, we found that neutrophils treated with human plasma that had been incubated with hemodialysis membranes greatly enhanced the microaggregate formation. The membrane-treated plasma also induced PSGL-1 to form a cap-like cluster on the neutrophil surface. Analysis of several hemodialysis membranes with different materials indicated that the inducibility for the cap-like cluster formation of PSGL-1 parallels their ability to activate the complement system. Both the enhancement of microaggregate formation and the redistribution of PSGL-1 induced by the hemodialysis membrane-treated plasma were almost completely abrogated in the presence of a specific antagonist for the complement component C5a receptor, W-54011. These results strongly suggest that the generation of anaphylatoxin C5a through complement activation induced by hemodialysis membranes is responsible for the clustered redistribution of PSGL-1 in neutrophils leading to the increase in the platelet-neutrophil microaggregate formation. The present study indicates the importance of synergistic exacerbation of complement activation and platelet-neutrophil microaggregate formation in developing hemodialysis-associated complications.


Structural dynamics of myoglobin: spectroscopic and structural characterization of ligand docking sites in myoglobin mutant L29W.
We have studied CO binding to the heme and CO migration among protein internal cavities after photodissociation in sperm whale carbonmonoxy myoglobin (MbCO) mutant L29W using Fourier transform infrared (FTIR) spectroscopy combined with temperature derivative spectroscopy (TDS) and kinetic experiments at cryogenic temperatures. Photoproduct intermediates, characterized by CO at particular locations in the protein, were selectively enhanced by applying special laser illumination protocols. These studies were performed on the L29W mutant protein and a series of double mutants constructed so that bulky amino acid side chains block passageways between cavities or fill these sites. Binding of xenon was also employed as an alternative means of occluding cavities. All mutants exhibit two conformations, A(I) and A(II), with distinctly different photoproduct states and ligand binding properties. These differences arise mainly from different positions of the W29 and H64 side chains in the distal heme pocket [Ostermann, A., et al. (2000) Nature 404, 205-208]. The detailed knowledge of the interplay between protein structure, protein dynamics, and ligand migration at cryogenic temperatures allowed us to develop a dynamic model that explains the slow CO and O(2) bimolecular association observed after flash photolysis at ambient temperature.


Endotracheal suture through extending tracheostoma for post-tracheostomy tracheal laceration: a case report.
Tracheal laceration is very rare but can be life-threatening if proper treatment is not provided. The general concept for the management of tracheal laceration is surgical repair through cervical incision or via thoracotomy. However, in the case of tracheal laceration after tracheostomy, tracheostoma could be extended to avoid urgent surgical repair and additional incision. A 30-year-old Asian woman suffered intracerebral hemorrhage. Tracheostomy was necessary for prolonged ventilator care. While tracheostomy was performed, the posterior tracheal wall was torn. After observing that, we reinserted endotracheal tube through the oral orifice. Following bronchoscopy showed torn posterior tracheal wall. The tearing wound was 5-6 cm in length, from the middle to distal parts of the trachea. We used minimally invasive procedure for extending the already existing tracheostoma. In the case of tracheal laceration related to tracheostomy, a new incision is not necessary because the tracheal opening already exists. Using the extended tracheostomy technique, tracheal laceration can be repaired by endotracheal suture method.


The effect of single and divided dose administration on the efficacy of fenbendazole against adult stages of benzimidazole resistant sheep trichostrongylids.
Sheep infected with benzimidazole resistant strains of Haemonchus contortus and Trichostrongylus colubriformis were used to compare the anthelmintic efficacy of fenbendazole given as a single dose or administered in a divided dose regime over five days. Statistical analysis showed no significant difference between the two methods of administration for H contortus. On the other hand, divided dose fenbendazole was significantly less effective than single doses against adult T colubriformis at dose rates of 5 and 7.5 mg/kg. In the case of H contortus a highly significant correlation coefficient between post treatment egg counts and worm counts (r = 0.789) was obtained. This suggests that reduction in faecal egg output following drug treatment would provide a useful field indication of anthelmintic performance of fenbendazole (and possibly related compounds) against benzimidazole resistant strains of this parasite.


