Associations of Vitamin D Receptor Single Nucleotide Polymorphisms with Susceptibility to Systemic Sclerosis.
This study aims to evaluate whether the Vitamin D receptor (VDR) gene polymorphisms were associated with systemic sclerosis (SSc) in a Chinese Han population. Using a hospital-based case-control study including 100 SSc patients and 100 healthy controls. Single nucleotide polymorphisms (SNPs) in the VDR region were genotyped by the improved multiplex ligase detection reaction (i MLDR) method. Haplotypes were also constructed after linkage disequilibrium (LD) analysis. Eight SNPs (rs731236 (TaqI), rs2228570 (FokI), rs7975232 (ApaI), rs1544410 (BsmI), rs11574010 (Cdx2), rs739837 (BglI), rs757343 (Tru9I) and rs11168267) were included. There were significant differences between SSc patients and healthy individuals in ApaI and BglI genotype (both adjusted p = 0.008). Through the genotyping, significantly association of SSc were found for: dominant model of ApaI and BglI (both OR (95% CI) = 1.80 (1.03,3.16), p = 0.040). Furthermore, the elevation of erythrocyte sedimentation rate (ESR) had a higher percentage of BglI GT genotype frequency (p = 0.034) and dominant model of ApaI (p = 0.016) in SSc. There was high linkage disequilibrium was detected in BglI and ApaI polymorphisms (r2 = 1.0, D' = 1.0), Tru9I and rs11168267 (r2 = 0.926, D' = 0.969), respectively. No significant difference were found in these four haplotypes (all p >0.05). The correlation between VD levels and VDR gene polymorphisms was not statistically significant. Our preliminary study indicates the ApaI and BglI genotype may possibly have a role in the pathogenesis of SSc patients. Dominant model of ApaI and BglI GT genotype frequency may be associated with the increased risk of ESR.


Incidence, Timing, and Causes of Late Bleeding After TAVR in an Asian Cohort.
Data regarding the incidence, predictive factors, and clinical outcomes of post-transcatheter aortic valve replacement (TAVR) bleeding is limited in the Asian cohort. This study sought to assess the predictors and prognostic impact of post-TAVR late bleeding. This study used the Japanese multicenter registry data to analyze 2,518 patients (mean age: 84.3 ± 5.2 years) who underwent TAVR. Late bleeding was defined as any postdischarge bleeding events after TAVR. Baseline characteristics, predictive factors, and clinical outcomes including death and rehospitalization were assessed in patients with and without late bleeding events. The cumulative incidence rate of all and major late bleeding and ischemic stroke were 7.4%, 5.2%, and 3.4%, respectively, 3 years after TAVR. The independent predictive factors of late bleeding were low platelet count, high score (≥4) on the clinical frailty scale, and a New York Heart Association functional class III/IV. The cumulative mortality rates up to 3 years were significantly higher in patients with late bleeding than in those without bleeding (P < 0.001). The multivariate Cox regression analysis revealed that late bleeding, included as a time-varying covariate in the model, was associated with an increased risk of mortality following TAVR (HR: 5.63; 95% CI: 4.28-7.41; P < 0.001). Late bleeding after TAVR was not a rare complication, and it significantly increased long-term mortality. It should be carefully managed, especially when it is predictable in the high-risk cohort, and efforts should be taken to reduce bleeding complications even after a successful procedure.


Integrated Stent Models Based on Dimension Reduction: Review and Future Perspectives.
Stent modeling represents a challenging task from both the theoretical and numerical viewpoints, due to its multi-physics nature and to the complex geometrical configuration of these devices. In this light, dimensional model reduction enables a comprehensive geometrical and physical description of stenting at affordable computational costs. In this work, we aim at reviewing dimensional model reduction of stent mechanics and drug release. Firstly, we address model reduction techniques for the description of stent mechanics, aiming to illustrate how a three-dimensional stent model can be transformed into a collection of interconnected one-dimensional rods, called a "stent net". Secondly, we review available model reduction methods similarly applied to drug release, in which the "stent net" concept is adopted for modeling of drug elution. As a result, drug eluting stents are described as a distribution of concentrated drug release sources located on a graph that fully represents the stent geometry. Lastly, new results about the extension of these model reduction approaches to biodegradable stents are also discussed.


Regulation of actin polymerization by non-polymerizable actin-like proteins.
Three functionally distinct actin-capping proteins from the slime mould Physarum are structurally closely related to actin itself. In Physarum, actin polymerization is regulated by a set of non-polymerizable actin-like proteins. It remains to be established whether these proteins and actin are each encoded by separate genes.


Genome-wide screen of promoter methylation analysis of ES cells and ES derived epidermal-like cells.
Embryonic stem cells (ESCs) are a population of pluripotent cells which can differentiate into different cell types. However, there are few reports with regard to differentiate ESCs into epidermal cells in vitro. In this study, we aimed to investigate differentially methylated promoters involved in process of differentiation from ESCs into epidermal-like cells (ELCs) induced by human amnion. We successfully induced ESCs into ELCs, which expressed the surface markers of CK19, CK15 and β1-integrin. With MeDIP-chip arrays, we identified 3435 gene promoters to be differentially methylated, involving 894 HCP (high CpG-containing promoter), 974 ICP (intermediate CpG-containing promoter) and 1567 LCP (low CpG-containing promoter) among all the 17,500 DNA methylation regions of gene promoters in both ESCs and ELCs. Gene oncology and pathway analysis demonstrated that these genes were involved in all the three categories of GO enrichment analysis, including biological process, molecular function and cellular component. All these data suggested that embryonic stem cells can differentiate into epidermal-like cells and promoter methylation is of great importance in this process.


MRI of soft tissue abnormalities: a primary cause of sickle cell crisis.
The early manifestations of sickle cell crisis in soft tissues are important to recognize, though rarely manifest on radiographs and difficult to evaluate on computed tomography and bone scans. Documentation is critical, however, if appropriate judgments as to emergency treatment versus conservative measures are to be made. Seventeen adults seen in the emergency room or hospitalized in presumed sickle cells crisis underwent magnetic resonance imaging within 24-72 h of presentation. Results indicate that magnetic resonance imaging is a sensitive modality for documenting early soft tissue pathology which may be the predominant or sole cause of sickle cell crisis.


Diagnostic trilemma: isorhythmic AV dissociation mimicking intermittent preexcitation and acute inferior myocardial infarction.
In this case report, we present a patient with intermittent isorhythmic atrioventricular dissociation mimicking two different electrocardiographic entities: ventricular preexcitation pattern and recurrent acute inferior myocardial infarction.


Common and critical inflammatory dermatoses every pathologist should know.
Inflammatory dermatopathology remains a challenging area for surgical pathologists. Yet every surgical pathologist encounters inflammatory dermatoses as part of routine practice. This review will focus on selected diagnoses that are either commonly encountered in the routine practice of surgical pathology or are critically important. The following entities will be covered: spongiotic dermatoses, lichen simplex chronicus, and early lichen sclerosus in the setting of vulvar biopsies, as well as graft versus host disease, Stevens-Johnson syndrome/toxic epidermal necrolysis, granuloma anulare, pyoderma gangrenosum, and calciphylaxis. Practical points and key histologic features will be emphasized.


Population density effects on fecundity of Hippelates pusio Loew (Diptera: Chloropidae).
A schematic model is constructed illustrating the pathways and mechanisms of adult density effects on birth rate that have been reported to operate in various taxa of insects. With this model as a guide, experimetal data were collected from laboratory populations of Hippelates pusio Loew within the range of 0.15 to 25 flies per cm3 (sex ratio 1:1), which revealed: a) that adult density did not affect oviposition rate via competition for oviposition site, b) the rates of oviposition for virgin and mated females were not significantly different, and c) density did not affect frequency of copulation to a degree detectable in the hatchability of eggs. These data and previous knowledge on the reproductive biology of Hippelates pusio indicate that the birth rate of this species is independent of adult density, within then density range investigated.


Feasibility of sentinel node lymphoscintigraphy in stage I testicular cancer.
The aim of this study was to investigate the feasibility of lymphoscintigraphy for sentinel node identification in testicular cancer. Five patients with clinical stage I testicular cancer were prospectively included. A single dose of technetium-99m nanocolloid (mean dose 99 MBq, volume 0.2 ml) was injected into the funiculus in the first patient and into the testicular parenchyma in the following four patients. Dynamic lymphoscintigraphy was performed over 10 min, followed by early and late static images after 15 min and 2 to 24 h, respectively. Lymphoscintigraphy was followed by laparoscopic sentinel node biopsy on the same day in the last two patients using patent blue dye and an endoscopic gamma probe. The funicular administration route showed five hot spots in the right inguinal region after 2 h. Intratesticular administration resulted in sentinel node visualisation in three of the four patients. Dynamic images showed afferent lymphatic vessels to one sentinel node in the left para-aortic region in two patients and two sentinel nodes in the left para-aortic region in another patient. Sentinel nodes were intraoperatively identified in one of two patients who underwent laparoscopic exploration. It is concluded that lymphoscintigraphy for sentinel node identification is feasible in stage I testicular cancer using intratesticular radiocolloid administration.


Cellulolytic activity of moulds. II. Various methods of precipitating and concentrating enzymes and their influence on the activity of cellulolytic preparation and xylanase of Aspergillus terreus F-413.
Complexes of cellulolytic enzymes and xylanase were precipitated and concentrated by various methods from post-culture liquids of Aspergillus terreus F-143, containing cellucotton as carbon source. The best results in regard to the specific activity of the preparations were obtained by precipitation of enzymes with acetone-denatured ethanol. Besides high cellulolytic and xylanase activity the crude enzyme preparation showed the presence of small amounts of amylase, protease and polygalacturonase.


