Left ventricular rotational mechanics in hypereosinophilic syndrome-Analysis from the three-dimensional speckle-tracking echocardiographic MAGYAR-Path Study.
Hypereosinophilic syndrome (HES) is a very heterogeneous group of disorders with varied etiologies characterized by peripheral eosinophilia and eosinophilic tissue/end-organ damage. Three-dimensional speckle-tracking echocardiography (3DSTE) was used for assessment of left ventricular (LV) rotational mechanics in HES patients. The study comprised 13 HES patients, from which one patient was excluded due to insufficient image quality. The remaining patient population consisted of 12 HES cases (mean age: 59.7 ± 13.7 years, eight males). The control group consisted of 36 healthy volunteers (mean age: 52.9 ± 8.3 years, 23 males). 3DSTE was used for the evaluation of LV rotational abnormalities. Both LV apical rotation (4.86 ± 1.92 degree vs 10.07 ± 3.92 degree, P < .0001) and LV twist (8.52 ± 2.79 degree vs 14.41 ± 4.26 degree, P < .0001) showed significant deteriorations in most of HES patients. Time-to-peak LV apical rotation (380 ± 115 ms vs 344 ± 69 ms, P = .56), LV basal rotation (335 ± 148 ms vs 337 ± 111 ms, P = .89), and LV twist (348 ± 91 ms vs 320 ± 60 ms, P = .64) were not significantly different between HES patients and controls. No correlations could be detected between absolute eosinophil count and eosinophil ratio and apical LV rotation (r = 0.12, P = .51 and r = 0.23, P = .45, respectively) and LV twist (r = 0.24, P = .39 and r = 0.31, P = .34, respectively). In two subjects, the absence of LV twist called LV "rigid body rotation" (RBR) was detected. Reduced LV apical rotation and twist could be demonstrated in HES. LV-RBR could be detected in some HES patients.


mTOR regulates skeletogenesis through canonical and noncanonical pathways.
The mechanistic/mammalian target of rapamycin (mTOR) regulates various cellular processes, in part through incorporation into distinct protein complexes. The mTOR complex 1 (mTORC1) contains the Raptor subunit, while mTORC2 specifically contains the Rictor subunit. Mouse genetic studies, including ours, have revealed a critical role for mTOR in skeletogenesis through its expression in undifferentiated mesenchymal cells. In addition, we have recently revealed that mTORC1 expression in chondrocytes is crucial for skeletogenesis. Recent work indicates that mTOR regulates cellular functions, depending on the context, through both complex-dependent (canonical pathway) and complex-independent roles (noncanonical pathway). Here, we determined that mTOR regulates skeletal development through the noncanonical pathway, as well as the canonical pathway, in a cell-type and context-specific manner. Inactivation of Mtor in undifferentiated mesenchymal cells or chondrocytes led to either severe hypoplasia in appendicular skeletons or a severe and generalized chondrodysplasia, respectively. Moreover, Rictor deletion in undifferentiated mesenchymal cells or chondrocytes led to mineralization defects in some skeletal components. Finally, we revealed that simultaneous deletion of Raptor and Rictor in undifferentiated mesenchymal cells recapitulated the appendicular skeletal phenotypes of Mtor deficiency, whereas chondrocyte-specific Raptor and Rictor double-mutants exhibited milder hypoplasia of appendicular and axial skeletons than those seen upon Mtor deletion. These findings indicate that mTOR regulates skeletal development mainly through the canonical pathway in undifferentiated mesenchymal cells, but at least in part through the noncanonical pathway in chondrocytes.


Bio-Inspired Synthetic Hydrogen-Bonded Organic Frameworks for Efficient Proton Conduction.
Hydrogen-bonded organic frameworks (HOFs) are a rising class of promising proton-conducting materials. However, they always suffer from the inherent contradiction between chemical stability and proton conduction. Herein, inspired by the self-assembly of lipid bilayer membranes, a series of aminomethylphosphonic acid-derived single-component HOFs are successfully developed with different substituents attached to the phosphonate oxygen group. They remain highly stable in strong acid or alkaline water solutions for one month owing to the presence of charge-assisted hydrogen bonds. Interestingly, in the absence of external proton carriers, the methyl-substituted phosphonate-based HOF exhibits a very high proton conductivity of up to 4.2 × 10-3 S cm-1 under 80 °C and 98% relative humidity. This value is not only comparable to that of HOFs consisting of mixed ligands but also is the highest reported in single-component HOFs. A combination of single-crystal structure analysis and density functional theory calculations reveals that the high conductivity is attributed to the strengthened H-bonding interactions between positively charged amines and negatively charged phosphonate groups in the channel of bio-inspired HOFs. This finding demonstrates that the well-defined molecular structure of proton conductors is of great importance in the precise understanding of the relationship between structure and property.


Anti-AIDS agents. 33. Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogues.
Four isomeric methyl substituted DCK analogues (2-5) were asymmetrically synthesized from different starting materials. 3-Methyl, 4-methyl, and 5-methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (2-4) all were extremely potent against HIV-1 replication in H9 lymphocyte cells with EC50 and therapeutic index values of < 4.23 x 10(-7) microM and > 3.72 x 10(8), respectively, which are much better than those of DCK and AZT in this assay.


Two-hybrid arrays.
The two-hybrid system is a genetic method for detecting protein-protein interactions. The assay can be applied to random libraries or arrays of colonies that express defined pairs of proteins. Arrays enable the testing of all possible protein pairs for interactions in a systematic fashion. The array format makes a large number of individual assays comparable and thus greatly simplifies the identification of false positives. Two-hybrid arrays have been used to study interactions among the proteins of yeast, hepatitis C virus, vaccinia virus, Drosophila, Caenorhabditis elegans, mouse and other species, and have already identified thousands of interactions.


Impact of nurse-led medication adherence therapy on bipolar affective disorder: A randomized controlled trial.
This study evaluated the impact of nurse-led medication adherence therapy (MAT) on medication adherence behavior and symptom severity of inpatients with bipolar disorder. Two arms, single-blind, randomized controlled trial on individuals with bipolar disorder was conducted at inpatient department of mental healthcare setting, India. Eighty-five participants were randomly allocated to MAT group and Treatment as usual group. Standard measures were used to assess medication adherence and symptom severity of both groups at baseline and follow-up time points. MAT improved medication adherence behavior resulting in marked decrease in symptom severity of participants with bipolar disorders. Psychiatric nurses can effectively implement MAT for bipolar inpatients, which improves better clinical outcomes, prevent relapse, and readmissions.


Topical instillation of triamcinolone acetonide-loaded emulsomes for posterior ocular delivery: statistical optimization and in vitro-in vivo studies.
The objective of the present investigation was to formulate and characterize a novel lipid-based carrier-emulsomes loaded with triamcinolone acetonide (TA)/Nile red (NR) for non-invasive delivery to the posterior segment of the eye upon topical application. To optimize and delineate the effect of independent variables on dependent variables, Box-Behnken design (BBD) was adopted. The optimized batch was characterized for size, zeta potential, surface morphology by transmission electron microscopy, drug-excipient interaction by differential scanning calorimetry, osmolarity, pH, ex vivo transcorneal permeation, and stability studies. A short-term exposure (STE) test was performed on Statens Seruminstitut Rabbit Corneal (SIRC) cell lines to evaluate the in vitro ocular irritation. Precorneal retention study was performed in rabbit eyes. Confocal microscopy was used for ocular distribution studies in mice eye by preparing dye (Nile red)-loaded formulations. The surface response and contour plots along with ANOVA results demonstrated an interaction between the factors. The optimized batch had particle size of 131.17 ± 3.17 nm and entrapment efficiency of 71.56 ± 4.19%. TEM image showed unimodal, nano-sized emulsomes. TA-loaded emulsomes exhibited higher transcorneal permeation as compared to drug solution. In vitro irritation studies confirmed the safety of excipients for ophthalmic use. Fluorescence microscopic images obtained after ocular distribution studies showed strong fluorescence in inner and outer plexiform layers of the retina in comparison to dye solution confirming the delivery of dye to the posterior segment of mice eye after topical ocular instillation. Graphical abstract.


Multimedia article: Transvaginal laparoscopic cholecystectomy: laparoscopically assisted.
Natural orifice transluminal endoscopic surgery (NOTES) is considered the new frontier for minimally invasive surgery. NOTES procedures such as peritoneoscopy, splenectomy, and cholecystectomy in animal models have been described. The aim of our experiment was to determine the feasibility and technical aspects of a new endoluminal surgical procedure. After approval from Columbia's IACUC, a transvaginal laparoscopically assisted endoscopic cholecystectomy was performed on four 30 kg Yorkshire pigs. The first step was to insert a 1.5 cm endoscope into the vagina under direct laparoscopic vision. Then the gallbladder was reached and, with the help of a laparoscopic grasper to hold up the gallbladder, the operation was performed. At the end of the procedure the gallbladder was snared out through the vagina attached to the endoscope. There were no intraoperative complications such as bleeding, common bile duct or endo-abdominal organ damage. Total operative time ranged between 110 and 155 min. Based on our experience in the porcine model, we believe that a transvaginal endoscopic cholecystectomy is feasible in humans.


Effects of type I and type II pyrethroids on the startle response in rats.
The effects of type I and type II pyrethroids on the acoustic startle response of male Wistar rats were studied in three experiments. Pyrethroids were administered p.o. in 0.2 ml corn oil. In Expt. 1, techn. cis-permethrin (0, 30, 60, 90 mg/kg) and techn. cis, trans-cypermethrin (0, 60, 90, 120 mg/kg) increased startle in a dose-dependent way, whereas overt behavior and habituation of the startle response were not affected. In Expt 2, NAK 1901 (0, 1, 2.5, 4 mg/kg) enhanced startle amplitudes dose dependently and deltamethrin (0, 2, 4, 6 mg/kg) had no effect on startle. After both deltamethrin and NAK 1901 toxic signs increased dose dependently but an effect on potentiation of the startle reflex was not found. In Expt. 3, deltamethrin (0, 2, 4, 6 mg/kg) was administered and the highest dose attenuated startle amplitudes significantly, whereas toxic signs increased dose dependently. Deltamethrin had no effect on habituation of the startle response. It is concluded that type I pyrethroids increase the amplitude of the startle reflex; this effect does not depend on the presence of overt signs of toxicity. Type II pyrethroids have dissimilar effects on startle. Results are discussed suggesting that the effects of type II pyrethroids on startle amplitude are mediated by an indirect metabolic effect and a direct effect at the site of the muscle.