Gαi2- and Gαi3-specific regulation of voltage-dependent L-type calcium channels in cardiomyocytes.
Two pertussis toxin sensitive G(i) proteins, G(i2) and G(i3), are expressed in cardiomyocytes and upregulated in heart failure. It has been proposed that the highly homologous G(i) isoforms are functionally distinct. To test for isoform-specific functions of G(i) proteins, we examined their role in the regulation of cardiac L-type voltage-dependent calcium channels (L-VDCC). Ventricular tissues and isolated myocytes were obtained from mice with targeted deletion of either Gα(i2) (Gα(i2) (-/-)) or Gα(i3) (Gα(i3) (-/-)). mRNA levels of Gα(i/o) isoforms and L-VDCC subunits were quantified by real-time PCR. Gα(i) and Ca(v)α(1) protein levels as well as protein kinase B/Akt and extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation levels were assessed by immunoblot analysis. L-VDCC function was assessed by whole-cell and single-channel current recordings. In cardiac tissue from Gα(i2) (-/-) mice, Gα(i3) mRNA and protein expression was upregulated to 187 ± 21% and 567 ± 59%, respectively. In Gα(i3) (-/-) mouse hearts, Gα(i2) mRNA (127 ± 5%) and protein (131 ± 10%) levels were slightly enhanced. Interestingly, L-VDCC current density in cardiomyocytes from Gα(i2) (-/-) mice was lowered (-7.9 ± 0.6 pA/pF, n = 11, p<0.05) compared to wild-type cells (-10.7 ± 0.5 pA/pF, n = 22), whereas it was increased in myocytes from Gα(i3) (-/-) mice (-14.3 ± 0.8 pA/pF, n = 14, p<0.05). Steady-state inactivation was shifted to negative potentials, and recovery kinetics slowed in the absence of Gα(i2) (but not of Gα(i3)) and following treatment with pertussis toxin in Gα(i3) (-/-). The pore forming Ca(v)α(1) protein level was unchanged in all mouse models analyzed, similar to mRNA levels of Ca(v)α(1) and Ca(v)β(2) subunits. Interestingly, at the cellular signalling level, phosphorylation assays revealed abolished carbachol-triggered activation of ERK1/2 in mice lacking Gα(i2). Our data provide novel evidence for an isoform-specific modulation of L-VDCC by Gα(i) proteins. In particular, loss of Gα(i2) is reflected by alterations in channel kinetics and likely involves an impairment of the ERK1/2 signalling pathway.


RNA-Seq mediated root transcriptome analysis of Chlorophytum borivilianum for identification of genes involved in saponin biosynthesis.
Chlorophytum borivilianum is an important species of liliaceae family, owing to its vital medicinal properties. Plant roots are used for aphrodisiac, adaptogen, anti-aging, health-restorative and health-promoting purposes. Saponins, are considered to be the principal bioactive components responsible for the wide variety of pharmacological properties of this plant. In the present study, we have performed de novo root transcriptome sequencing of C. borivilianum using Illumina Hiseq 2000 platform, to gain molecular insight into saponins biosynthesis. A total of 33,963,356 high-quality reads were obtained after quality filtration. Sequences were assembled using various programs which generated 97,344 transcripts with a size range of 100-5,216 bp and N50 value of 342. Data was analyzed against non-redundant proteins, gene ontology (GO), and enzyme commission (EC) databases. All the genes involved in saponins biosynthesis along with five full-length genes namely farnesyl pyrophosphate synthase, cycloartenol synthase, β-amyrin synthase, cytochrome p450, and sterol-3-glucosyltransferase were identified. Read per exon kilobase per million (RPKM)-based comparative expression profiling was done to study the differential regulation of the genes. In silico expression analysis of seven selected genes of saponin biosynthetic pathway was validated by qRT-PCR.