The coagulation system and pulmonary endothelial function in acute lung injury.
Acute lung injury (ALI) is a disease marked by diffuse endothelial injury and increased capillary permeability. The coagulation system is a major participant in ALI and activation of coagulation is both a consequence and contributor to ongoing lung injury. Increased coagulation and depressed fibrinolysis result in diffuse alveolar fibrin deposition which serves to amplify pulmonary inflammation. In addition, existing evidence demonstrates a direct role for different components of coagulation on vascular endothelial barrier function. In particular, the pro-coagulant protein thrombin disrupts the endothelial actin cytoskeleton resulting in increased endothelial leak. In contrast, the anti-coagulant activated protein C (APC) confers a barrier-protective actin configuration and enhances the vascular barrier in vitro and in vivo. However, recent studies suggest a complex landscape with receptor cross-talk, temporal heterogeneity and pro-coagulant/anti-coagulant protein interactions. In this article, the major signaling pathways governing endothelial permeability in lung injury are reviewed with a particular focus on the role that endothelial proteins, such as thrombin and APC, which play on the vascular barrier function.


A retrospective database analysis of erythropoiesis-stimulating agent treatment patterns and associated healthcare resource use in patients with non-dialysis-dependent chronic kidney disease-related anaemia in Japan.
This study was conducted to evaluate clinical characteristics, treatment patterns, and healthcare resource use (HCRU) for patients in Japan with non-dialysis-dependent chronic kidney disease (CKD) and anaemia. This retrospective, longitudinal, epidemiological database extraction study used the JMDC Claims Database, comprising ~9.4 million unique beneficiaries. The observation period for anaemia and erythropoiesis-stimulating agent (ESA)/iron treatment was 1 January 2015 to 31 December 2018, and for HCRU and costs was 1 April 2016 to 31 March 2018. The non-dialysis-dependent CKD anaemia population, and the ESA treatment, iron treatment, and no-treatment cohorts were evaluated. Patient characteristics, treatment patterns, and outcomes were summarised descriptively. The non-dialysis-dependent CKD anaemia population included 5908 patients (7.9%), with 464 patients in the ESA treatment cohort, 809 patients (13.7%) in the iron treatment cohort (13.7%), and 4405 (74.6%) patients in the no-treatment cohort. The prevalence of patients prescribed an antihypertensive, antidiabetic, and/or antihyperlipidaemic medication generally increased with increasing baseline CKD stage. Proportions of no treatment for anaemia decreased while ESA treatment increased with increasing CKD stage; ESA treatment increased with decreasing baseline haemoglobin levels. Patients in the ESA treatment cohort generally had more frequent events associated with HCRU and higher costs from HCRU-associated activities (e.g., inpatient and outpatient care, pharmacy). As CKD severity increased, anaemia management changed from iron use or no treatment to ESA use; however, anaemia may be undertreated across all CKD stages. ESA-treated patients incurred greater HCRU-associated costs relative to other patients with non-dialysis-dependent CKD anaemia in Japan.


Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen-glucose deprivation in vitro.
Postsynaptic density protein 95 (PSD-95) plays important roles in the regulation of glutamate signaling, such as that of N-methyl-D-aspartate receptors (NMDARs). In this study, the functional roles of PSD-95 in tyrosine phosphorylation of NMDAR subunit 2A (NR2A) and in apoptosis-like cell death induced by oxygen-glucose deprivation (OGD) in cultured rat cortical neurons were investigated. We used immunoprecipitation and immunoblotting to detect PSD-95 protein level, tyrosine phosphorylation level of NR2A, and the interaction between PSD-95 and NR2A or Src. Apoptosis-like cells were observed by 4,6-diamidino-2-phenylindole staining. Tyrosine phosphorylation of NR2A and apoptosis-like cell death were increased after recovery following 60-min OGD. The increases were attenuated by pretreatment with antisense oligonucleotides against PSD-95 before OGD, but not by missense oligonucleotides or vehicle. PSD-95 antisense oligonucleotides also inhibited the increased interaction between PSD-95 and NR2A or Src, while NR2A expression did not change under this condition. PSD-95 may be involved in regulating NR2A tyrosine phosphorylation by Src kinase. Inhibition of PSD-95 expression can be neuroprotective against apoptosis-like cell death after recovery from OGD.


Epidural hematoma after thoracic epidural analgesia in a patient treated with ketorolac, mefenamic acid, and naftazone: a case report.
A 26-year-old male undergoing thoracotomy and bleeding control received a preoperative thoracic epidural for postoperative analgesia. On the fifth postoperative day, paralysis of both lower limbs occurred and urgent magnetic resonance imaging showed massive anterior epidural hematoma. During laminectomy and decompression, platelet dysfunction was diagnosed and preoperative non-steroidal anti-inflammatory drugs medications were supposed to the cause of platelet dysfunction. After infusion of ten units of platelet concentrate, coagulopathy was improved. We should be more careful to drugs with antiplatelet effect when using regional analgesia.


Editorial: Refeeding in Anorexia Nervosa: Quo Vadis?
Refeeding is the cornerstone of treatment in anorexia nervosa (AN), a life-threatening eating disorder characterized by severe undernutrition. During refeeding, patients typically gain a large proportion of their body weight within a couple of weeks or months. The aims of this drastic nutritional intervention are mainly somatic stability and the improvement of the mental state of the patient, as a prerequisite for psychotherapy. There has been a recent trend away from the conventional low-calorie "start low, go slow" refeeding approach to higher calorie refeeding with a more rapid weight gain, shorter hospitalization time, and consequently, psychosocial and economic benefits. In favor of higher calorie refeeding, the rate of initial weight gain has been shown to predict weight recovery.1 Furthermore, recent neuroimaging studies suggest that the widespread reductions of gray matter volume and cortical thickness in acutely underweight AN patients abate rapidly after refeeding.2 Although the first studies provided evidence for the relative safety of higher calorie refeeding, particularly in the refeeding syndrome, a rare but possibly fatal complication,3,4 little is known about less acute side effects. However, relative to its significant clinical importance, the topic is understudied, and guidelines vary considerably across different countries. The clinical review at the focus of this editorial seeks to advance the medical literature by juxtaposing the details of refeeding protocols of 3 well-known specialized eating disorder centers.


A generally applicable cryopreservation method for nitrite-oxidizing bacteria.
Nitrite-oxidizing bacteria are key members of the global nitrogen cycle but their study is hampered by their limited availability in culture, mostly due to laborious cultivation procedures and the lack of stable preservation methods. In this study, it was demonstrated that long-term cryopreservation of nitrite-oxidizing bacteria assigned to the genera Nitrobacter, Nitrospina, Nitrococcus, Nitrotoga and Nitrospira was possible using a simple and rapid protocol. Their survival was tested with different cryoprotecting agents, DMSO and Hatefi, and in various carbon-rich preservation media, ten-fold diluted TSB, and ten-fold diluted TSB supplemented with 1% trehalose, and 1% sucrose. Optimal preservation conditions were strain-dependent and marine strains appeared to be more sensitive to freezing than non-marine strains. Nevertheless, a general cryopreservation protocol using 10% dimethyl sulfoxide with or without ten-fold diluted trypticase soy broth as a preservation medium allowed successful preservation of all tested strains.


How to perform and interpret a middle cerebral artery transcranial Doppler examination in children at risk of brain injury.
Transcranial Doppler (TCD) ultrasound is a non-invasive neuromonitoring technique that falls under the umbrella of point-of-care ultrasound. In this article, we provide a primer to encourage clinicians to perform TCD examinations and to aid them with accurately interpreting the scans. We focus on the middle cerebral artery waveforms and use traumatic brain injury as a model for brain insult.


Identifying RBP Targets with RIP-seq.
Throughout their lifetime RNA molecules interact with a variety of RNA-binding proteins (RBPs). RBPs control gene expression by regulating splicing, polyadenylation, editing, transport, stability, and translation of RNA. There are ~1500 RBPs encoded by the human genome and recent studies have detected ~1100 proteins directly interacting with polyadenylated RNA. Identifying the RNAs bound by RBPs will continue to provide important insights into the regulation of gene expression.


Blood storage XXIII: 2,3-DPG maintenance for six weeks in a CPD-adenine-inosine preservative with and without methylene blue.
In a pilot study the optimal concentration of inosine for 2,3-DPG maintenance in a CPD-adenine (0.25 mM) preservative was confirmed to be at lease 10 mM. In these experiments, 2,3-DPG maintenance was nearly normal for six weeks of storage in CPD-adenine-inosine (10 mM) preservative with or without methylene blue. The control preservative lacking inosine showed a statistically significant decrease in 2,3-DPG concentrations after the 3rd week. Finally, 2,3-DPG levels were significantly better maintained in CPD-adenine preservatives that contained 15 mM concentrations of inosine, whether methylene blue was present or not (10(-6)M), compared to CPD-adenine-inosine preservatives that contained 5 mM inosine, with or without methylene blue. The methylene blue effect, while it can be demonstrated in most experiments to help the red blood cell maintain 2,3-DPG during prolonged blood storage, is judges to be a slight value. However, inosine is of great value in maintaining 2,3-DPG for prolonged (five to six weeks) liquid storage.


Mechanosensitive Piezo1 channel in physiology and pathophysiology of the central nervous system.
Since the discovery of the mechanosensitive Piezo1 channel in 2010, there has been a significant amount of research conducted to explore its regulatory role in the physiology and pathology of various organ systems. Recently, a growing body of compelling evidence has emerged linking the activity of the mechanosensitive Piezo1 channel to health and disease of the central nervous system. However, the exact mechanisms underlying these associations remain inadequately comprehended. This review systematically summarizes the current research on the mechanosensitive Piezo1 channel and its implications for central nervous system mechanobiology, retrospects the results demonstrating the regulatory role of the mechanosensitive Piezo1 channel on various cell types within the central nervous system, including neural stem cells, neurons, oligodendrocytes, microglia, astrocytes, and brain endothelial cells. Furthermore, the review discusses the current understanding of the involvement of the Piezo1 channel in central nervous system disorders, such as Alzheimer's disease, multiple sclerosis, glaucoma, stroke, and glioma.


Super-resolution microscopy for the study of store-operated calcium entry.
The use of a variety of techniques based on super-resolution (SR) microscopy unveiled a close and complex relationship between cytoskeleton reorganization and SOCE. By using SR microscopy many new proteins involved in SOCE regulation have been identified over the last few years. Many enigmas remain unsolved in this highly dynamic field, however, recent developments in SR microscopy promise new answers soon. In the present review, we describe the most relevant findings in SOCE components and SOCE modulation using different methods derived from SR microscopy.