[Percutaneous transthoracic fine-needle biopsy of the lung. Indications, results and complications in 578 punctures].
578 fine-needle biopsies of lung lesions in 319 patients were performed. This investigation was mainly done by means of Rotex-biopsy instruments. The procedure proved to be efficient in 84%, complicated in 19,7% of the patients. Major complications were seen in 5,6% only. Percutaneous needle biopsy in appropriate for obtaining a cytological diagnosis to clarify the etiology of localized lung lesions.


Establishment of Caenorhabditis elegans SID-1-dependent DNA delivery system in cultured silkworm cells.
The systemic RNA interference defective-1 (SID-1) can transport double-stranded RNA (dsRNA) into cytosol across the cytoplasmic membrane. We report here that ectopic expression of Caenorhabditis elegans SID-1 allows BmN4 cells to import extracellular plasmid dsDNA into cells via the direct soaking method. Interestingly, BmN4-SID1 cells incorporate dsRNA and plasmid DNA simultaneously. Furthermore, the ectopic SID-1 allows us to establish a stably transformed cell line by the simple soaking method. Our results provide an alternative method for silkworm gene function analysis with low cost and low cell toxicity.


The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review.
Venous thromboembolism (VTE) frequently complicates the course of patients with cancer, and there is evidence to suggest that patients with brain tumors are at particularly high risk. The objective of this methodology-based literature review was to quantify the rate of incidence of VTE in patients with malignant glioma and to determine the factors that predict an increased risk of this complication. Studies meeting predefined inclusion criteria were evaluated independently on an eight-item methodology index by three raters. Authors were contacted to resolve ambiguities. The results of the studies were summarized and the incidence rate of VTE within the early postoperative phase and during extended follow-up were reported separately. Within 6 weeks after surgery the incidence rate of deep venous thrombosis (DVT) ranged from 3% to 60%, varying with the prophylaxis regimen used, the method of diagnosis, and the study design. Beyond 6 weeks postoperatively, the rates of DVT ranged from 0.013 to 0.023 per patient-month of follow-up. The single study with no significant methodologic deficiencies found a 24% rate of incidence of symptomatic DVT over the 17 months of follow-up beyond the first 6 postoperative weeks. In 6 studies the presence of leg paresis, histologic diagnosis of glioblastoma multiform, age >/= 60 years, large tumor size, use of chemotherapy, and length of surgery > 4 hours were identified as possible risk factors. The incidence of VTE is high throughout the course of malignant glioma. A randomized, controlled trial is needed to clarify whether the benefits of long term anticoagulant prophylaxis outweigh the risks and costs of such therapy.


Efficacy of liposomal amphotericin B against four species of Candida biofilms in an experimental mouse model of intravascular catheter infection.
The formation of Candida biofilms on implanted medical devices is crucial to the development of infections and an important clinical problem because of elevated resistance to antifungals. The aim of this study was to compare the in vitro activity of liposomal amphotericin B (L-AMB) and micafungin (MCFG) against four species of Candida biofilms, and the efficacy of systemic plus lock therapy with L-AMB and MCFG in a Candida biofilm-associated catheter infection model. An XTT-reduction assay was used to measure the metabolic activity of the biofilms to evaluation of in vitro antibiofilm activity. MCFG had better in vitro activity than L-AMB against Candida glabrata biofilms, whereas L-AMB had better activity than MCFG against Candida albicans and Candida tropicalis biofilms. L-AMB and MCFG had comparable efficacy against Candida parapsilosis biofilms. In an in vitro lock therapy model, 2 mg/ml L-AMB, unlike 2 mg/ml MCFG, significantly reduced the metabolic activity of all the strains of biofilms by >96%. Systemic and intraluminal lock treatment with L-AMB for 3-days resulted in more than about 2 log10 reduction of Candida compared with that of systemic treatment and the control group in the C. albicans SP-20012, C. glabrata SP-20040, C. glabrata SP-20131, C. parapsilosis SP-20137, and C. tropicalis SP-20047 infection models. L-AMB was more effective at eradicating Candida biofilms in 3-day course of systemic and lock therapy than MCFG. L-AMB may be useful for the treatment of catheter-related Candida biofilm infections, but this finding will need to be confirmed by further studies including a long treatment duration.


Should We Separate the Pulmonary Surveillance Protocol for Postsurgical T1a and T1b Renal Cell Carcinoma? A Multicenter Database Analysis.
To investigate the incidence of pulmonary metastases (PM) and the utility of the surveillance chest radiography (CXR) in detecting PM after curative treatment to better define surveillance recommendations for T1a and T1b renal cell carcinoma. A retrospective review of a multi-institutional database was performed to include patients with renal masses treated with partial nephrectomy or radical nephrectomy. Patients were excluded for ≥T2 disease, benign pathology, and metastases. The primary outcome was the incidence of asymptomatic pulmonary lesion concerning for PM detected by CXR within 3 years. Five hundred sixty-eight patients met criteria of which 384 had T1a and 184 had T1b at a mean follow-up of 45 and 43 months, respectively. Patients averaged 2.96 and 2.99 CXRs for T1a and T1b with 46.8% having surveillance beyond 3 years. Indeterminate lesions were found in 5.7% (22) of T1a and 5.4% (10) in T1b of which 0.01% (2) and 1.1% (2) were confirmed PM by chest computed tomography and biopsy. Three-year CXR surveillance period detected asymptomatic PM in zero and two patients for T1a and T1b, respectively. High risk pathological features were not present in patients with PM. There was no difference in the incidence PM for patients undergoing partial nephrectomy (3/290) or radical nephrectomy (1/278) (P = .62). Our review suggests that post-treatment pulmonary surveillance should be reserved for T1b and may not be required for T1a given the low yield and false positives of CXR leading to unnecessary radiation and potential biopsies.


Exploring the Solvent-Anti-solvent Method of Nanosuspension for Enhanced Oral Bioavailability of Lovastatin
Lovastatin is an antilipidemic drug that belongs to the class of statins that has poor oral bioavailability due to its low solubility and variable dissolution rate. The main aim of this study was to enhance the solubility and dissolution rate of the drug and understand its oral bioavailability. Lovastatin nanosuspension was formulated using a solventanti-solvent method using a probe sonication technique. A nanosuspension was prepared, using hydroxypropyl methylcellulose (HPMC) K15M and pluronic F68 as stabilizers. The formulated nanosuspensions were characterized for particle size, polydispersity index (PDI) zeta potential, surface morphology, and in vitro release rate. Further, an in vivo bioavailability study and stability studies were also performed. Optimized formulation showed a particle size of 127±0.01 nm, a PDI of 0.492±0.001, and a zeta potential of -37.9 mV, which indicates good stability. Morphological study showed that the particles were in the nano range. The drug content was found to be in the range of 73-87%. In vitro release revealed much faster release of the drug in one hour compared to the pure drug and its marketed formulation. In vivo bioavailability study was carried out in Wistar rats, which showed improvement in bioavailability by approximately 2.5 folds compared with the marketed formulation. Stability studies indicated that the optimized formulation F2 was more stable at 4°C±2°C. The prepared lovastatin nanosuspension showed improvement in solubility, dissolution rate, and oral bioavailability compared to the pure drug and its marketed formulation. Hence, lovastatin nanosuspension may be a potentially valuable tool for improving the oral bioavailability of lovastatin.


A unique subphenotype of myasthenia gravis.
While extraocular muscles (EOMs) are affected early in generalized myasthenia gravis (MG), and their treatment responsiveness is similar to nonocular muscles, we have identified an ophthalmoplegic (OP) subphenotype that remains resistant to treatment. This subphenotype of ophthalmoplegic MG (OP-MG) most commonly affects acetylcholine receptor antibody-positive cases with juvenile-onset MG and African genetic ancestry. However, a few OP-MG cases have been found with MuSK antibodies and triple-seronegative MG. In a proportion of OP-MG cases, the EOM treatment resistance manifests from treatment initiation, while in others the EOMs may initially respond until a critical trigger, such as treatment interruption or crisis. The management of OP-MG is an unmet need. Managing the visual disability may require a surgical or nonsurgical solution. The ideal case selection for surgery and the timing of surgery should be carefully considered. The pathogenesis of OP-MG remains unknown. A genetic study, using extended whole-exome sequencing and an "extreme" phenotype sample of OP-MG versus control MG cases differing only by their EOM responsivity to therapy, discovered several potentially functional OP-MG risk variants. These variants implicate myogenesis and gangliosphingolipid biosynthesis pathways at the EOM endplates in OP-MG.


Purification and characterization of proteoliaisin, a coordinating protein in fertilization envelope assembly.
We report the purification and characterization of proteoliaisin, a protein that participates in the assembly of the sea urchin fertilization envelope. Proteoliaisin was purified from egg cortical granule exudate to greater than 99% homogeneity using chromatography on DEAE-Sepharose and on phenyl-Sepharose. Native proteoliaisin is a highly asymmetric protein (f/fo = 2.0) composed of a single Mr approximately 230,000 peptide. Its asymmetry was demonstrated both by analytical ultracentrifugation and by nondenaturing polyacrylamide gel electrophoresis, a novel analysis that detects molecular asymmetry in heterogeneous protein mixtures. Proteoliaisin is enriched in six amino acids: aspartic acid/asparagine, glutamic acid/glutamine, glycine, and cysteine, which account for over 50% of its mass. Nearly all of the cysteine residues are disulfide bonded. The protein contains a small proportion of aromatic amino acids with phenylalanine greater than tyrosine greater than tryptophan. At neutral pH its absorbance maximum is at 274.5 nm, with an extinction coefficient of 0.43 ml mg-1 cm-1. Proteoliaisin forms a 1:1 Ca2+-stabilized complex with ovoperoxidase, another component of the fertilization envelope, with Kd = 1.1 X 10(-6) M. Proteoliaisin, a constituent of the specialized echinoderm extracellular matrix called the fertilization envelope, has certain structural similarities to mammalian extracellular matrix proteins.