Triglyceride-glucose index predicts independently type 2 diabetes mellitus risk: A systematic review and meta-analysis of cohort studies.
Our objective was to perform a systematic review and meta-analysis of cohort studies evaluating the triglyceride-glucose (TyG) index as a tool for type 2 diabetes (T2D) prediction in adults and older adults. Studies were identified in PubMed, Cochrane, Scopus, and Lilacs. Studies with cohort design, which evaluated the T2D incidence through the hazard ratio (HR) or relative risk (RR) or odds ratio values were included. Were included both studies that evaluated the incidence of T2D from tertiles, quartiles, quintiles, or single TyG index values. First, a meta-analysis only for studies that reported data in HR values was performed. Additionally, given the different association measurements used, the number of T2D cases, non-T2D cases, and the total number of participants were extracted from exposed and non-exposed groups when available. Then the risk ratio was calculated. A meta-analysis using the inverse variance method and the random-effects model was performed. Heterogeneity was assessed by I2 statistics and by inspecting funnel plots. Thirteen cohort studies with a total of 70,380 subjects, both sexes, adults, and older adults were included in the meta-analysis. Ten studies showed a significant association of the TyG index with T2D risk through HR estimative (overall HR: 2.44, 95% CI: 2.17-2.76). After estimating RR for nine studies, we also observed a significant association of the TyG index with T2D risk (RR: 3.12, 95 CI: 2.31-4.21). For all analyses, high heterogeneity was verified by I2 and visual inspection of funnel plots. TyG index has a positive and significant association with T2D risk, suggesting that the TyG index may become an applicable tool to identify subjects with T2D risk. However, due to the high heterogeneity observed in overall HR and RR analysis, more studies could be necessary to confirm these results.


Hepatic glucose production during intraperitoneal and intravenous closed-loop insulin regulation of blood glucose in type 1 (insulin-dependent) diabetic patients.
Intraperitoneal infusion of insulin should be more physiological than intravenous insulin since part of the insulin is directed toward the portal vein, which allows the liver to retain its major role in glucose homeostasis. The regulation of hepatic glucose production during the intraperitoneal and intravenous infusions of insulin were compared in eight Type 1 (insulin-dependent), C-peptide-deficient diabetic patients. Primed, continuous infusions of [6,6-2H]glucose were given in the postabsorptive state and during continuous infusion of unlabelled glucose at 1.5 and 4 mg/kg.min, while normoglycaemia was maintained by closed-loop intraperitoneal and intravenous insulin delivery. During all three periods, plasma glucose concentrations remained near normal (variations 3.8-6.1%). The insulin infusion rates required for normal plasma glucose concentrations were essentially the same for the intravenous and intraperitoneal routes in all cases, although the variations were greater with intraperitoneal insulin. Plasma free-insulin levels were only slightly, non-significantly lower with intraperitoneal infusion than with intravenous infusion. Hepatic glucose production was significantly lower with intraperitoneal insulin during all three conditions: basal: 1.71 +/- 0.14, i.p. vs 2.37 +/- 0.26 mg/kg.min, i.v.; 1.5 mg/kg.min glucose infusion: 0.49 +/- 0.23, i.p. vs 0.88 +/- 0.18 mg/kg.min, i.v.; 4 mg/kg.min glucose infusion: 0.31 +/- 0.10, i.p. vs 0.56 +/- 0.12 mg/kg.min, i.v.. These results, obtained with steady-state conditions for plasma glucose, isotopic plasma glucose enrichments and unlabelled glucose infusion rates, suggest that better control of hepatic glucose production leading to normoglycaemia was achieved with the intraperitoneal infusion.


Should Genetics Now Be Considered the Pre-eminent Etiologic Factor in Endometriosis?
Endometriosis is a common, estrogen-dependent, inflammatory disorder characterized by the growth of endometrial-like tissue at extrauterine locations. Its pathogenesis and mechanisms underlying its pathophysiology are poorly understood, although genetic variation is strongly implicated in these processes. Genetic studies reveal that approximately 50% of risk for endometriosis is due to genetic factors and the other 50% likely owing to environmental factors. As with other complex diseases, genetic variants in the DNA sequence increasing endometriosis risk all have small effects, unlike most single-gene disorders. It is the combinations of these variants adding together that contribute to higher risks for individual women. In addition, recent data on disease lesions demonstrate a high frequency of somatic (likely acquired) mutations, some of which are present in the eutopic endometrium and specifically in the epithelial cell compartment, raising the possibility that abnormal epithelial progenitors in the eutopic endometrium give rise to ectopic disease. Discovery in this field is occurring at a rapid pace, and further definitions of genetic (germline) and environmental (somatic) contributions to the pathogenesis and pathophysiology of this disorder are anticipated soon. These discoveries are expected to increase diagnostic, therapeutic, and preventive strategies to minimize disease and its associated morbidities.