Multidetector CT of the colon.
Multidetector technology, enabling faster imaging, higher spatial resolution and reduction in radiation dose, increases the role of CT in colonic diagnostic. The higher spatial resolution in the z-direction also changes the way to analyze the images. Instead of reading axial sections, now the colon can be systematically assessed in 3D by scrolling through multiplanar reconstructions or in CT colonography by virtual endoscopy. With ongoing improvements in computer-aided diagnosis CT colonography becomes an alternative to fiberoptic colonocopy for screening (http://www. multiorganscreening.org). In this article we propose a CT examination protocol for the colon, describe the typical imaging findings of different colonic diseases, and summarize the current status of CT colonography.


Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors.
The design, synthesis, and biological evaluation of novel C3-substituted cyclopentyltetrahydrofuranyl (Cp-THF)-derived HIV-1 protease inhibitors are described. Various C3-functional groups on the Cp-THF ligand were investigated in order to maximize the ligand-binding site interactions in the flap region of the protease. Inhibitors 3c and 3d have displayed the most potent enzyme inhibitory and antiviral activity. Both inhibitors have maintained impressive activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 3c-bound HIV-1 protease revealed a number of important molecular insights into the ligand-binding site interactions.


CTCF-mediated chromatin looping in EGR2 regulation and SUZ12 recruitment critical for peripheral myelination and repair.
Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.


Development of tooth regenerative medicine strategies by controlling the number of teeth using targeted molecular therapy.
Analysis of various genetically modified mice, with supernumerary teeth, has revealed the following two intrinsic molecular mechanisms that increase the number of teeth. One plausible explanation for supernumerary tooth formation is the rescue of tooth rudiments. Topical application of candidate molecules could lead to whole tooth formation under suitable conditions. Congenital tooth agenesis is caused by the cessation of tooth development due to the deletion of the causative gene and suppression of its function. The arrest of tooth development in Runx2 knockout mice, a mouse model of congenital tooth agenesis, is rescued in double knockout mice of Runx2 and Usag-1. The Usag-1 knockout mouse is a supernumerary model mouse. Targeted molecular therapy could be used to generate teeth in patients with congenital tooth agenesis by stimulating arrested tooth germs. The third dentition begins to develop when the second successional lamina is formed from the developing permanent tooth in humans and usually regresses apoptotically. Targeted molecular therapy, therefore, seems to be a suitable approach in whole-tooth regeneration by the stimulation of the third dentition. A second mechanism of supernumerary teeth formation involves the contribution of odontogenic epithelial stem cells in adults. Cebpb has been shown to be involved in maintaining the stemness of odontogenic epithelial stem cells and suppressing epithelial-mesenchymal transition. Odontogenic epithelial stem cells are differentiated from one of the tissue stem cells, enamel epithelial stem cells, and odontogenic mesenchymal cells are formed from odontogenic epithelial cells by epithelial-mesenchymal transition. Both odontogenic epithelial cells and odontogenic mesenchymal cells required to form teeth from enamel epithelial stem cells were directly induced to form excess teeth in adults. An approach for the development of targeted therapeutics has been the local application of monoclonal neutralizing antibody/siRNA with cationic gelatin for USAG-1 or small molecule for Cebpb.


Analysis of specific lysine histone H3 and H4 acetylation and methylation status in clones of cells with a gene silenced by nickel exposure.
We have previously reported that the gpt transgene in G12 Chinese hamster cells could be silenced by water-insoluble nickel compounds nickel sulfide (NiS) or nickel subsulfide (Ni(3)S(2)) and showed that the transgene was silenced by de novo DNA methylation and chromatin condensation. To further understand the nature of this silencing, we used the chromatin immunoprecipitation assay to elucidate the chromatin structure in nickel-induced silenced G12 clones. We also analyzed the effects of the DNA methyltransferase inhibitor 5-azacytidine (5-AzaC) and a histone deacetylase inhibitor trichostatin A (TSA) on histone H3 and H4 acetylation and gpt gene expression in selected nickel-silenced clones. We observed that both histone H3 and H4 were hypoacetylated and a methyl DNA-binding protein MeCP2 was targeted to the gpt gene locus, resulting in a localized inactive chromatin configuration in nickel-silenced cell clones. The histone H3K9 was also found methylated in three of four nickel- silenced cell clones, whereas the histone H3K9 was deacetylated in all four cell clones, indicating that the H3K9 methylation was involved in nickel-induced gene silencing. The acetylation of the gpt gene could be increased by a combination of 5-AzaC and TSA treatment, but not by either 5-AzaC or TSA alone. The gpt transcript was studied by either Northern blot or by semiquantitative RT-PCR following treatment of the silenced clones with TSA or 5-AzaC. An increase in gpt mRNA could be detected by RT-PCR in the clones that regained acetylation of H3 and H4. These data show that gene silencing induced by nickel in the gpt transgenic cell line involved a loss of histone acetylation and an activation of histone methylation. Both H4 and H3 histone acetylation were lost in the silenced clones and these clones exhibited an increase in the methylation of the lysine 9 in histone H3.


Assessing the executive function deficits of patients with Parkinson's disease: utility of the Tower of London-Drexel.
The aim of the study was to investigate the utility of the Tower of London-Drexel (TOLDX) in assessing the executive deficits associated with Parkinson's disease (PD). We sought to determine whether the TOLDX would differentiate between (a) patients with PD and healthy control participants (HCP), (b) demented and nondemented patients, and (c) depressed and nondepressed patients. A new TOLDX score, stimulus bound, was introduced to assess utilization behaviors. Furthermore, the convergent and divergent validity of the TOLDX was examined. The TOLDX total move, rule and time violation, and stimulus-bound scores of patients with PD significantly differed from the HCP. Demented and nondemented patients also differed significantly in their TOLDX performance, with the stimulus-bound score being the most significantly differentiating score. However, the depressed and nondepressed patients did not differ in their TOLDX performance. Support was found for the convergent and divergent validity of the TOLDX. The clinical and theoretical implications of the findings are discussed.


A liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of actinomycin-D and vincristine in children with cancer.
Actinomycin-D (Act-D) and vincristine (VCR) are cytotoxic agents commonly used in the treatment of pediatric cancers. To date, there are few published methods on quantifying Act-D or VCR and no published methods on quantifying the two drugs together. We present a methodology for the simultaneous quantification of Act-D and VCR in human plasma using liquid chromatography-tandem mass spectrometry (LC/MS/MS) detection. Following solid phase extraction, plasma samples were separated and analyzed using electrospray ionization (ESI). The lower limit of quantitation (LLOQ) for both Act-D and VCR was 0.5 ng/ml. The analytical accuracy for detection of both Act-D and VCR was > or = 90%. The analytical precision, as estimated by the coefficient of variation was < or = 6% for Act-D and < or = 11% for VCR. Given the prevalence of the use of the two drugs as combination therapy in a variety of pediatric oncological indications, the small sample volume requirements and the assay sensitivity, this methodology is expected to support several ongoing and future pediatric trials.


Correction to: Treatment of Rare and Aggressive Pancreatic Carcinosarcoma.
[This corrects the article on p. e00379 in vol. 7, PMID: 32607379.].


Mice expressing the variant rs1143679 allele of ITGAM (CD11b) show impaired DC-mediated T cell proliferation.
Genome-wide association studies (GWAS) and functional genomic analyses have implicated several ITGAM (CD11b) single-nucleotide polymorphisms (SNPs) in the development of SLE and other disorders. ITGAM encodes the αM chain of the β2 integrin Mac-1, a receptor that plays important roles in myeloid cell functions. The ITGAM SNP rs1143679, which results in an arginine to histidine change at amino acid position 77 of the CD11b protein, has been shown to reduce binding to several ligands and to alter Mac-1-mediated cellular response in vitro. Importantly, however, the potential contribution of this SNP variant to the initiation and/or progression of immune and inflammatory processes in vivo remains unexplored. Herein, we describe for the first time the generation and characterization of a mouse line expressing the 77His variant of CD11b. Surprisingly, we found that 77His did not significantly affect Mac-1-mediated leukocyte migration and activation as assessed using thioglycollate-induced peritonitis and LPS/TNF-α-induced dermal inflammation models. In contrast, expression of this variant did alter T cell immunity, as evidenced by significantly reduced proliferation of ovalbumin (OVA)-specific transgenic T cells in 77His mice immunized with OVA. Reduced antigen-specific T cell proliferation was also observed when either 77His splenic dendritic cells (DCs) or bone marrow-derived DCs were used as antigen-presenting cells (APCs). Although more work is necessary to determine how this alteration might influence the development of SLE or other diseases, these in vivo findings suggest that the 77His variant of CD11b can compromise the ability of DCs to induce antigen-driven T cell proliferation.


Interleukin-6 and cytokine release syndrome: A new understanding in drug hypersensitivity reactions.
Immediate drug hypersensitivity reactions (DHRs) are historically thought to be because of immunoglobulin E (IgE) cross-linking, causing mast cell degranulation and release of mediators like tryptase and histamine. With the increasing use of monoclonal antibodies, it has become apparent that some patients present atypical features during immediate DHRs, including occurrence in initial exposure, a lack of urticaria and angioedema, and the presence of fever, chills, rigors and musculoskeletal pain as the predominant symptoms. This observation led to the recognition of a novel phenotype of immediate DHRs called cytokine release syndrome (CRS). Other types of immediate DHRs include infusion-related reactions (which present similarly to CRS), and mixed reactions (which share overlapping features of both type 1 reactions and CRS). Desensitization to culprit drugs can be a lifesaving option in patients who develop immediate DHRs to first-line treatment. Whereas robust data are supporting the safety and efficacy of drug desensitization, breakthrough reactions can still occur and CRS seems to be a more common cause than type 1 reactions. Tryptase has been the only available biomarker for immediate DHRs and is associated with type 1 reactions. Emerging evidence consistently found the association between increased serum interleukin 6 level and DHR-related CRS, suggesting that interleukin 6 can be a novel biomarker, in addition to tryptase, to distinguish various types of DHRs. In the era of precision medicine, phenotyping and endotyping hypersensitivity reactions to chemotherapy and monoclonal antibodies using validated biomarkers should be part of routine drug allergy care.