[Characteristics of qualitative changes in the Mycobacteria population during the treatment of middle-aged and elderly patients with newly detected pulmonary tuberculosis].
Clinicobacteriological investigations were applied to 142 new cases of pulmonary tuberculosis at the age of 60 to 89 years. The control group consisted of 132 patients of young and middle ages (from 17 to 40 years). The form of the process, its extent and the character of the destructions in them were the same as those in the elderly and senile patients. It was shown that the pathogen bacterial forms in the elderly and senile patients were much more frequent than L-forms of M. tuberculosis (67.6 and 42.9 per cent, respectively). The tubercle bacilli were mainly isolated from pure cultures (45.8 per cent). L-transformants of M. tuberculosis in the elderly and senile patients were markedly less frequent than in the patients of the control group (69.7 per cent) with analogous forms of tuberculosis. The frequency of L-forms and their rapid reversion into the initial bacterial form of M. tuberculosis (28.0 per cent) and the same period of isolating both the bacterial and L-forms were the distinctive features of the L-forms isolated from the elderly and senile patients. It was suggested that L-forms of M. tuberculosis played an important role in reactivation of the specific process.


A comparison of the flow of iodine 125 through three different intestinal anastomoses: standard, Gambee, and stapler.
Angiogenesis determines blood supply, and it is postulated that after surgery, the healing of a wound is directly related to the blood supplied to the surrounding tissues. As a first step in evaluating the process of flow through different surgical anastomoses, the flow rate of 125I through three different types of anastomoses in the intestines of dogs was determined. When the results were compared, the flow rate through the stapler anastomosis was significantly higher than the flow rate through the standard and Gambee anastomoses.


Quantification of sonographic echogenicity by the gray-level histogram in patients with supraspinatus tendinopathy.
The aim of this study was to compare the gray-level value of the supraspinatus tendon of a painful shoulder with that of a normal shoulder measured by ultrasonography, and to investigate whether a low mean gray-level value of the supraspinatus tendon could indicate a partial-thickness or incomplete full-thickness tear. Two hundred and ten patients had significant unilateral shoulder pain with the clinical suspicion of rotator cuff tendinopathy. They underwent bilateral shoulder ultrasonography, and the mean echogenicity of the histogram was calculated on the screen. The mean gray-level value of each patient's contralateral asymptomatic shoulder was compared with that of the painful shoulder. Based on the scan of transverse and longitudinal planes, a significant difference existed between the symptomatic shoulder and contralateral asymptomatic shoulder (p < 0.0001). The mean gray-level values of symptomatic shoulders showed no statistically significant difference between the patients who underwent surgery and the patients who underwent conservative treatment. We demonstrated that the ultrasound gray-level histogram is a promising tool for detecting the hypoechogenic appearance of supraspinatus tendinopathy. A decrease in the mean gray-level value on the symptomatic shoulder may be used as an alternative sonographic indicator of rotator cuff partial-thickness tear or tendinopathy. Diagnostic level III.


TPH1 A218C polymorphism and temperament in major depression.
In major depression, one of the candidate genes possibly affecting the risk and severity of symptoms has been found to be tryptophan hydroxylase (TPH1). Variation in treatment response to antidepressive agents according to TPH1 genotype has also been found in several studies. However, the relationship between temperament and TPH1 genotype in major depression is poorly understood, as only one study has been published so far. There are no earlier studies on the interaction between temperament traits, antidepressive medication response and TPH1 genotype. This interaction was studied in 97 subjects with major depression treated for six weeks with selective serotonine reuptake inhibitors. Temperament dimensions Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD) and Persistence (P) scores at baseline (1) and endpoint (2) were rated with the Temperament and Character Inventory (TCI) and compared between TPH1 A218C genotypes. Multivariate analysis of co-variance (MANCOVA) was used to analyze the interaction between the TPH1 genotype, treatment response and the different temperament dimensions at baseline and endpoint. In the analysis model, treatment response was used as a covariate and TPH1 genotype as a factor. A post hoc analysis for an interaction between remission status and TPH1 A218C genotype at endpoint HA level was also performed. The number of TPH1 A-alleles was associated with increasing levels in NS1 and NS2 scores and decreasing levels in HA1 and HA2 scores between TPH1 A218C genotypes. In the MANCOVA model, TPH1 genotype and treatment response had an interactive effect on both HA1 and HA2 scores, and to a lesser degree on NS2 scores. Additionally, an interaction between remission status and TPH1 A218C genotype was found to be associated with endpoint HA score, with a more marked effect of the interaction between CC genotype and remission status compared to A-allele carriers. Our results suggest that in acute depression TPH1 A218C polymorphism and specifically the CC genotype together with the information on remission or treatment response differentiates between different temperament profiles and their changes.


Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA.
In various organisms, including nematodes and plants, RNA interference (RNAi) is a defense system against virus infection; however, it is unclear whether RNAi functions as an antivirus system in mammalian cells. Rather, a number of DNA viruses, including herpesviruses, utilize post-transcriptional silencing systems for their survival. Here we show that Dicer efficiently suppresses the replication of adenovirus (Ad) via cleavage of Ad-encoding small RNAs (VA-RNAs), which efficiently promote Ad replication via the inhibition of eIF2α phosphorylation, to viral microRNAs (mivaRNAs). The Dicer knockdown significantly increases the copy numbers of VA-RNAs, leading to the efficient inhibition of eIF2α phosphorylation and the subsequent promotion of Ad replication. Conversely, overexpression of Dicer significantly inhibits Ad replication. Transfection with mivaRNA does not affect eIF2α phosphorylation or Ad replication. These results indicate that Dicer-mediated processing of VA-RNAs leads to loss of activity of VA-RNAs for enhancement of Ad replication and that Dicer functions as a defence system against Ad in mammalian cells.


Self-other integration and distinction in schizophrenia: A theoretical analysis and a review of the evidence.
Difficulties in self-other processing lie at the core of schizophrenia and pose a problem for patients' daily social functioning. In the present selective review, we provide a framework for understanding self-other integration and distinction, and impairments herein in schizophrenia. For this purpose, we discuss classic motor prediction models in relation to mirror neuron functioning, theory of mind, mimicry, self-awareness, and self-agency phenomena. Importantly, we also discuss the role of more recent cognitive expectation models in these phenomena, and argue that these cognitive models form an essential contribution to our understanding of self-other integration and distinction. In doing so, we bring together different lines of research and connect findings from social psychology, affective neuropsychology, and psychiatry to further our understanding of when and how people integrate versus distinguish self and other, and how this goes wrong in schizophrenia patients.


Elevated Cardiac Troponin I in Preservation Solution Is Associated With Primary Graft Dysfunction.
Although primary graft dysfunction (PGD) is a leading cause of mortality and morbidity early post-heart transplant, relatively little is known regarding mechanisms involved in PGD development. We examined the relationship between cardiac troponin I (cTnI) concentrations in the preservation solution from 43 heart transplant procedures and the development of PGD. Donor hearts were flushed with cold preservation solution (University of Wisconsin [UW] or Custodiol) and stored in the same solution. cTnI concentrations were measured utilizing the i-STAT System and normalized to left ventricular mass. Recipient medical records were reviewed to determine PGD according to the 2014 ISHLT consensus conference. Nineteen patients developed PGD following cardiac transplantation. For both UW and Custodiol, normalized cTnI levels were significantly increased (P = .031 and .034, respectively) for those cases that developed PGD versus no PGD. cTnI levels correlated with duration of ischemic time in the UW group, but not for the Custodiol group. Donor age and donor cTnI (obtained prior to organ procurement) did not correlate with preservation cTnI levels in either UW or Custodiol. Increased preservation solution cTnI is associated with the development of PGD suggesting preservation injury may be a dominant mechanism for the development of PGD.


The ameliorative effects of virgin olive oil and olive leaf extract on amikacin-induced nephrotoxicity in the rat.
Amikacin is an important antibiotic, and its use is limited because of the induced nephrotoxicity. Thus, search for natural and synthetic agents that can moderate amikacin toxicity never stopped. The present study aims to investigate the possible ameliorative effects of virgin olive oil and olive leaf extract against the amikacin-induced nephrotoxicity in rat. 48 rats were distributed into 6 groups: 1-Animals of control (C) group were injected intraperitoneally (ip) with saline, 2-(AK); injected ip with amikacin {300 mg/kg/day for 12days}, 3-(OO) group: given olive oil {7 ml/kg/day for 16days}, 4-(OOAK) group: given olive oil as in OO and amikacin for 12days, 5-(OL) group: given olive leaf extract {50 mg/kg/day for 16days}, 6-(OLAK) group: given leaf extract as in OL and amikacin for 12days. Animals were fasted and sacrificed. Serum was used for biochemical analysis and kidneys for histopathology. Serum urea and creatinine were significantly (P < 0.001) elevated in AK, and significantly dropped in the OOAK and OLAK groups. Serum uric acid was reduced in AK by 45.29%. Kidneys from AK showed necrosis, whereas, those from OOAK and OLAK showed mild histology. The serum triglyceride was decreased by 17.8% in OL, by 37.02% in OOAK and by 31.48% in OLAK. The calculated amikacin effect showed a significant positive correlation with urea (r = 0.521, P = 0.0004), and a negative correlation with uric acid (r = ⿿ 0.58, P < 0.0001). The study confirmed nephrotoxicity of amikacin in rat which was ameliorated by virgin olive oil and by olive leaf extract. Amikacin did not cause dyslipidemia but reduced serum uric acid.


Structural and functional characterization of a cell surface binding protein of vaccinia virus.
The nature of the interaction between the enveloped DNA-containing poxviruses and the surfaces of host cells as a first step in virus infection is not known. In this investigation we have identified and defined structural and functional properties of a 32-kDa protein of vaccinia virus. This protein is part of the virus envelope and binds to the cell surface of various cultured cells. The gene encoding the 32-kDa viral protein was mapped and sequenced. It was found to code a 35,426-Da protein with a large N-terminal domain with sequence homology to carbonic anhydrases and a C-terminal domain with sequences similar to those of the attachment glycoprotein VP7 of rotavirus and to transmembrane proteins. A potential cell surface binding domain was within the last 50 amino acid residues of the C terminus. The 32-kDa protein is basic, predicted pI 8.67, is synthesized at late times post-infection, may form dimers held by disulfide bonds at the single cysteine 262, and is apparently non-glycosylated. The 32-kDa protein is a vaccinia virus antigen, with predicted antigenic sites located near amino acids 108-110 (carbonic anhydrase domain) and 298-299 (transmembrane domain). Several lines of evidence suggest that the 32-kDa protein is needed for efficient virus replication in cultured cells but that in addition to this protein other viral proteins are involved in the process of virus entry into cells.