Effects of the rd1 mutation and host strain on hippocampal learning in mice.
Many of the inbred mouse strains commonly used in biomedical research are homozygous for the rd1 mutation of the Pde6b gene, which causes retinal degeneration. To dissociate the behavioural effects of rd1 homozygosity from those of the genetic background of the host strain in the most widely used paradigms for evaluating the cognitive abilities of mice, two rd1 homozygous strains (C3H/HeJ and CBA/J) were compared with two Pde6b wild-type strains, each possessing a genetic background identical (C3A.BLiA-Pde6b+/J) or very similar (CBA/CaJ) to that of its rd1 homozygous relative. In the fear conditioning procedure, the presence of the rd1 mutation had no effect on performance at any stage, as the superior contextual learning of the CBA/J and CBA/CaJ strains could be explained by genetic background effects alone. In the Morris water maze, only the Pde6b wild-type C3A.BLiA-Pde6b+/J and CBA/CaJ strains were able to demonstrate spatial learning. The study thus demonstrates how retinal degeneration and genetic background have different effects in these two tests of hippocampus-dependent learning and memory.


Do conviction narratives drive individual decisions?
Conviction Narrative Theory is an interesting and plausible way to think about how individuals make decisions when quantitative assessments are not open to them. The question I pose is the following. Is there any general result about how decisions should be taken independent of the particular circumstances of that decision?


Year-round changes in tropospheric nitrogen dioxide caused by COVID-19 in China using satellite observation.
The lockdown policy deals a severe blow to the economy and greatly reduces the nitrogen oxides (NOx) emission in China when the coronavirus 2019 spreads widely in early 2020. Here we use satellite observations from Tropospheric Monitoring Instrument to study the year-round variation of the nitrogen dioxide (NO2) tropospheric vertical column density (TVCD) in 2020. The NO2 TVCD reveals a sharp drop, followed by small fluctuations and then a strong rebound when compared to 2019. By the end of 2020, the annual average NO2 TVCD declines by only 3.4% in China mainland, much less than the reduction of 24.1% in the lockdown period. On the basis of quantitative analysis, we find the rebound of NO2 TVCD is mainly caused by the rapid recovery of economy especially in the fourth quarter, when contribution of industry and power plant on NO2 TVCD continues to rise. This revenge bounce of NO2 indicates the emission reduction of NOx in lockdown period is basically offset by the recovery of economy, revealing the fact that China's economic development and NOx emissions are still not decoupled. More efforts are still required to stimulate low-pollution development.


Lymphocyte development in fetal piglets: facts and surprises.
The developing porcine fetus offers an excellent opportunity for the study of lymphocyte development. Studies on B cell, alphabeta T cells and gammadelta T cells in the last decade have expanded our knowledge of lymphocyte development in pigs. These studies have revealed several interesting differences between swine, mice and humans. For example, porcine peripheral lymphocytes include CD4+CD8+ alphabeta T cells and an abundance of gammadelta T cells that may even prevail over the alphabeta population. There are numerous CD2- gammadelta T cells in the blood and a large number of CD8alphaalpha-bearing cells that include NK cells, conventional gammadelta and alphabeta T cells. All porcine B lymphocytes are CD25(lo) and sIgM+ B cells may differ in the expression of CD2 antigen. Unlike mice, porcine B cells appear approximately 2 weeks before T cells and progenitors undergo VDJH rearrangement at 20th day of gestation (DG20) in the yolk sac and DG30 in the fetal liver before consummating high level lymphogenesis in the bone marrow after DG45. Early B cells show an unexpectedly high proportion of in-frame rearrangements, undergo switch recombination in thymus on DG60 and use N-region insertion from the time of the earliest VDJ rearrangement. The genomic repertoire of VH, DH and JH genes is small compared to mice and humans and swine appear to depend on junctional diversity for the majority of their repertoire. The limited VH repertoire of swine contrasts sharply with the porcine TCRbeta repertoire, which is extensive, extraordinarily conserved and nearly identical to that in humans. Therefore, swine present an example of two highly related receptor systems that have diverged in the same species.


Synthesis of New Bis(pyrazolo[1,5-a]pyrimidines) Linked to Different Spacers as Potential MurB Inhibitors.
An efficient protocol was adopted to efficiently prepare three new series of bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers. The new bis(pyrazolo[1,5-a]pyrimidines) were prepared in 80-90 % yields by reacting the respective bis(enaminones) and 4-(4-substituted benzyl)-1H-pyrazole-3,5-diamines in pyridine at reflux temperature for 5-7 h. The new products showed a wide spectrum of antibacterial activity against six different bacterial strains. In general, propane- and butane-linked bis(pyrazolo[1,5-a]pyrimidines), which are attached to 3-(4-methyl- or 4-methoxybenzyl) units, had the best antibacterial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values up to 2.5 and 5.1 μM, respectively. Additionally, the previous products demonstrated promising MurB inhibitory activity with IC50 values up to 7.2 μM.


The Know-Do Gap: Understanding and Improving Service Quality Among Pharmacies Providing Injectable Contraceptives Through a Mystery Client Study in Nepal.
Nepal is one of the first countries to license pharmacists to administer injectable contraceptives, through Nepal CRS Company's (CRS) Sangini private pharmacy network. There are more than 3,400 Sangini pharmacies in Nepal, including in hard-to-reach mountain areas, where these outlets are a key access point to injectables and other short-acting methods for those who lack access through the public sector or prefer the private sector.We compared the performance of Sangini pharmacists in (1) CRS-led technical support visits, when providers were aware of being observed, and (2) mystery client visits, when providers were not aware of being observed, to assess any gaps between pharmacists' knowledge and practices. We also assessed how well Sangini providers counseled on injectables and compared counseling on injectables with counseling for oral contraceptives.We found high levels of adherence to training guidelines on counseling on injectables. However, we identified significant differences between pharmacists' understanding of what they should do and what they actually do in practice, referred to as the know-do gap, in providing privacy, assessing client needs, and determining medical eligibility for hormonal methods. CRS took several steps to narrow the know-do gap through its programming, which may be a useful example for other countries as they expand the role of pharmacies in family planning service provision. Despite highlighting several areas for improvement, the findings show that Sangini providers both know how to and practice appropriate counseling on both injectable and oral contraceptives, suggesting that pharmacists can successfully expand their family planning offerings and equip clients with the information needed to select an appropriate method of their choice.


Quantal analysis of suppressing action of baclofen on mossy fiber synapses in guinea pig hippocampus.
Baclofen, a selective agonist at the gamma-aminobutyric acidB (GABAB) receptor, has been considered to reduce the release of transmitter from nerve terminals by acting on presynaptic GABAB receptors, in addition to its postsynaptic action. The purpose of this study has been to re-examine quantitatively the action of baclofen in the hippocampus by a rigorous quantal analysis. (+/-)-Baclofen suppressed field potentials and intracellularly-recorded synaptic potentials induced in the subfield CA3 by mossy fiber stimulation in thin transverse sections of the guinea pig hippocampus. The amplitude distribution of excitatory postsynaptic potentials (EPSPs) induced monosynaptically by a granule cell could be described by the Pascal statistics. Suppression of the unitary EPSPs by baclofen (1 and 5 microM) was accompanied by decreases both in mean quantal content (m) and by mean quantal amplitude (q). The reduction in q was smaller than expected from a decrease in the input resistance of the postsynaptic neuron. It was suggested that the presynaptic and postsynaptic actions of baclofen contribute almost equally to suppression of the transmission at 1 microM, whereas the presynaptic action predominates at 5 microM.


Association Between Statin Use and Inflammatory Bowel Diseases: Results from a Swedish, Nationwide, Population-based Case-control Study.
In addition to their potent lipid-lowering action, statins may modulate inflammation. However, data on statin use and the risk of inflammatory bowel diseases [IBD] have been inconsistent. We searched the Nationwide Swedish Patient Register [inpatient and non-primary outpatient care] to identify adults diagnosed with Crohn's disease [CD, n = 7637] or ulcerative colitis [UC, n = 15 652] from 2006 to 2014. Each case was matched to 10 general population controls [n = 232 890]. Data on dispensed statin prescriptions were extracted from the Prescribed Drug Register. Conditional logistic regression models estimated odds ratios [ORs] for risk of IBD according to statin exposure while controlling for potential confounders, including indications for statin therapy. In multivariable adjusted models, compared with no statin use, any statin use was associated with a lower risk of CD (OR = 0.71; 95% confidence interval [CI], 0.63-0.79), but not UC [OR = 1.03; 95% CI, 0.96-1.11]. The lowest OR for CD was seen for current statin use [OR = 0.67; 95% CI, 0.60-0.75]. For CD, the lowest category of cumulative statin dose [31-325 defined daily dose, DDD] was associated with an OR of 0.73 [95% CI, 0.61-0.88] and the highest category [>1500 DDD] with an OR of 0.66 [95% CI, 0.55-0.80], ptrend = 0.10. For UC, the lowest and highest dose categories yielded ORs of 1.12 [95% CI, 1.00-1.25] and 0.99 [95% CI, 0.88-1.13], respectively, ptrend = 0.13. Statin use was associated with a lower risk of CD, but not of UC. The association with CD risk appeared strongest for current statin use. Our findings suggest that statin use may influence the development of CD.


Lateral habenula neurons signal step-by-step changes of reward prediction.
In real life, multiple objects of different values are mixed in a variety of environments. To survive, animals need to find rewarding objects that may be located but hidden in particular contexts (e.g., environments) with bad objects that are unassociated with reward. Then, animals and humans pay attention to the enriched environment so that they can find the rewarding object vigorously. How can the brain initiate such behavior based on the context? We thus created a behavioral task for monkeys in which multiple contextual events (environment, action cue) sequentially occurred before objects appeared. We then studied the lateral habenula (LHb), which inhibit dopamine neurons (Matsumoto and Hikosaka, 2007). LHb neurons showed phasic responses in each event step-by-step across the sequential events, whose direction (excitation or inhibition) corresponded to the immediate change of the predicted value. Moreover, LHb neurons sequentially compared detailed prediction errors based on their significance in multiple contexts.


Poor sleep quality and physical performance in older adults.
This study aimed to examine the association between sleep quality and physical performance among a group of UK community-dwelling older adults, according to sex. Sleep quality was assessed using the Pittsburgh Sleep Quality Index. Physical performance was assessed using a short physical performance battery (SPPB), a timed up-and-go, and a hand-grip strength test. Of 591 eligible study members, 401 completed the Pittsburgh Sleep Quality Index. In regression analyses, men who reported poor sleep quality were significantly more likely to have a poor SPPB score, even after adjustment for confounding factors (OR = 2.54, 95% CI 1.10-5.89, P= .03). The direction of the relationship was reversed among women, where those who reported poor sleep were less likely to have a low SPPB score (OR = 0.36, 95% CI 0.15-0.85, P = .02). Poor sleep quality was associated with poorer hand-grip strength among women (regression coefficient = -0.34 z score, 95% CI -0.64, -0.04, P = .03), but this relationship was not observed among men (regression coefficient = 0.28 z score, 95% CI -0.01, 0.57, P = .06). We found evidence of an association between poor sleep quality and poorer physical performance in older adults, though there appear to be important sex differences.


Percutaneous Fine-Needle 5% Ethanol-Cisplatin Intratumoral Injection Combined with Second-Line Chemotherapy Improves On the Standard of Care in Patients with Platinum-Pretreated Stage IV Non-Small Cell Lung Cancer.
Efficacy of second-line chemotherapy in platinum-pretreated non-small cell lung cancer (NSCLC) is poor. This study investigated efficacy of computed tomography-guided percutaneous fine-needle 5% ethanol-cisplatin intratumoral injection (CT-PFNECII) combined with second-line chemotherapy in patients with platinum-pretreated stage IV NSCLC. Between October 2011 and July 2013, 34 eligible patients were randomly assigned to receive either CT-PFNECII combined with second-line chemotherapy (combination group, n = 17) or second-line chemotherapy alone (chemotherapy group, n = 17). The primary end points were the proportions of patients who achieved an overall response rate (ORR) and disease control rate (DCR). Secondary end points were median survival and progression-free survival (PFS). The ORR and DCR in the combination group were significantly higher than in the chemotherapy group (23.53% vs 11.76% for ORR, P < .01; and 58.82% vs 35.29% for DCR, P < .01). Compared with patients in the chemotherapy group, patients in the combination group had significantly longer PFS (5.4 months vs 3.0 months, P < .01) and median survival (9.5 months vs 5.3 months, P < .01). CT-PFNECII combined with second-line chemotherapy provided a higher response rate and improved survival than second-line chemotherapy for patients with platinum-pretreated stage IV NSCLC.


Heterotopic ossification in a throwing athlete after elbow arthroscopy.
A case of heterotopic ossification occurring after elbow arthroscopy in a young, healthy, throwing athlete is reported. The heterotopic bone caused a loss of motion post-arthroscopy in the patient and was confirmed with plain radiographs and bone scan. Twenty-two months after elbow arthroscopy, the patient underwent an open excision of the heterotopic bone. He returned to competitive throwing the next season. While this complication is rare after such minimally invasive procedures, this entity should be considered in the differential diagnosis in the throwing athlete who is unable to recover full range of motion after elbow arthroscopy.


Feasibility of a return-sludge nursery concept for mainstream anammox biostimulation: Creating optimal conditions for anammox to recover and grow in a parallel tank.
To overcome limiting anammox activity under sewage treatment conditions, a return-sludge nursery concept is proposed. This concept involves blending sludge reject water treated with partial nitritation with mainstream effluent to increase the temperature, N levels, and electrical conductivity (EC) of the anammox nursery reactor, which sludge periodically passes through the return sludge line of the mainstream system. Various nursery frequencies were tested in two 2.5 L reactors, including 0.5-2 days of nursery treatment per 3.5-14 days of the total operation. Bioreactor experiments showed that nursery increased nitrogen removal rates during mainstream operation by 33-38%. The increased anammox activity can be partly (35-60%) explained by higher temperatures. Elevated EC, higher nitrogen concentrations, and a putative synergy and/or unknown factor were responsible for 15-16%, 12-14%, and 10-36%, respectively. A relatively stable microbial community was observed, dominated by a "Candidatus Brocadia" member. This new concept boosted activity and sludge growth, which may facilitate mainstream anammox implementations based on partial nitritation/anammox or partial nitrification/denitratation/anammox.


Urate hydroperoxide oxidizes endothelial cell surface protein disulfide isomerase-A1 and impairs adherence.
Extracellular surface protein disulfide isomerase-A1 (PDI) is involved in platelet aggregation, thrombus formation and vascular remodeling. PDI performs redox exchange with client proteins and, hence, its oxidation by extracellular molecules might alter protein function and cell response. In this study, we investigated PDI oxidation by urate hydroperoxide, a newly-described oxidant that is generated through uric acid oxidation by peroxidases, with a putative role in vascular inflammation. Amino acids specificity and kinetics of PDI oxidation by urate hydroperoxide was evaluated by LC-MS/MS and by stopped-flow. Oxidation of cell surface PDI and other thiol-proteins from HUVECs was identified using impermeable alkylating reagents. Oxidation of intracellular GSH and GSSG was evaluated with specific LC-MS/MS techniques. Cell adherence, detachment and viability were assessed using crystal violet staining, cellular microscopy and LDH activity, respectively. Urate hydroperoxide specifically oxidized cysteine residues from catalytic sites of recombinant PDI with a rate constant of 6 × 103 M-1 s-1. Incubation of HUVECs with urate hydroperoxide led to oxidation of cell surface PDI and other unidentified cell surface thiol-proteins. Cell adherence to fibronectin coated plates was impaired by urate hydroperoxide, as well as by other oxidants, thiol alkylating agents and PDI inhibitors. Urate hydroperoxide did not affect cell viability but significantly decreased GSH/GSSG ratio. Our results demonstrated that urate hydroperoxide affects thiol-oxidation of PDI and other cell surface proteins, impairing cellular adherence. These findings could contribute to a better understanding of the mechanism by which uric acid affects endothelial cell function and vascular homeostasis.


Regioselective synthesis and molecular docking studies of functionalized imidazo [1,2-a]pyridine derivatives through MCRs.
A efficient protocol has been developed for the synthesis of regioselective imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives through cascade reaction between 2-aminopyridine, arylelglyoxal, and 4-hydroxypyran via three-component reaction to prepare targeted compounds with good to excellent yields. The advantages of this transformation are a catalyst-free reaction, green solvent, operationally simple, scalable, and eco-friendly. The product collects with simple filtration which avoided tedious and expensive purification techniques. In addition, computational studies like molecular docking were conducted to provide the theoretical possibilities of binding these types of synthesized compounds to the VEGFR2 receptors as potential key inhibitors of tumor cell growth and angiogenesis.


Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes.
Evidence from mice suggests that brain infiltrating immune cells contribute to neurodegeneration, and we previously identified a deleterious lymphocyte infiltration in Parkinson's disease mice. However, this remains controversial for monocytes, due to artifact-prone techniques used to distinguish them from microglia. Our aim was to reassess this open question, by taking advantage of the recent recognition that chemokine receptors CCR2 and CX3CR1 can differentiate between inflammatory monocytes and microglia, enabling to test whether CCR2+ monocytes infiltrate the brain during dopaminergic (DA) neurodegeneration and whether they contribute to neuronal death. This revealed unexpected insights into possible regulation of monocyte-attracting CCL2 induction. We used acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice and assessed monocyte infiltration by combining laser microdissection-guided chemokine RNA profiling of the substantia nigra (SN) with immunohistochemistry and CCR2-GFP reporter mice. To determine contribution to neuronal loss, we used CCR2-deletion and CCL2-overexpression, to reduce and increase CCR2+ monocyte infiltration, and CX3CR1-deletion to assess a potential implication in CCL2 regulation. Nigral chemokine profiling revealed early CCL2/7/12-CCR2 axis induction, suggesting monocyte infiltration in MPTP mice. CCL2 protein showed early peak induction in nigral astrocytes, while CCR2-GFP mice revealed early but limited nigral monocyte infiltration. However, blocking infiltration by CCR2 deletion did not influence DA neuronal loss. In contrast, transgenic astrocytic CCL2 over-induction increased CCR2+ monocyte infiltration and DA neuronal loss in MPTP mice. Surprisingly, CCL2 over-induction was also detected in MPTP intoxicated CX3CR1-deleted mice, which are known to present increased DA neuronal loss. Importantly, CX3CR1/CCL2 double-deletion suggested that increased neurotoxicity was driven by astrocytic CCL2 over-induction. We show that CCR2+ monocytes infiltrate the affected CNS, but at the level observed in acute MPTP mice, this does not contribute to DA neuronal loss. In contrast, the underlying astrocytic CCL2 induction seemed to be tightly controled, as already moderate CCL2 over-induction led to increased neurotoxicity in MPTP mice, likely due to the increased CCR2+ monocyte infiltration. Importantly, we found evidence suggesting that during DA neurodegeneration, this control was mediated by microglial CX3CR1 signaling, which protects against such neurotoxic CCL2 over-induction by astrocytes, thus hinting at an endogenous mechanism to limit neurotoxic effects of the CCL2-CCR2 axis.