Potentiating effects of serotonin and vasoactive intestinal peptide on the action of glutamate on suprachiasmatic neurons in brain slices.
Using extracellular single-unit recording in brain slices, we have tested the effects of serotonin and vasoactive intestinal peptide (VIP) on the action of glutamate on hypothalamic suprachiasmatic neurons. We hypothesized that serotonin and VIP may interact with glutamate so that a modulation of the circadian rhythm entrainment to the light-dark may be possible. Given individually, glutamate excited 32% and inhibited 1% (n = 65), serotonin excited 8% and inhibited 27% (n = 73), and VIP excited 7% and inhibited 7% (n = 41) of suprachiasmatic neurons. When administered together, however, serotonin or VIP not only increased the percentage of neurons (up to 50%) that responded to glutamate, but also potentiated the neuronal responses to glutamate. These findings substantiated our hypothesis that both serotonin and VIP may modulate the action of glutamate in the suprachiasmatic nucleus.


Biomedical Big Data: New Models of Control Over Access, Use and Governance.
Empirical evidence suggests that while people hold the capacity to control their data in high regard, they increasingly experience a loss of control over their data in the online world. The capacity to exert control over the generation and flow of personal information is a fundamental premise to important values such as autonomy, privacy, and trust. In healthcare and clinical research this capacity is generally achieved indirectly, by agreeing to specific conditions of informational exposure. Such conditions can be openly stated in informed consent documents or be implicit in the norms of confidentiality that govern the relationships of patients and healthcare professionals. However, with medicine becoming a data-intense enterprise, informed consent and medical confidentiality, as mechanisms of control, are put under pressure. In this paper we explore emerging models of informational control in data-intense healthcare and clinical research, which can compensate for the limitations of currently available instruments. More specifically, we discuss three approaches that hold promise in increasing individual control: the emergence of data portability rights as means to control data access, new mechanisms of informed consent as tools to control data use, and finally, new participatory governance schemes that allow individuals to control their data through direct involvement in data governance. We conclude by suggesting that, despite the impression that biomedical big data diminish individual control, the synergistic effect of new data management models can in fact improve it.


[Prevalence of peripheral artery disease among diabetics in Parakou in 2013].
We aimed to determine the prevalence of peripheral artery disease and its associated factors among diabetics. The cross-sectional study was conducted and included all diabetics admitted to the diabetic clinic at the Parakou University hospital during the period of 1st February and 31st July 2013. The diagnosis of peripheral artery disease was based on the Ankle Brachial Index (ABI)<0.9. The socio-demographics data, the data concerning the diabetes and its complications were recorded in each patient. They were 401 diabetics and 59.5 % were females. The mean age was 53.7±11.5 years. Among the diabetics, 168 fulfilled the criteria of PAD, the overall prevalence was 41.9 %. In total, 31.5 % were symptomatics according to Leriche and Fontaine classification. The main associated factors were the increase of age (P=0.01), the absence of activity with high income (P=0.004), the absence of physical activity (P=0.023), the duration of diabetes (P=0.007), the presence of peripheral neuropathy (P=0.003), the glycosylated hemoglobin≥7 % (P<0.001). After a multivariate analysis, only diabetes control was independently associated with arteriopathy (P=0,004). The PAD was more frequent among diabetics in Parakou. The associated factors must be taken into account in order to improve the management of the disease and to reduce the burden of the PAD.


Phylogeography and morphological variation of the branching octocoral Pseudopterogorgia elisabethae.
Coral reef anthozoans exhibit extensive morphological variation across and within environmental clines making it difficult to define species boundaries. The relative contributions of genetic variation and ecophenotypic plasticity to the observed phenotypic variation are unknown in most cases. The branching octocoral Pseudopterogorgia elisabethae is widely distributed throughout the Caribbean and colonies vary in appearance within and among populations. We performed genetic and morphological analyses of P.elisabethae from multiple locations within the Bahamas, as well as a Florida Keys and a distant western Caribbean location to determine the levels of genetic and morphological variation (colony form and sclerites characteristics) across populations from different sites, and assessed whether there was congruence between the genetic and morphological variation. Based on sequences of the internal transcribed spacer region of the ribosomal DNA, four groups were found that generally correspond to the geography of the Bahamas. Morphometric analysis of branch and branchlet characteristics indicated that colonies from two of the sites differed from the rest, but there was no clear correspondence between genetic and morphological variation. In general, there were no qualitative differences in the sclerites from the different populations. However, there were some differences in the dimensions of scaphoids and rods of colonies from different sites. This study has shown that P. elisabethae displays genetic and morphologic variation among some populations of the Bahamas, Florida and San Andres, Colombia. P. elisabethae is harvested in the Bahamas and these findings should be considered in management plans and conservation efforts for the species.


An Italian case of intestinal anisakiasis with a presurgical diagnosis: Could this parasite represent an emerging disease?
Anisakiasis is a parasitic infection caused by the consumption of raw fish containing larvae of the Anisakis species. Since the first description in 1960 of a patient suffering from this pathogen, in the Netherlands, most of the cases have been reported in Japan, where consumption of raw fish is common, but the number of cases is increasing worldwide. The first case identified in Italy dates back to 1996 and a few cases have been reported since then. In Italy the intestinal form occurs almost as frequently as the gastric form, which is far more frequent in Japan. Intestinal Anisakiasis represents a diagnostic challenge as it is clinically misdiagnosed and most of the patients require surgery due to the occurrence of complications such as bowel occlusion or perforation. Practically no cases of the intestinal form are diagnosed preoperatively. We report the first case, to our knowledge, of intestinal Anisakiasis in which surgery was avoided, due to a prompt diagnosis suspected on intestinal biopsies. A literature review of Anisakiasis cases reported in Italy is also carried out.


An accessible optimisation method for barrier removal planning in stream networks.
Barriers associated to human infrastructure are a widespread impact in freshwater ecosystems worldwide, disrupting connectivity along river networks and key processes. Restoration of connectivity has risen in the last decade, with thousands of dams, weirs and culverts removed. Spatial optimisation methods can help inform decision on what barriers to remove to maximise gain in connectivity under limited budgets. However, current optimisation approaches rely on programming skills that are not easily accessible to stakeholders, which restrict the use of these methods. We demonstrate how Marxan, a publicly available tool, can be used to prioritise the allocation of barrier removal projects. We mapped the distribution of >900 barriers in the Tagus River (Iberian Peninsula) and 29 freshwater fish species with different movement abilities and needs. We assessed the passability of each barrier by all species and relative removal cost. We then identified priority barriers for removal to increase connectivity of populations of all species simultaneously. We tested two alternative scenarios: i) locking out barriers assesses as non-removable for their high strategic value or removal cost and ii) making all barriers available for removal. We found that connectivity recovery targets could be achieved by removing a small proportion of barriers, and avoiding large infrastructure. However, for some species, large recovery targets could only be achieved by removing some of these large infrastructures at high increases in cost. We also found some spatial differences in the recovery value of particular barriers for improving upstream and downstream connectivity. Our study demonstrates how to use a robust optimisation approach in an accessible tool, to address the complexity of prioritisation exercises commonly faced by stakeholders when deciding where to invest in barrier removal projects. This will improve decision-making for river connectivity restoration through a transparent, reproducible, and better-informed approach than traditional opportunistic or ranking-based approaches.


Lack of long term effect of p-chlorophenylalanine on brain 5-hydroxytryptamine and electrocortical activity in conscious fetal sheep.
Daily infusion of p-chlorophenylalanine (p-CPA) into unanesthetized fetal sheep for 3-6 days did not reduce brain 5-hydroxytryptamine (5-HT) concentrations or produce long-term changes in the pattern of electrocortical activity.


Fracture fragment of the condyle determines the ramus height of the mandible in children with intracapsular condylar fractures treated conservatively.
This study aimed to explore and impart understanding of bone remodelling in children with intracapsular fractures treated conservatively. Records of children (less than 12 years), who sustained intracapsular fractures and treated conservatively, were retrieved consecutively for the period of March 2011 to February 2016. Data about age, gender, date of injury, dates of admission and discharge, mechanism of trauma, location and pattern of fracture, other mandibular fractures, treatment methods and time of review were recorded and analysed. Image dates of pre- and post-treatments, including date of review, were also recorded. A total of 22 patients complete their follow-up and show bone remodelling process. During their follow-up, all the displaced condylar fragments fused with the ramus stump at the displaced position. Regardless of the type of conservative procedure, both treatments cannot promote the spontaneous fracture reduction in patients with intracapsular condylar fractures. During follow-up, the absorption of the lateral process of the condyle after the closed treatment becomes close to the 'horizontal absorption', until the height (or articular surface) of the lateral condylar process dropped and aligned to the articular surface of the medial process. In children with intracapsular condylar fractures, the fracture fragment of the condyle determines the ramus height of the mandible. Closed treatment cannot restore the fracture fragment. If the height of the fracture fragments dropped remarkably, then open reduction and rigid internal fixation become more suitable.


Occlusion-derived baculovirus: interaction with human cells and evaluation of the envelope protein P74 as a surface display platform.
To develop complementary baculovirus-based tools for gene delivery and display technologies, the interaction of occlusion-derived baculovirus (ODV) with human cells, and the functionality of the P74 ODV envelope protein for display of the IgG-binding Z domains (ZZP74) were evaluated. The cellular binding of ODV was concentration-dependent and saturable. Only minority of the bound virions were internalized at both 37 and 4 degrees C, suggesting usage of direct membrane fusion as the entry mode. The intracellular transport of ODV was confined in vesicular structures peripheral to the plasma membrane, impeding subsequent nuclear entry and transgene expression. Transduction of ODV was not rescued by mimicking the preferred alkaline environment and lowered temperature of the ODV infective entry, or following treatment with the microtubule depolymerizing agent nocodazole or with the histone deacetylase inhibitor sodium butyrate. Similar to unmodified P74, the ZZP74 chimera localized in the intranuclear ring zone, and was enriched in virus-induced microvesicles. However, Western blotting of ODV and budded virions (BV), as well as viral envelope and nucleocapsid fractions combined with functional infection/transduction studies revealed incorporation of the ZZP74 fusion protein into viral nucleocapsids. The ZZP74 BV preserved normal infectivity, polypeptide profile, and morphology, but became incapable of entering and transducing human cells.