Complex dynamics in a fractional order nephron pressure and flow regulation model.
Cardiovascular diseases can be attributed to irregular blood pressure, which may be caused by malfunctioning kidneys that regulate blood pressure. Research has identified complex oscillations in the mechanisms used by the kidney to regulate blood pressure. This study uses established physiological knowledge and earlier autoregulation models to derive a fractional order nephron autoregulation model. The dynamical behaviour of the model is analyzed using bifurcation plots, revealing periodic oscillations, chaotic regions, and multistability. A lattice array of the model is used to study collective behaviour and demonstrates the presence of chimeras in the network. A ring network of the fractional order model is also considered, and a diffusion coupling strength is adopted. A basin of synchronization is derived, considering coupling strength, fractional order or number of neighbours as parameters, and measuring the strength of incoherence. Overall, the study provides valuable insights into the complex dynamics of the nephron autoregulation model and its potential implications for cardiovascular diseases.


Do the indices of deprivation or smoking affect post-operative 1-year mortality in patients undergoing a craniotomy for a brain tumour in a public healthcare system?
We sought to determine the 1-year survival following craniotomy for tumour resection in a public healthcare system and analyse the effect of indices of multiple deprivation (IMD) as well as smoking, alcohol, BMI, ASA grade and medical co-morbidities on post-operative morbidity and mortality. This is a retrospective, single-centre study in a high volume neurosurgical centre, over a 2-year period. All patients undergoing a craniotomy for a brain tumour were included. Data was collected from the neuro-oncology database and electronic patient records. Individual patient IMD data was obtained using their postcode from a national government database. Each English postcode being ranked from 1 to 32,844, with 1 being the most deprived and 32,844 the most affluent. Descriptive results are described along with further data analysis using multiple linear and logistic regression analyses. 630 patients underwent an elective or urgent craniotomy for tumour. 10% of all patients underwent urgent surgery. 68% (95% CI: 64 to 71%) survived at least 1-year post-surgery. Our study found that social deprivation (IMD postcode rank) was not associated with mortality at 1 year after adjusting for potential confounding factors. Those from decile 1 had the lowest risk of death at 12 months for all tumour types (p = 0.0070). Previous smokers carried an increased risk of death at 12 months when compared with people who had never smoked RR 1.40 CI 1.10-1.78 (p = 0.006) but this risk was not evident in current smokers RR 0.92 CI 0.65-1.31 (p = 0.64). Increasing age and male gender were also found to be associated with higher mortality at 1 year (p = < 0.001). In the UK despite the discrepancy in the health of the general population between the north and south, social deprivation does not appear to be detrimental to neurooncological outcomes although smoking status, advancing age and male sex are.


The stricter criteria for Class I CRT indication suggested by the 2016 ESC Guidelines reliably exclude patients with a worse prognosis in comparison with the 2013 ESC indication criteria.
The European Society of Cardiology (ESC) Guidelines published in 2016 modified indications for cardiac resynchronization therapy (CRT) in comparison with the 2013 ESC Guidelines. The aim of this analysis was to evaluate the impact of the stricter criteria suggested by the 2016 ESC Guidelines on patient outcome in a real-world population. We collected data on 930 consecutive patients with complete outcome information who had undergone CRT implantation from 2011 to 2013 from the CRT-MORE registry. Patients were classified according to 2013 (Reference) and 2016 (Current) ESC Guidelines. The primary end-point of the study was death from any cause and heart failure hospitalization. According to the Reference Guidelines, 650 (69.9%) patients met Class I indications, 190 (20.4%) Class IIa, 39 (4.2%) Class IIb and 51 (5.5%) Class III. According to the Current Guidelines, 563 (60.5%) patients met Class I indications, 145 (15.6%) Class IIa, 108 (11.6%) Class IIb and 114 (12.3%) Class III. On comparing the Reference and Current Guidelines, the 538 patients who confirmed their Class I indication had a better outcome in terms of freedom from the combined end-point of heart failure (HF) hospitalization or death from any cause (hazard ratio (HR) of 0.64; 95% CI 0.42 to 0.99; p = 0.0436) when compared to the 112 patients who lost their class I indication (84 moved to class IIb and 28 moved to class III). The stricter criteria for Class I CRT indication suggested by the 2016 ESC Guidelines excluded about 20% of patients with a worse prognosis. CRT MORE: Cardiac Resynchronization Therapy Modular Registry URL: http://clinicaltrials.gov/Identifier:NCT01573091.


Evolution of the Hoffmann Fixators.
Dr. Raoul Hoffmann of Geneva, Switzerland with the collaboration of Henri Jaquet developed the original Hoffmann external fixateur as a system for treating broken bones without necessarily opening a fracture site to reposition the bone ends. This system has evolved to a more flexible, modular concept with input from surgeons and engineers. In this chapter the modifications of the Hoffmann family of fixators are traced and the important steps in the development of the concept and the instrumentation emphasized.


Acute hepatitis B virus window-period blood donations detected by individual-donation nucleic acid testing: a report on the first two cases found and interdicted in Spain.
Mathematical models predict that, in Spain, a significant number of blood units will be obtained during the window period of the hepatitis B virus (HBV) infection. Routine nucleic acid testing (NAT) on individual blood units may provide experimental data to evaluate such a theoretical risk. Between February and July 2005, a total of 34,631 individual units were screened for HBV DNA by a multiplex transcription-mediated amplification (TMA) test. Units that repeatedly reacted in the test, but did not react for HBV surface antigen (HBsAg), were submitted to additional testing by both molecular and conventional assays, and the donors were recalled for follow-up studies and the collection of clinical and epidemiologic data. Confirmatory testing and follow-up studies identified 2 blood units donated during the HBV infection window period (1/17,316 units studied). Sequencing of amplification products obtained by nested polymerase chain reaction (n-PCR) revealed two HBV strains from genotypes D/ayw3 and F/adw4q-, but did not identify HBsAg mutants. The HBV DNA concentration in the index donations was estimated to be below the n-PCR detection level (180 IU/mL), in both cases. One donor developed acute hepatitis 2 months after donating blood, but the other remained asymptomatic and displayed normal alanine aminotransferase levels at follow-up. The HBV infection window period is a real issue in the setting of Spanish blood transfusions. NAT of individual units by TMA would make a significant contribution to improving the safety of the blood supply in Spain. Additional studies involving a larger number of units and longer periods of time are required, however, to ascertain the true incidence of the problem in this country.


Frequencies of Combined Dysfunction of Cytochromes P450 2C9, 2C19, and 2D6 in an Italian Cohort: Suggestions for a More Appropriate Medication Prescribing Process.
Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug-drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.


Elucidating the evolutionary relationships of the Aiptasiidae, a widespread cnidarian-dinoflagellate model system (Cnidaria: Anthozoa: Actiniaria: Metridioidea).
Sea anemones of the family Aiptasiidae sensu Grajales and Rodríguez (2014) are conspicuous members of shallow-water environments, including several species widely used as model systems for the study of cnidarian-dinoflagellate symbiosis and coral bleaching. Although previously published phylogenetic studies of sea anemones recovered Aiptasiidae as polyphyletic, they only included a sparse sample in terms of its taxonomic diversity and membership of the family had not been yet revised. This study explores the phylogenetic relationships of this family using five molecular markers and including newly collected material from the geographical distribution of most of the currently described genera and species. We find a monophyletic family Aiptasiidae. All the currently proposed genera were recovered as monophyletic units, a finding also supported by diagnostic morphological characters. Our results confirm Bellactis and Laviactis as members of Aiptasiidae, also in agreement with previous morphological studies. The monophyly of the group is congruent with the morphological homogeneity of the members of this family. The obtained results also allow discussing the evolution of morphological characters within the family. Furthermore, we find evidence for and describe a new cryptic species, Exaiptasia brasiliensis sp. nov., based on molecular data, geographical distribution, and the identity of its endosymbiotic dinoflagellate.


Value of positron emission tomography in diagnosing synchronous penile metastasis from urothelial bladder cancer.
Metastases to the penis are extremely rare events. Most frequently, penile metastases come from the urogenital system (bladder, prostate) or the rectum-sigmoid colon. Usually painful, penile lesions may be asymptomatic, making diagnosis more challenging. Hence, we report the adding value of (18)F-fludeoxyglucose-positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the detection of penile metastases originating from urothelial carcinoma of the bladder. Arguably, penile metastases must be considered as an advanced disease requiring essentially palliative care. Therefore, accurate staging of clinically localized muscle-invasive bladder cancer is crucial to avoid useless curative intent radical surgery.


Development of forensic medicine in Rwanda- past, present, and future perspectives.
The Republic of Rwanda is a landlocked country with more than 12.6 million people. Similar to other nations in Africa, Rwanda is still developing its forensic medicine capabilities. This paper attempts to provide a concise history of forensic medicine in Rwanda, as well as a critique of the current state of affairs and recommendations for reform. The Rwanda Investigation Bureau (RIB) investigates any suspicious or unexplained deaths in the country, after which the body is sent to the nearest public hospital for medico-legal autopsy. Except for the Rwanda Forensic Laboratory, which has forensic practitioners with minimal training in forensic medicine, the majority of medical practitioners engaged in medicolegal activities in Rwanda lack forensic medicine training. To standardize medico-legal practices and forensic medicine education in the country, a competent medico-legal authority must be established to host frequent seminars, conferences, and various training programs for both forensic and non-forensic medicine experts.


Toward a Fault Tolerant Architecture for Vital Medical-Based Wearable Computing.
Advancements in computers and electronic technologies have led to the emergence of a new generation of efficient small intelligent systems. The products of such technologies might include Smartphones and wearable devices, which have attracted the attention of medical applications. These products are used less in critical medical applications because of their resource constraint and failure sensitivity. This is due to the fact that without safety considerations, small-integrated hardware will endanger patients' lives. Therefore, proposing some principals is required to construct wearable systems in healthcare so that the existing concerns are dealt with. Accordingly, this paper proposes an architecture for constructing wearable systems in critical medical applications. The proposed architecture is a three-tier one, supporting data flow from body sensors to cloud. The tiers of this architecture include wearable computers, mobile computing, and mobile cloud computing. One of the features of this architecture is its high possible fault tolerance due to the nature of its components. Moreover, the required protocols are presented to coordinate the components of this architecture. Finally, the reliability of this architecture is assessed by simulating the architecture and its components, and other aspects of the proposed architecture are discussed.


Expression of microsomal lanosterol 14alpha-demethylase (CYP51) in an engineered soluble monomeric form.
We prepared a soluble monomeric form of bovine cytochrome P450 lanosterol 14alpha-demethylase (CYP51), which in mammals is a ubiquitously expressed membrane protein of the endoplasmic reticulum. We constructed two variants of bovine CYP51 (bCYP51) with different truncations and modifications in their N-terminal membrane-spanning domains. Both of these were expressed in Escherichia coli at levels of 500nmol/l. The protein variants were purified and tested for the solubility in the absence of detergent. Variant bCYP51-d1 exhibited approximately 10-fold better solubility over variant bCYT51-d2. The bCYP51-d1 eluted as a single peak in size-exclusion chromatography, corresponding to its monomeric form. The activity of bCYP51-d1 is similar to that of recombinant human CYP51 with a non-truncated membrane-spanning region. High solubility and low tendency to non-specific oligomer formation make bCYP51-d1 a promising candidate for successful crystallization, which may finally allow the structural determination of this important mammalian enzyme.


Pilot of a therapist-guided digital mental health intervention (eHealth CF-CBT) for adults with cystic fibrosis.
eHealth CF-CBT is the first digital mental health intervention for depression/anxiety in adults with cystic fibrosis (awCF); an 8-session therapist-guided internet-delivered program that was developed in English and Dutch with stakeholder input and evaluation indicating high acceptability and usability. Dutch eHealth CF-CBT was piloted in awCF with mild-moderate symptoms of depression and/or anxiety. Feasibility, usability, acceptability, and preliminary efficacy were assessed, measuring pre-post changes in depression (PHQ-9), anxiety (GAD-7), perceived stress (PSS), and health-related quality of life (CFQ-R). All participants (n = 10, seven female, mean age 29 [range 21-43], mean FEV1 71%pred [range 31-115]) completed all sessions. Patient-rated feasibility, usability, and acceptability of eHealth CF-CBT were positive on validated scales, as were qualitative assessments of content and format. GAD-7 improved in 90% of participants; in 50% by ≥the minimally important difference (MID) of four points. PHQ-9 improved in 90%; 40% by ≥the MID of 5. PSS improved in 80%. CFQ-R improved in the domain health perceptions (70%). eHealth CF-CBT demonstrated feasibility, usability, acceptability, and promising preliminary efficacy in this pilot trial with Dutch awCF with mild to moderate symptoms of depression and anxiety.


[Clinico-morphologic aspects of the combined treatment of locally disseminated cancer of the rectum].
In 1174 patients, the pathomorphosis of rectal cancer conditioned by the combined treatment with preoperative irradiation was studied. Preoperative radiotherapy caused considerable disorders in the morphologic structure of a tumour. The survival of patients and incidence of tumour recurrences, depending on the pronouncement of morphologic changes after radiotherapy, were studied. The use of radiation modifiers in combination with radiotherapy facilitated more pronounced damage to the tumour.


Evaluation of the efficacy, safety, and clinically recommended dose of dienogest in the treatment of primary dysmenorrhea: a randomized, double-blind, multicenter, placebo-controlled study.
To evaluate the efficacy, safety, and clinically recommended dose of dienogest (DNG; 0.5 mg/d, 1 mg/d, and 2 mg/d) in the treatment of primary dysmenorrhea. A phase II, randomized, double-blind, multicenter, placebo-controlled study. Twenty study sites. A total of 235 patients with primary dysmenorrhea. Patients were randomized to receive orally a placebo, DNG (0.5 mg/d, 1 mg/d, or 2 mg/d) or ethinylestradiol 0.02 mg/drospirenone 3 mg (an open-label reference drug) for 12 weeks. The primary endpoint was the change from baseline in the dysmenorrhea score at week 12 of treatment. The secondary endpoint was the change from baseline in the visual analogue scale at week 12 of treatment. Subjects were assessed for lower abdominal pain and/or low back pain. All DNG arms were superior to the placebo arm in terms of the change from baseline in the dysmenorrhea score. The results suggest an equal or greater effect of DNG 1 and 2 mg/d in relieving pain, when compared to the reference drug. In the safety profile of DNG, including irregular uterine bleeding, there was no obvious difference among the doses of DNG. A significant decrease in the serum estradiol concentration compared to that in the placebo arm was not observed in the DNG 1 mg/d arm but was observed in the DNG 2 mg/d arm. The results suggest that DNG at a dose of 1 mg/d is an effective and well-tolerated treatment for primary dysmenorrhea. JapicCTI-152977 (en).


Androstadienetrione, a boldenone-like component, detected in cattle faeces with GC-MS(n) and LC-MS(n).
Boldenone (1,4-androstadiene-17-ol-3-one, Bol) has been the subject of a heated debate because of ongoing confusion about its endogenous or exogenous origin when detected in one of its forms in faecal or urine samples from cattle. An expert report was recently written on the presence and metabolism of Bol in various animal species. Androstadienedione (ADD) is a direct precursor of 17beta-boldenone (betaBol). It is a 3,17-dione; ssBol is a 17-ol-3-one. Not much is published on 1,4-androstadiene-3,17-diol, which is a 3,17-diol (ADL). If animals were exposed for a longer period to one of these analytes, a metabolic pathway would be initiated to eliminate these compounds. Similar to recent testosterone metabolism studies in the aquatic invertebrate Neomysis integer, ADD, ssBol and ADL could also be eliminated as hydroxymetabolites after exposure. The presence of 11-keto-steroids or 11-hydroxy-metabolites in faecal samples can interfere with a confirmation method by gas chromatography-negative chemical ionization mass spectrometry (GC-NCI-MS), after oxidation of corticosteroids with a double bond in the A-ring (e.g. prednisolone or its metabolite prednisone). The presence of androstadienetrione (ADT) in faecal samples of cattle has never been reported. The origin of its presence can be explained through different pathways, which are presented in this paper.


Automated method for the measurement of fentanyl-induced muscular rigidity.
An automated method is described that can accurately and reliably measure weight displacement resulting from hindlimb extension due to muscular rigidity following opioid administration in rats. IV administration of fentanyl (0.035 mg/kg) immediately induced rigidity. Rigidity was dose dependently reversed by the alpha 2-agonist clonidine with an ED50 value equal to 0.011 mg/kg IV. Second, rigidity was restored following administration of the alpha 2-antagonist idazoxan (0.3 mg/kg, IV) thereby confirming an alpha 2-mediated mechanism of action. Previously, reversal of fentanyl-induced muscular rigidity was measured by subjective rating criteria not suitable for quantitative potency comparisons. The new automated rigidity model provides a simple yet precise measurement of the ability of alpha 2-agonists to attenuate opioid-induced muscular rigidity in rats.


Sperm segregation analysis of a complex chromosome rearrangement, 2;22;11, by whole chromosome painting.
Using the human sperm-hamster oocyte fusion technique and whole chromosome painting, we studied sperm chromosome segregation in a male heterozygous for a complex chromosome rearrangement, 46,XY,-2, +der(2)t(2;11)(q13; q23),-11,+der(11)t(11;22)(q23;q11.2),-22, +der(22)t(2;22)(q13; q11.2). A total of 208 sperm complements were analyzed. The frequency of sperm carrying a normal or a balanced complement was 13.5% (9.62% and 3.85%, respectively). The frequency of unbalanced sperm was 86.5% (64.9% from 3:3 segregation, including 30 different types; 20.7% from 4:2 segregation, including 21 different types; and 0.96% from 5:1 segregation, including 2 different types). The sex ratio, determined in 134 sperm complements, did not differ from the expected 1:1 ratio. The results obtained in this study are compatible with the formation, during the synaptic process, of a complex hexavalent figure involving chromosomes 2, 11, and 22. The behavior and segregation of this complex figure would explain the high frequency (86.5%) of unbalanced complements observed in this carrier.


Preparation and evaluation of dual-enzyme microreactor with co-immobilized trypsin and chymotrypsin.
The preparation of capillary microfluidic reactor with co-immobilized trypsin and chymotrypsin with the use of a low-cost commercially available enzymatic reagent (containing these proteases) as well as the evaluation of its usefulness in proteomic research were presented. The monolithic copolymer synthesized from glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EDMA) was used as a support. Firstly, the polymerization conditions were optimized and the monolithic bed was synthesized in the fused silica capillary modified with 3-(trimethoxysilyl)propyl methacrylate (γ-MAPS). The polymer containing epoxy groups was then modified with 1,6-diaminohexane, followed by the attachment of glutaraldehyde and immobilization of enzymes. The efficiency of the prepared monolithic Immobilized Enzyme Microreactor (μ-IMER) with regard to trypsin activity was evaluated using the low-molecular mass compound (Nα-benzoyl-l-arginine ethyl ester, BAEE). The activities of both enzymes were investigated using a macromolecular protein (human transferrin, Tf) as a substrate. In the case of BAEE, the reaction product was separated from the substrate using the capillary liquid chromatography and the efficiency of the reaction was determined by the peak area of the substrate. The hydrolysis products of transferrin were analyzed with MALDI-TOF which allows for the verification of the prepared enzymatic system applicability in the field of proteomic research.


Improving the impact of didactic resident training with online spaced education.
Educational programmes are frequently developed to improve the knowledge of medical trainees. The impact of a programme may be limited if there is no follow-up to reinforce the message. Online Spaced Education (SE) has been developed to address this limitation. This study was performed to assess whether an SE programme would improve the impact of a didactic seminar. A randomized trial of an online SE programme occurred as part of the 2010 Clinical Oncology Society of Australia Breast Cancer Trainee Workshop. Consenting participants were randomized to undertake SE or not and were then invited to undertake a 22-question knowledge test. A questionnaire was administered relating to the perceived value of the SE programme. Participants consisted largely of surgical and medical oncology trainees. Two hundred people attended the workshop and 97 consented to randomization. Thirty-eight of 49 randomized to the SE group commenced the SE course. Seventy-one percent of participants answered each question at least once and 55% of participants completed the entire programme. Fifty-nine participants completed the post-test. The SE participants performed significantly better than the control group (P < 0.05). The questionnaire was completed by 26 of the SE group. Ninety-two percent strongly agreed or agreed that SE would improve their practice and 96% agreed that SE effectively reinforced key aspects of workshop. This study demonstrates the utility of SE to increase knowledge retention following a face-to-face workshop. The programme was very well received by the participants and may be an appropriate reinforcing methodology for other similar seminars.