Association between gut microbiota and gastrointestinal cancer: a two-sample bi-directional Mendelian randomization study.
The gut microbiome is closely related to gastrointestinal (GI) cancer, but the causality of gut microbiome with GI cancer has yet to be fully established. We conducted this two-sample Mendelian randomization (MR) study to reveal the potential causal effect of gut microbiota on GI cancer. Summary-level genetic data of gut microbiome were derived from the MiBioGen consortium and the Dutch Microbiome Project. Summary statistics of six GI cancers were drawn from United Kingdom Biobank. Inverse-variance-weighted (IVW), MR-robust adjusted profile score (MR-RAPS), and weighted-median (WM) methods were used to evaluate the potential causal link between gut microbiota and GI cancer. In addition, we performed sensitivity analyses and reverse MR analyses. We identified potential causal associations between 21 bacterial taxa and GI cancers (values of p < 0.05 in all three MR methods). Among them, phylum Verrucomicrobia (OR: 0.17, 95% CI: 0.05-0.59, p = 0.005) retained a strong negative association with intrahepatic cholangiocarcinoma after the Bonferroni correction, whereas order Bacillales (OR: 1.67, 95% CI: 1.23-2.26, p = 0.001) retained a strong positive association with pancreatic cancer. Reverse MR analyses indicated that GI cancer was associated with 17 microbial taxa in all three MR methods, among them, a strong inverse association between colorectal cancer and family Clostridiaceae1 (OR: 0.91, 95% CI: 0.86-0.96, p = 0.001) was identified by Bonferroni correction. Our study implicates the potential causal effects of specific microbial taxa on GI cancer, potentially providing new insights into the prevention and treatment of GI cancer through specific gut bacteria.


Association between BMI, vitamin D, and estrogen levels in postmenopausal women using adjuvant letrozole: a prospective study.
Studies have suggested that women with elevated BMI or 25-OH vitamin D levels may derive less benefit from AIs versus tamoxifen. We prospectively investigated whether high BMI or 25-OH vitamin D levels were associated with higher estrogen levels in post-menopausal women receiving standard adjuvant letrozole (2.5 mg/day). Furthermore, we evaluated whether an increased dose of letrozole resulted in lower serum estrogens in women with BMI > 25 kg/m2. Correlation between entry BMI and day 29 serum biomarkers (estrogens, 25-OH vitamin D, insulin, CRP, leptin) was assessed in all patients. On day 29, participants with BMI > 25 kg/m2 switched to letrozole 5 mg/day for 4-weeks and blood was drawn upon completion of the study. The change in serum estrogen levels was assessed in these patients (BMI > 25 kg/m2). 112 patients completed days 1-28. The Pearson correlations of estradiol and estrone with BMI or serum 25-OH vitamin D levels were near zero (-0.04 to 0.07, p = 0.48-0.69). Similar results were obtained for correlation with markers of obesity (insulin, CRP, and leptin) with estradiol and estrone (-0.15 to 0.12; p = 0.11-0.82). Thirty-one patients (BMI > 25 kg/m2) completed the interventional component; Increasing the dose of letrozole did not further reduce estradiol or estrone levels (change 0.1 and 0.4 pmol/L respectively; p = 0.74 and 0.36). There was no observed association between markers of obesity (BMI, insulin, leptin, and CRP), serum 25-OH vitamin D levels and estradiol or estrone levels. Additionally, an increased dose of letrozole did not further reduce estradiol or estrone levels compared to the standard dose.


Anti adipogenic activity of Aegle marmelos Correa.
In continuation of evaluating the anti-obesity effect of Aegle marmelos, we have screened the n-hexane, dichloro methane (DCM), ethyl acetate (EtOAc) and methanol (MeOH) extracts of the leaves at the concentration of 25, 50, 75 and 100 μg/ml for adipogenesis inhibition in the adipocytes. Nile red staining with the help of fluorometry was used as indicator of the antiobesity activity. The most active DCM extract showed the 33.98±3.55% lipid content at 100μg/ml and was selected for the further isolation. 14 compounds were isolated from DCM extract of A. marmelos leaves. The compounds were screened for the adipogenesis inhibition at 50 and 100 μM concentrations. Out of the 14 compounds, halfordinol, ethyl ether aegeline and esculetin were showing 10.04±0.52, 16.29±0.85 and 25.09±1.31% lipid content respectively at 100 μM. We hereby report the adipogenesis inhibition by A. marmelos as one of the pathway for its antiobesity effect.


Long-term efficacy of sodium-glucose cotransporter 2 inhibitor therapy in preventing atrial fibrillation recurrence after catheter ablation in type 2 diabetes mellitus patients.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce new-onset atrial fibrillation (AF) in patients with type 2 diabetes mellitus (T2DM). We aimed to determine the long-term effects of SGLT2i on atrial tachyarrhythmia recurrence after catheter ablation (CA) in T2DM patients. This retrospective study enrolled consecutive patients with T2DM undergoing CA for AF between January 2016 and December 2021. Patient baseline demographic characteristics and use of anti-diabetic and anti-arrhythmic medications were analyzed. Echocardiographic parameters were obtained one day and 6 months after CA. Our study population comprised 122 patients (70% paroxysmal AF). The baseline patient characteristics were similar between the SGLT2i-treated group (n = 45) and the non-SGLT2i-treated group (n = 77) except for stroke. At 6-month follow-up, body-mass index (BMI) was significantly decreased and left ventricular ejection fraction (LVEF) was significantly increased only in the SGLT2i group. E/e' was decreased 6 months after CA in both groups. During a mean follow-up of 33.7 ± 21.6 months, 22 of 122 patients had atrial tachyarrhythmia recurrence. The long-term atrial tachyarrhythmia-free survival rate was significantly higher in the SGLT2i-treated patients, and multivariate analysis revealed that AF type and SGLT2i use were independently associated with atrial tachyarrhythmia recurrence after CA. The use of SGLT2i and AF type were independent risk factors associated with atrial tachyarrhythmia recurrence after CA in T2DM patients with AF. This result was at least partly due to the pleiotropic effects of SGLT2i on BMI reduction and left ventricular function improvement.


The significance of endogenous erythroid colonies (EEC) in haematological disorders.
The myeloproliferative disorders are the result of an underlying abnormality of the pluripotential stem cell. One feature of this abnormality is a greatly increased sensitivity of the committed erythroid progenitors (BFU-E and CFU-E) to the hormone erythropoietin. Culture in vitro of these bone marrow or peripheral blood cells results in the growth of a proportion of colonies in the absence of added erythropoietin. These endogenous erythroid colonies (EEC) are seen in the great majority of cases of polycythaemia vera, as well as in some cases of thrombocythaemia, chronic myeloid leukaemia and idiopathic myelofibrosis. The presence of EEC appears to be a marker for the stem cell mutation and may serve to distinguish the neoplastic disorders from reactive increases of red cell mass or platelet numbers. Their absence in idiopathic erythrocytosis may also distinguish this condition from early polycythaemia vera and be useful in deciding on appropriate treatment. In patients with even a modest increase in the platelet count endogenous colonies provide firm evidence for a myeloproliferative disorder. Provision of myelosuppressive treatment can avert or improve vaso-occlusive or haemorrhagic complications. The mechanism of erythropoietin hypersensitivity is unknown but it has been shown to be a feature acquired rather late in maturation and by only a proportion of the progeny of the mutated clone. Normal erythroid progenitors co-exist with these abnormal cells in polycythaemia vera and the way in which their growth in vivo is inhibited has yet to be determined.


The rich non-coding RNA landscape of the Drosophila antenna.
Emerging evidence suggests that long non-coding RNAs (lncRNAs) play diverse and critical roles in neural development, function, and disease. Here, we examine neuronal lncRNAs in a model system that offers enormous advantages for deciphering their functions: the Drosophila olfactory system. This system is numerically simple, its neurons are exquisitely well defined, and it drives multiple complex behaviors. We undertake a comprehensive survey of linear and circular lncRNAs in the Drosophila antenna and identify a wealth of lncRNAs enriched in it. We generate an unprecedented lncRNA-to-neuron map, which reveals that olfactory receptor neurons are defined not only by their receptors but also by the combination of lncRNAs they express. We identify species-specific lncRNAs, including many that are expressed primarily in pheromone-sensing neurons and that may act in modulation of pheromonal responses or in speciation. This resource opens many new opportunities for investigating the roles of lncRNAs in the nervous system.


Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions.
Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. Furthermore, transcriptomic analysis and cell differentiation approaches underline GRG5 as a multifaceted signaling regulator that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 promotes neuroectodermal specification via Wnt and BMP signaling suppression. Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor and a neural fate specifier.


Optimism, abstinence self-efficacy, and self-mastery: a comparative analysis of cognitive resources.
The relationship between optimism, abstinence self-efficacy, and self-mastery was examined by investigating levels of these cognitive resources among two samples of recovering substance abusers: Oxford House residents who attended twelve-step groups and twelve-step members who had never lived in an Oxford House. Participants 'levels of optimism were significantly and positively related to both abstinence self-efficacy and self-mastery scores, as abstinence self-efficacy was significantly and positively related to participants' number of days abstinent. Participants who reported having more than 180 days abstinent reported significantly higher levels of abstinence self-efficacy than participants who reported having less than 180 days abstinent. In addition, among participants who reported having less than 180 days abstinent, Oxford House residents reported significantly higher levels of abstinence self-efficacy than twelve-step members. Overall, findings suggest that cognitive resources facilitate substance abusers' recovery and that the Oxford House model might provide high levels of support in their ongoing abstinence.


The transition from water to air in aeshnid dragonflies is associated with a change in ventilatory responses to hypoxia and hypercapnia.
Dragonflies are amphibiotic, spending most of their lives as aquatic nymphs before metamorphosing into terrestrial, winged imagoes. Both the nymph and the adult use rhythmic abdominal pumping movements to ventilate their gas exchange systems: the nymph tidally ventilates its rectal gill with water, while the imago pumps air into its tracheal system through its abdominal spiracles. The transition from water to air is known to be associated with changes in both respiratory chemosensitivity and ventilatory control in vertebrates and crustaceans, but the changes experienced by amphibiotic insects have been poorly explored. In this study, dragonfly nymphs (Anax junius) and imagoes (Anax junius and Aeshna multicolor) were exposed to hypoxia and hypercapnia while their abdominal ventilation frequency and amplitude was recorded. Water-breathing nymphs showed a significant increase in abdominal pumping frequency when breathing hypoxic water (<10 kPa O2), but no strong response to CO2, even in severe hypercapnia (up to 10 kPa CO2). In contrast, both species of air-breathing imago increased their abdominal pumping amplitude when exposed to either hypoxia or hypercapnia, but did not show any significant increase in frequency. These results demonstrate that aquatic dragonfly nymphs possess a respiratory sensitivity that is more like other water breathing animals, being sensitive to hypoxia but not hypercapnia, while their air-breathing adult form responds to both respiratory challenges, like other terrestrial insects. Shifting from ventilating a rectal gill with water to ventilating a tracheal system with air is also associated with a change in how abdominal ventilation is controlled; nymphs regulate gas exchange by varying frequency while imagoes respond by varying amplitude.


Competitive bidding: the challenge for health care managers.
The survival and growth of existing health care organizations will depend largely on their ability to adapt to the various cost containment efforts of private and public purchasers of medical care.


Spondyloepiphyseal dysplasia congenita: Use of complementary 3D reconstruction imaging for preoperative planning.
We present a case of spondyloepiphyseal dysplasia congenita (SEDC), a rare autosomal dominant genetic disorder that results in short stature and skeletal anomalies. Children with SEDC have disproportionate short-trunked short stature, platyspondyly, coxa vara, and epiphyseal involvement. Those with coxa vara can develop osteoarthritis of the hip early and a valgus hip osteotomy is recommended to preserve hip function and delay progression to osteoarthritis. Surgery is difficult due to the three-dimensional deformity, unossified femoral head, and small patient size. In this case, a patient-specific surgical plan and implant sizing was developed using a composite 3D reconstruction from computed tomography (CT) and magnetic resonance imaging (MRI). The complementary use of both modalities allowed for a complete visualization of the patient's dysplastic femoral head & neck anatomy.


[Aneuploid model of meiotic transformation mechanisms in wheat. 2. Prevention of homologue synapsis].
Two main elements of the mechanism of preventing the homoeologue synapsis were revealed using statistical analysis of the univalent behavior in meiotic anaphase I in the whole series of monosomic lines of wheat cultivar Milturum 553. One of the elements was found to be controlled by chromosomes 1B, 3B and 6A, and the latter being equally effective in both double and single doses.


Breast cancer detection centers and case-control studies of the efficacy of screening.
Case-control studies of screening efficacy have been proposed as a cost- and time-efficient alternative to randomized controlled trials. Possible source populations for such retrospective studies of breast cancer screening are considered, including women from (i) pre-existing randomized trials, (ii) non-experimental population-based studies and (iii) detection centers. On practical grounds women attending detection centers are seen to comprise the most readily accessible source of adequate numbers of cases and controls. Potential biases are addressed, involving incomplete case ascertainment, self-selection, and different screening recommendations. Data from the Guttman Breast Diagnostic Institute are used for illustration.


Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection.
Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for non-hospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection. Moreover, the efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.


Residue determination of glufosinate in plant origin foods using modified Quick Polar Pesticides (QuPPe) method and liquid chromatography coupled with tandem mass spectrometry.
A sensitive and specific method for the determination of glufosinate in plant origin foods was developed. The method involves extraction using modified QuPPe method, clean-up by multi-walled carbon nanotubes (MWCNTs), derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl) and detection with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was validated on twelve matrices spiked at 10 or 20, 100 and 500 μg/kg. The recovery ranged from 80% to 108% with intra-day RSDs (n=5) of 0.6-9.8% and inter-day RSDs (n=15) of 3.0-9.4%. Good linearities (R(2)⩾0.9991) were obtained for all matrices. The limit of detection (LOD) and limit of quantification (LOQ) for the selected matrices ranged from 0.3 to 3.3 μg kg(-1) and from 1 to 10 μg kg(-1), respectively. The method was demonstrated to be reliable and sensitive for the routine monitoring of glufosinate in plant origin foods.


Wegener's granulomatosis--exacerbation with pulmonary manifestation.
There was described a case of a 56-year-old woman with lesions in chest X-ray. Three years before she was treated in the Department of Laryngology of Medical University of Lublin because of ulcerations of nasopharynx. There was established diagnosis of Wegener's granulomatosis.


[Curcumin inhibits hypoxia-induced proliferation of MRC-5 and collagen I synthesis].
To investigate the effect of curcumin on MRC-5 in human embryo fibroblast (HEF) under hypoxia and possible underlying mechanism. The MRC-5 were cultured in vivo under 5 different conditions, including normal control, SB203580 (10 micromol/L), LY-294002 (10 micromol/L) and curcumin (5,10 and 20 micromol/L, respectively). The proliferation of MRC-5 was assessed by MTT assay and the expressions of pro-collal, p-p38 and p-AKT were detected by western blot. Compared with the nomoxia control, hypoxia enhanced the proliferation of MRC-5 and the expressions of pro-collal, p-p38 and p-AKT (P < 0.05). Curcumin inhibited the hypoxia-induced proliferation of MRC and the expression of pro-collal and p-p38 (P < 0.05), but not the expression of p-AKT (P > 0.05). Hypoxia might enhance the proliferation of MRC-5 cells and the expression of collagen I through PI3K/AKT and p38MAPK. Curcumin blocks the hypoxia influence through is impact on p38MAPK.


Molecular identification of four phenotypes of human Demodex in China.
Traditional classification of Demodex mites by hosts and phenotypic characteristics is defective because of environmental influences. In this study, we proposed molecular identification of four phenotypes of two human Demodex species based on mitochondrial cox1 fragments for the first time. Mites collected from sufferers' facial skin were classified into four phenotypes: phenotype A-C with finger-like terminus, and phenotype D with cone-like terminus. The results of molecular data showed that cox1 sequences were all 429 bp. Divergences, genetic distances and transition/transversion ratios among the three phenotypes with finger-like terminus were 0.0-3.0%, 0.000-0.031, and 6/3-5/0, respectively, in line with intraspecific differences. However, those measures between the phenotype with cone-like terminus and phenotypes with finger-like terminus were 19.6-20.5%, 0.256-0.271, and 0.58 (31/53)-0.66 (35/53), respectively, reaching interspecific level. Phylogenetic trees also showed that the three phenotypes with finger-like terminus clustered as one clade, and the phenotype with cone-like terminus formed another one. Therefore, we conclude that mitochondrial cox1 sequence is a good marker for identification of two human Demodex species. Molecular data indicate no subspecies differentiation. Terminus is an effective character for species identification. Mites with finger-like terminus are Demodex folliculorum, and those with cone-like terminus are Demodex brevis.


External field-assisted techniques for polymer matrix composites with electromagnetic interference shielding.
The rapid development of mobile devices has greatly improved the lives of people, but they have also caused problems with electromagnetic interference (EMI) and information security. Therefore, there is an urgent need to develop high performance EMI shielding materials to suppress electromagnetic radiation and prevent information leakage. Some reports point out that the self-orientation behavior of fillers under external forces contributes to the improvement of EMI shielding performance. So how to construct an effective filler orientation structure in the polymer matrix is becoming a hot topic in the research of EMI shielding materials. In view of the fact that there are few reports on the preparation of polymer matrix EMI shielding composites by external field induction, from this perspective, we first highly focus on strategies for the construction of conductive networks within composites based on external field induction. Subsequently, the research progress on the preparation of polymer matrix EMI shielding composites by inducing the orientation of inorganic fillers through external fields, including temperature, electrostatic, gravity, mechanical force and magnetic fields, is organized and sorted out in detail. Notably, the particular response relationship between the unique composite structures prepared by external field induction and the incident electromagnetic waves is further dissected. Finally, the key scientific problems that need to be solved in the preparation of polymer matrix EMI shielding composites assisted by external fields are proposed. The approach discussed and the strategies proposed are expected to provide some guidance for the innovative design of high-performance polymer matrix EMI shielding composites.


Dementia with Lewy bodies: disease concept and genetics.
Dementia with Lewy bodies (DLB) was first recognized as a clinicopathological entity about 20 years ago. It is the second most-common degenerative dementia after Alzheimer's disease. Clinically, DLB differs from Alzheimer's disease in that disease symptoms are prone to fluctuate and patients often suffer from visual hallucinations, while short-term memory is relatively preserved. As many as 70% of patients have parkinsonism and up to 50% are sensitive to the extrapyramidal side effects of neuroleptic drugs. About 3 million Europeans will be affected by DLB in 2020 if no cure or effective treatment is found. This article reviews the current disease concept, as well as existing problems concerning classification and delineation of DLB from other conditions with dementia. The literature on genetic findings in this complex disease is critically discussed.


Transformation by human papillomavirus type 16 (HPV16) DNA but not HPV6b DNA is enhanced by addition of the human cytomegalovirus enhancer.
Primary human cervical epithelial cells immortalized by human papillomavirus type 16 (HPV16) DNA exhibit altered morphology and differentiation characteristic of transformation, but show a lack of transformed phenotype relative to HPV18 DNA immortalized cells in terms of anchorage-independent growth (Pecoraro, Lee, Morgan, and Defendi, 1991, Am. J. Pathol. 138, 1-8). This is completely corrected by inserting a strong heterologous enhancer derived from human cytomegalovirus DNA upstream from the HPV16 long control region. The cells immortalized by this DNA form colonies in agar comparable to those formed by HPV18 DNA immortalized cells. The enhanced transformation capability correlates with increased levels of HPV16 E6-E7 and E5 transcripts. The HPV16 DNA containing this strong enhancer also transforms C127 mouse cells with increased efficiency and strength relative to the natural HPV16 DNA, as measured by the numbers and size of the colonies in agar. The positive effects of this strong enhancer appear specific for HPVs associated with genital malignancies such as HPV16, since HPV6b DNA (primarily in benign tumors) with or without the strong cytomegalovirus enhancer is incapable of immortalizing primary human cervical epithelial cells or allowing efficient growth of C127 mouse cells in agar. These results suggest that the diminished oncogenic properties of HPV16 versus HPV18 DNA in cultured cells and in human malignancies may reside in the long control regions of these viruses and, additionally, may define another difference in the oncogenic properties of HPVs associated with benign or malignant genital neoplasia.


An advanced pharmacy practice experience in application of evidence-based policy.
To determine the impact of an advanced pharmacy practice experience (APPE) to develop skills needed to apply an evidence-based approach to population-level practice decisions. A 4-week evidence-based medicine APPE was implemented that included active-learning techniques and online learning modules, participation in state drug-policy committee meetings, and completion of an evidence-based medicine review for a specific drug agent or class. Students' mean score on application of principles related to biostatistics and information mastery on posttests increased 15.8% from pretest to posttest. Students' mean score on a 22-question information mastery quiz was 90.8%. Mean scores for course evaluation components ranged from 4.8 to 5.0 on a 5-point Likert scale. All respondents indicated they would recommend the APPE to other students. An APPE that incorporated content from active drug-policy committees increased students' evidence-based medicine skills and enhanced their understanding of, appreciation for, and confidence in evidence-based practice.


Prednisolone does not improve olfactory function after COVID-19: a randomized, double-blind, placebo-controlled trial.
Prednisolone has been suggested as a treatment for olfactory disorders after COVID-19, but evidence is scarce. Hence, we aimed to determine the efficacy of a short oral prednisolone treatment on patients with persistent olfactory disorders after COVID-19. We performed a randomized, double-blind, placebo-controlled, single-centered trial in the Netherlands. Patients were included if they were > 18 years old and if they had persistent (> 4 weeks) olfactory disorders within 12 weeks after a confirmed COVID-19 test. The treatment group received oral prednisolone 40 mg once daily for 10 days and the placebo group received matching placebo. In addition, all patients performed olfactory training. The primary outcome was the objective olfactory function on Sniffin' Sticks Test (SST) 12 weeks after the start of treatment, measured in Threshold-Discrimination-Identification (TDI) score. Secondary outcomes were objective gustatory function assessed by the Taste Strip Test (TST) and subjective self-reported outcomes on questionnaires about olfactory, gustatory and trigeminal function, quality of life, and nasal symptoms. The CONSORT 2010 guideline was performed. Between November 2021 and February 2022, we included 115 eligible patients, randomly assigned to the treatment (n = 58) or placebo group (n = 57). No difference in olfactory function between groups was obtained after 12 weeks. Median TDI score on SST was 26.8 (IQR 23.6-29.3) in the placebo group and 28.8 (IQR 24.0-30.9) in the prednisolone group, with a median difference of 2.0 (95% CI 0.75 to 1.5). There was similar improvement on olfactory function in both groups after 12 weeks. Furthermore, on secondary outcomes, we obtained no differences between groups. This trial shows that prednisolone does not improve olfactory function after COVID-19. Therefore, we recommend not prescribing prednisolone for patients with persistent olfactory disorders after COVID-19. This trial is registered on the ISRCTN registry with trial ID ISRCTN70794078.


Parotid gland calculus. Report of a case.
A patient, was admitted with multiple calculi in the left parotid gland. Plain radiography and sialography confirmed the diagnosis. A partial parotidectomy was done and the calculi were removed.


Deletion of narfl leads to increased oxidative stress mediated abnormal angiogenesis and digestive organ defects in zebrafish.
Nuclear prelamin A recognition factor-like (NARFL) is a human protein that participates in cytosolic iron-sulfur (Fe-S) protein biogenesis and cellular defense against oxidative stress. Previous studies of Narfl knockout mice did not reveal well the regulatory mechanisms of embryonic development mediated by Narfl because the homozygous mice die in utero. Here, we investigated the function of narfl in an established zebrafish knockout model by taking advantage of zebrafish external fertilization and ease of embryonic development examination. Our experiments showed that narfl deletion resulted in larvae lethality, subintestinal vessel (SIV) malformation and digestive organ defects in the early stages of embryonic development. Biochemical analyses and western blot revealed increased oxidative stress and upregulated hypoxia-inducible factor-1α (HIF-1α) expression in narfl-/- fish. The use of HIF-1α inhibitor 2-methoxyestradiol (2ME2) for the treatment of mutants partially rescued the SIV sprouting. These results suggest that narfl deletion causes increased oxidative stress and subintestinal vessel malformation, which further influence the development of digestive organs and might contribute to the lethality of the narfl knockout fish.


Use of a polynomial exponential function to describe migration of proteins on sodium dodecyl sulfate-polyacrylamide gels.
Standard mixtures of proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Polynomial regression analysis was used to fit curves to the data points obtained by plotting log10 of protein molecular weight versus electrophoretic mobility. Polynomials with orders ranging from 1 to 4 were generated. The coefficients of each equation were analyzed for statistical significance. It was found that a third order polynomial was the highest-order equation in which all coefficients contributed significantly to the prediction of molecular weights. Using this equation, it was possible to estimate the molecular weights of known proteins in the range from 97,400 to 14,400 with a maximum error of 1%, compared with a maximum error of 17% when a first-order equation was used to describe the migration of the standards.


Crucial amides for dimerization inhibitors of HIV-1 protease.
An inhibitor based on crosslinked peptides from the interfacial region of HIV-1 protease, previously shown to act by dimerization inhibition, was modified by N-methylation to ascertain the importance of the amide hydrogens on inhibition. The effects of N-methylation on HIV-1 protease inhibition, as well as the effects on degradation by proteases are described.


Assessment of symptoms of DSM-IV anxiety and depression in children: a revised child anxiety and depression scale.
The practical significance of assessing disorders of emotion in children is well documented, yet few scales exist that possess conceptual if not empirical relevance to dimensions of DSM anxiety or depressive disorders. The current study evaluated an adaptation of a recently developed anxiety measure (Spence Children's Anxiety Scale; [Spence, S. H. (1997). Structure of anxiety symptoms among children: a confirmatory factor-analytic study. Journal of Abnormal Psychology, 106, 280-297; Spence, S. H. (1998). A measure of anxiety symptoms among children. Behaviour Research and Therapy, 36, 545-566]), revised to correspond to dimensions of several DSM-IV anxiety disorders as well as major depression. This investigation involved initial evaluation of the factorial validity of the revised measure in a school sample of 1641 children and adolescents and reliability and validity in an independent sample of 246 children and adolescents. Results yielded an item set and factor definitions that demonstrated structure consistent with DSM-IV anxiety disorders and depression. The revised factor structure and definitions were further supported by the reliability and validity analyses. Some implications for assessment of childhood anxiety and depressive disorders are discussed.


Current therapy of hilar cholangiocarcinoma.
Hilar cholangiocarcinoma (HC) is an adenocarcinoma of the extrahepatic biliary tree arising from the main left or right hepatic ducts or their confluence. This tumor is still considered to be difficult to treat or to cure. We reviewed the medical literature on HC. Relevant and updated information on this tumor was analyzed in a concise and easy-to-read manner. The article is not intended to be a systematic review, but an extensive search was conducted on PubMed and MEDLINE using the keywords "hilar cholangiocarcinoma" and "Klatskin tumor" until July 2011. The selection and the timing of management options for patients with HC are determined by the degree of certainty of the diagnosis, the general condition of the patients, the underlying liver function and the stage of the disease. Current treatment of HC can be divided into curative and palliative treatment. For the curative treatment, local excision should only be used on small tumors which are confined to the bile duct wall and Bismuth I papillary carcinoma. Partial hepatectomy should be combined with caudate lobe resection and porta-hepatis lymph node dissection. The results of these major resections can be improved with portal vein embolization, and staging laparoscopy and laparoscopic ultrasound. The role of preoperative biliary drainage is controversial. Autotransplantation for HC gave disappointing results while the Mayo Protocol of chemoradiation for selecting patients with unresectable HC for orthotopic liver transplantation has been widely accepted. Palliative treatment included bypass surgery, endoscopic or percutaneous stenting, photodynamic therapy, intraluminal brachytherapy, and external radiation and systemic therapy. Adequate surgery with R0 resection should be the main goal of treatment. For patients with unresectable HC, treatment aims to improve the quality and quantity of their survival.


Therapeutic responses to chemotherapy or immunotherapy by molecular subtype in bladder cancer patients: A meta-analysis and systematic review.
To systematically evaluate the differences in therapeutic response to chemotherapy or immunotherapy between different molecular subtypes of bladder cancer (BC). A comprehensive literature search was performed up to December 2021. Consensus clusters 1 (CC1), CC2 and CC3 molecular subtypes were used to perform meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the therapeutic response by fix-effect modeling. Eight studies involving 1,463 patients were included. For immunotherapy, CC3 showed the highest response rate (CC1 vs. CC3: OR=0.52, 95% CI=0.34-0.78, p=0.002; CC2 vs. CC3: OR=0.42, 95% CI=0.28-0.62, p<0.001), which was mainly reflected in the highest response rate to atezolizumab (CC1 vs. CC3: OR=0.47, 95% CI=0.29-0.75, p=0.002; CC2 vs. CC3: OR=0.38, 95% CI=0.24-0.59, p<0.001). For chemotherapy, CC3 had the lowest response rate to the overall chemotherapy (CC1 vs. CC3: OR=2.05, 95% CI=1.23-3.41, p=0.006; CC2 vs. CC3: OR=2.48, 95% CI=1.50-4.10, p<0.001). Compared with CC2, CC3 responded poorly to both neo-adjuvant chemotherapy (NAC) (OR=1.93, 95% CI=1.09-3.41, p=0.020) and chemoradiation therapy (CRT) (OR=6.07, 95% CI=1.87-19.71, p<0.001). Compared with CC1, CC3 only showed a poorer response to CRT (OR=4.53, 95% CI=1.26-16.27, p=0.020), and no difference in NAC. Our study suggested that molecular classifications are important predictors of cancer treatment outcomes of BC patients and could identify subgroup patients who are most likely to benefit from specific cancer treatments.


Immunostimulatory sequence CpG elicits Th1-type immune responses in inflammatory skin lesions in an atopic dermatitis murine model.
Atopic dermatitis (AD) is a chronic inflammatory skin disease, for which no fundamental therapy exists. Immunostimulatory sequence CpG (ISS CpG) has potential in reducing susceptibility to allergic diseases and reversing established allergic reactions. To investigate the effects of ISS CpG in the prevention and treatment of AD in an AD murine model. BALB/c mice were epicutaneously exposed to ovalbumin (OVA) for 3 or 4 weeks with a 2-week resting period between each exposure week. ISS i.d. injection was given either on the 1st day of each exposure week (in the prevention experiment) or 3 days before and on the 1st, 4th and 7th day of the last exposure week (in the treatment experiment). Skin biopsy and blood were obtained at the end of the experiments. ISS CpG treatment increased drastically mRNA expression of proinflammatory and Th1-type cytokines and chemokines in OVA-treated skin both in the prevention and treatment experiments. The suppressing effect of ISS CpG on Th2-type cytokines and chemokines was weak and limited to IL-13 and CCL24 in the treatment experiment. No significant reduction in OVA-elicited infiltration of eosinophils and T cells in the skin was seen after ISS administration but infiltration of plasmacytoid dendritic cells was absent in ISS CpG-treated skin. In contrast, ISS injection elicited dramatic infiltration of F4/80+ and CCR5+ cells into the dermis and subcutaneous tissue. Due to unwanted side effects and minor beneficial effects in our model, administration of ISS CpG may not be suitable for the treatment of AD in humans.


Devices and methods for administering carbon dioxide-enriched air in experimental and clinical settings.
Although researchers successfully have used carbon dioxide-enriched air in experimental and clinical preparations, its functional properties may differ across laboratories due to procedural differences. Additionally, current procedures may be too simplistic for more complex experimental designs. To address these issues, we present three devices for administering carbon dioxide-enriched air. Although these devices differ concerning variables such as mode of operation, ease and cost of implementation, and complexity of experimental designs that may be undertaken, a reasonable level of standardization may be achieved because the inhalations experienced by participants are functionally equivalent across devices. We discuss advantages and disadvantages of these devices regarding experimental panic provocation and aversive conditioning preparations.


Enrichment of human milk lymphocytes by discontinuous density gradient sedimentation.
A simple method is described for the enrichment of lymphocytes from human colostrum and early milk. Washed leucocytes from colostrum or milk were suspended in balanced salt solution containing 25% human serum and separated by discontinuous density gradient centrifugation over Lymphoprep (1.077 g/ml) and Nycodenz (1.070 g/ml). The cell fraction harvested from the interface between these two media contained a mean of 56% lymphocytes (9-92%), as compared to 5.6% (0-17%) in the unseparated samples, representing an average enrichment of 12.6 fold. The percentage yield of lymphocytes ranged from 70 to 100%. Enriched preparations of lymphocytes from human colostrum and early milk should prove valuable in studies of the distribution of lymphocyte subpopulations in breast milk and could lead to more definitive studies of their functions in vitro.


Temporal trends in initiation of mineralocorticoid receptor antagonists and risk of subsequent withdrawal in patients with heart failure: a nationwide study in Denmark from 2003-2017.
Despite landmark heart failure (HF) with reduced ejection fraction (HFrEF) trials showing effect of mineralocorticoid receptor antagonists (MRA) on the risk of death and HF hospitalization, it has been suggested that MRAs are underutilized or frequently withdrawn. This study sought to identify temporal trends in the initiation of MRAs and the subsequent risk of withdrawal and adherence of MRAs in HF patients treated with a renin-angiotensin system inhibitor and a beta-blocker in Denmark from 2003-2017. From nationwide registries, we identified patients receiving a diagnosis of HF. Use of MRA was identified by at least one prescription within 6 months after the diagnosis. The absolute risk of withdrawal with treatment was assessed with cumulative incidence, accounting for the competing risk of death. To estimate adherence, we calculated the proportion of days covered. We included 51 512 patients with incident HF. During the study period, 20 779 (40.3%) patients initiated MRA therapy. The incidence of withdrawal of MRA was 49.2% throughout the study period; 48.0% of the HF patients were adherent to the treatment. Among patients withdrawing treatment with MRA, the cumulative incidence of reinitiating was 36.6%. In a nationwide cohort of patients with HF, approximately half of the patients received MRA as third-line therapy within the first 6 months after diagnosis and approximately half of these withdrew MRA within 5 years. These findings warrant an increasing focus on retention to MRA treatment in a real-life setting.


Disclosure of sex when incidentally revealed as part of preimplantation genetic testing (PGT): an Ethics Committee opinion.
Clinics may develop a policy to disallow selecting which embryos to transfer based on sex and choose to use only embryo quality as selection criteria. Clinics may also develop a policy to use randomization to select those embryos for transfer if more embryos suitable for transfer are available than can be transferred.


Evaluating the relationship between ankylosing spondylitis and periodontal disease: a case-control study.
This study aimed to determine the possible relationship between periodontal disease and ankylosing spondylitis (AS) by evaluating clinical periodontal measurements and gingival crevicular fluid (GCF) levels of sclerostin, interleukin-1β (IL-1ß), and matrix metalloproteinase-8 (MMP-8) levels. Twenty-eight patients with AS (AS group) and 28 systemically healthy controls (C group) were enrolled in this study. Full-mouth periodontal measurements: plaque index, bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) measurements were obtained from all patients. AS-related parameters were included in the data analyses. An enzyme-linked immunosorbent assay determined GCF IL-1β, MMP-8, and sclerostin levels. There were no significant differences in the clinical periodontal measurements between the two groups (p > 0.05). Interestingly, patients with AS had significantly lower GCF sclerostin levels than the C group (p < 0.05). But there were no statistical differences in the GCF levels of IL-1ß and MMP-8 between the two groups (p > 0.05). Serum C-reactive protein (CRP) levels strongly correlated with both BOP (r = 0.497, p < 0.05) and PPD (r = 0.570, p < 0.05) in the AS group. Bath AS Metrology Index (BASMI) also positively correlated with both BOP (r = 0.530, p < 0.05) and CAL (r = 0.568, p < 0.05). Similarly, Maastrıcht Ankylosing Spondylitis Enthesis Score (MASES) strongly correlated with both BOP (r = 0.487, p < 0.05) and CAL (r = 0.522, p < 0.05). These results suggest that the patient's systemic condition may influence local sclerostin levels in GCF, and the strong correlations between periodontal measurements and AS-related parameters may indicate an interrelationship between inflammatory periodontal disease and AS. The present study provides important information concerning the relationship between periodontal disease and ankylosing spondylitis. Thai Clinical Trials.gov (TCTR20200908001) (08. September 2020).


von Hippel-Lindau tumor suppressor protein represses platelet-derived growth factor B-chain gene expression via the Sp1 binding element in the proximal PDGF-B promoter.
VHL is the causative gene for von Hippel-Lindau disease and sporadic clear cell renal cancer. It has been shown that pVHL can suppress the expression of certain genes that are overexpressed in renal carcinomas. One such gene is that encoding the potent mitogen and chemoattractant, platelet-derived growth factor B-chain (PDGF-B). The regulatory mechanisms underlying pVHL suppression of PDGF-B expression, however, are completely unknown. This understanding would shed vital light on the control of growth factor gene expression by this tumor suppressor. Here we report that pVHL can repress both endogenous steady-state PDGF-B mRNA expression and PDGF-B promoter-dependent transcription in WKY12-22 cells. Transient transfection analysis utilizing PDGF-B promoter-chloramphenicol acetyl transferase (CAT) reporter constructs revealed that pVHL inhibition of PDGF-B expression is mediated via the Sp1-binding element in the proximal region of the PDGF-B promoter. Recent studies have demonstrated a physical interaction between pVHL and Sp1, which activates the PDGF-B promoter. We show that Sp1 can rescue PDGF-B promoter activity and endogenous PDGF-B mRNA expression from pVHL repression. These findings thus demonstrate a pivotal role for Sp1 in pVHL inhibition of PDGF-B transcription.


Protective effect of L-carnosine against 12-O-tetradecanoylphorbol-13-acetate- or hydrogen peroxide-induced apoptosis on v-myc transformed rat liver epithelial cells.
Apoptotic processes have been associated with cancer and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease etc. beta-Alanyl-L-histidine (L-carnosine), occurring abundantly in skeletal muscles has been suggested to possess antioxidative activity. We investigated whether L-carnosine prevents 12-O-tetradecanoylphorbol-13-acetate (TPA)- or hydrogen peroxide (H2O2)-induced apoptosis involving mitochondria in the v-myc transformed rat liver epithelial cells (WB-myc cells). L-Carnosine prevented both TPA- and H2O2-induced DNA fragmentation, the loss of mitochondrial membrane potentials and blocked the release of cytochrome c into cytosol. Subsequently, the cleavages of poly (ADP-ribose) polymerase were significantly reduced in L-carnosine-treated cells. However, western blotting analysis revealed that p53 protein level did not change for 12h after TPA- and H2O2-treatment. Therefore, these results suggested that L-carnosine, an antioxidant, protected both H2O2- and TPA-induced apoptosis through mitochondrial pathways.


Very long-term molecular follow-up of minimal residual disease in patients with neuroblastoma.
In high-risk neuroblastoma (HR-NB), the clinical significance of long-term minimal residual disease (MRD) monitoring using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for neuroblastoma mRNAs has not been investigated. We report long-term MRD follow-ups of four patients with HR-NB throughout the disease (diagnosis, remission, and relapse) and treatment course (chemotherapy, autologous and allogeneic stem cell transplantation, and donor lymphocyte and natural killer cell infusions). The results showed the stability of mRNA marker expression after different treatments and demonstrated their validity to predict relapse and assess therapeutic response. This opens up the possibility of investigating the utility of long-term molecular monitoring of MRD in prospective multicenter studies.


Creutzfeldt-Jakob disease with plaques and paired helical filaments.
A 32-year-old man with rapidly progressive dementia, pyramidal signs, myoclonic jerks and dystonic movements died following brain biopsy. neuropathological examination revealed minimal neuronal loss accompanied by mild spongiform change and astrocytic reaction. Numerous plaques and neurofibrillary tangles composed of paired helical filaments dominated the ultrastructural picture. This patient had features of both Creutzfeldt-Jakob disease and Alzheimer's disease, providing additional support for the existence of an overlap between these disorders.


Severe subluxation of the femoral head after rotational acetabular osteotomy: a case report.
We encountered a rare case of severe subluxation of the femoral head after the performance of rotational acetabular osteotomy to treat osteoarthritis of the hip, secondary to acetabular dysplasia. The subluxation was corrected by performing varus and flexion osteotomy.