Qualitative and quantitative reversed-phase high performance liquid chromatographic analysis of glycoprotein hormones in the presence of a large excess of human serum albumin.
The present work describes reversed-phase high performance liquid chromatographic methodologies (RP-HPLC) for the qualitative and quantitative analysis of the human glycoprotein hormones thyrotropin (hTSH), follitropin (hFSH), choriogonadotropin (hCG) and lutropin (hLH) in the presence of a large excess (up to 250:1) of human serum albumin (HSA). Chromatographic profiles with a good separation between the hormone and HSA were obtained by using a C4 column and specific gradient elution conditions for each hormone. Parameters such as resolution factor, tailing factor and relative retention time, were determined, and are useful for the evaluation of the quality of the separation obtained between the active pharmaceutical ingredient and the excipient present in the final formulation. The potential of each method for quantification of both HSA and the hormone was also demonstrated. Besides furnishing chromatographic quantifications that can substitute for in vivo bioassays and animal use, the chromatograms also provide a direct panorama of the quality and heterogeneity of the protein of interest.


[Management of thromboembolic risk in patients with cancer].
Venous thromboembolism is a frequent complication in cancer patients and affects their morbidity and mortality. The risk of this event differs according to the characteristics of the tumor, the patient's circumstances, and the treatments provided. Although the benefits of thromboprophylaxis in certain subgroups of patients with cancer have been demonstrated, currently generic prescription is not recommended unless other risk factors are present, or the patient has multiple myeloma and has been treated with thalidomide or lenalidomide. The insertion of a central venous catheter in these patients does not imply prescription of thromboprophylaxis, although the risk factors for catheter thrombosis are known. Finally, a risk scoring model for the prediction of venous thromboembolism has been defined in outpatients with cancer starting chemotherapy, which has been externally validated and supplemented with the addition of two biomarkers.


Inflammatory mediator patterns in tracheal aspirate and their association with bronchopulmonary dysplasia in very low birth weight neonates.
Alterations in inflammatory mediators are an important finding in neonates who develop bronchopulmonary dysplasia (BPD); however, there is a lack of research examining the relationship between multiple inflammatory mediators in premature neonates and the development of BPD. This study investigated whether the distribution of 12 inflammatory mediators detected in the tracheal aspirate (TA) of neonates within 24 h of birth could differentiate between neonates who did and who did not develop BPD. TA samples were collected from 27 very low birth weight neonates (BPD+=11), and the concentrations of 12 biomarkers associated with BPD were determined. Linear discriminant analysis (LDA) was used to classify neonates into two outcome groups. LDA based on the 12 measured biomarkers displayed a significant level of discriminant function (P=0.007). Using linear discriminant analysis, predictive models of BPD can be generated. Our results suggest that multiple inflammatory mediators collected within 24 h of birth may be used to classify neonates into who will and who will not develop BPD.


Bibliometric analysis of research trends in stem cell therapy for knee osteoarthritis over the period 2001-2021.
Stem cell therapy is a promising treatment for knee osteoarthritis, but few bibliometric studies have been performed on the subject. Bibliometric analysis is helpful for identifying the most influential studies in a specific field and can evaluate the global research trends in stem cell therapy for knee osteoarthritis. The Web of Science Core Collection was searched for publications from 2001 to 2021. Publication performance was analyzed using several bibliometric parameters, including VOSviewer, to identify the research landscape of trends in topics, and CiteSpace was investigated to identify the keywords that have the strongest citation bursts. From 2001 to 2021, in total, 1,345 publications explored the research on stem cells in knee osteoarthritis. The United States contributed the largest number of publications and at the top list of international collaborations. Tokyo Medical and Dental University ranked first among institutions in the overall number of articles and citations. The journal of Osteoarthritis and Cartilage had the largest number of publications. Sekiya Ichiro was the most cited author, with 32 articles. The keywords with the most frequent occurrence were "osteoarthritis," "mesenchymal stem cells," and "cartilage," in descending order of frequency. "fibroblast growth factor" and "extracellular vesicle" were the first and last searched theme terms, respectively. The number of publications on stem cells for knee osteoarthritis stays growing. Cartilage repair and paracrine function are current research hotspots for the stem cell therapy mechanism. Stem cell therapy has gradually advanced from basic research to the clinical application stage.


[Causes and management of gingival coloration caused by metal ceramic crows].
To analyse the marginal gingival coloration caused by metal based ceramic crowns in 28 patients,and to explore the methods to remove or reduce this abnormal coloration. 28 patients with metal based ceramic crowns developed gingival coforation. The period of wearing crowns ranged from 2 weeks to 3 years. To remove or reduce gingival coloration,the original metal based ceramic crowns were discarded. Temporary plastic crowns were utilized for 2 weeks. The cervical ceramic approach was used for rehabilitation,or the abutments were re-prepared for metal based ceramic crowns. At the end of follow up,gingival coloration disappeared in patients managed with cervical ceramic approach. While in patients managed with second metal crowns, gingival coloration was improved greatly. Gingiral coloration can be removed or reduced by cervical ceramic approach or re-fabrication of metal based ceramic crowns.


MicroRNA-18a regulates invasive meningiomas via hypoxia-inducible factor-1α.
The aim of the present study was to investigate the effects of microRNA-18a (miR-18a) on the invasiveness and metastasis of invasive meningiomas and the underlying mechanism. A total of 69 patients with meningiomas (30 patients in the invasive meningioma group and 39 patients in the non-invasive meningioma group) and 48 cases in the control group were enrolled. Samples of meningioma tissues, serum and cerebrospinal fluid were collected. Reverse transcription-quantitative polymerase chain reaction was performed to quantify the expression levels of hypoxia-inducible factor-1α (HIF-1α) mRNA and miR-18a. Western blot analysis was used to determine protein expression levels of HIF-1α. The expression levels of HIF-1α mRNA and protein in all three types of sample from the invasive meningioma group were significantly higher compared with those in the control and non-invasive meningioma groups (P<0.05), and the expression levels of HIF-1α mRNA in the serum and cerebrospinal fluid of the non-invasive meningioma group were significantly higher compared with those in the control group (P<0.05). The expression levels of miR-18a in the invasive meningioma group were significantly reduced compared with those in the control and non-invasive meningioma groups (P<0.05), whereas the levels of miR-18a in the non-invasive meningioma group were significantly lower compared with those in the control group (P<0.05). The expression of HIF-1α is significantly upregulated in patients with invasive meningiomas, possibly due to the downregulation of miR-18a expression. Therefore, miR-18a may regulate invasive meningiomas via HIF-1α.


The proportion of HIV disclosure to sexual partners among people diagnosed with HIV in China: A systematic review and meta-analysis.
Sexual behavior is one of the main routes of HIV/AIDS spread. HIV disclosure to sexual partners has been confirmed to be an important strategy for HIV/AIDS prevention and control. We conducted a systematic review and meta-analysis to pool proportions and characteristics of HIV disclosure to sexual partners among people diagnosed with HIV in China. We searched eight databases and extracted the data on HIV disclosure to partners. Heterogeneity of the data was tested with I 2. Published bias subjectively and objectively analyzed through the funnel plot and Egger's regression test. Subgroup analyses were performed to explore the variation in the proportion by sexual partnership types (unclassified, regular, casual sexual partners), whether being men who have sex with men (MSM), and when to diagnose. The sources of heterogeneity were analyzed. Sensitivity analysis was carried out to evaluate the stability of the results. Out of 3,698 studies, 44 were included in the review; 11 targeted on MSM. The pooled proportion of HIV disclosure to sexual partners was 65% (95% CI: 56%-75%; 34 studies). Sub-group analyses indicated the proportions of HIV disclosure to regular, casual and unclassified sexual partners were 63% (95% CI: 45%-81%; 31 studies), 20% (95% CI: 8%-33%; nine studies), and 66% (95% CI: 59%-73%; 14 studies), respectively. Fifty-seven percent (95% CI: 45%-69%; three studies) disclosed on the day of diagnosis, 62% (95% CI: 42%-82%; four studies) disclosed within 1 month, and 39% (95% CI: 2%-77%; four studies) disclosed 1 month later. Among MSM, the disclosure to regular male partners, regular female sexual partners, spouses, and casual partner were 47% (95% CI: 29%-65%; six studies), 49% (95% CI: 33%-65%; three studies), 48% (95% CI: 18%-78%; seven studies), and 34% (95% CI: 19%-49%; four studies), respectively. The disclosure prevalence of people diagnosed with HIV to sexual partners still need improving in China, and it varies among partner types, key populations, and time being diagnosed. HIV disclosure strategies and procedures need to be developed more detailed and tailored based on the pain points of disclosure status, so as to ultimately prevent HIV transmission through sexual contact. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022291631, identifier: CRD42022291631.


Trispiral tomography for the evaluation of wrist problems.
Trispiral tomography is an x-ray technique that is essential in the diagnosis and management of a wide variety of problems involving the carpal bones and their joints. It facilitates the visualization of acute fractures, particularly those of the scaphoid and hook of the hamate, as well as cysts, sclerosis, and erosive lesions. It is useful in differentiating between acute and chronic changes, and it is often indispensable in evaluating healing after acute fractures or bone grafts to treat nonunions.


Locomotor velocity and striatal adaptive gene expression changes of the direct and indirect pathways in Parkinsonian rats.
In Parkinson's disease (PD), bradykinesia, or slowness of movement, only appears after a large striatal dopamine depletion. Compensatory mechanisms probably play a role in this delayed appearance of symptoms. Our hypothesis is that the striatal direct and indirect pathways participate in these compensatory mechanisms. We used the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD and control animals. Four weeks after the lesion, the spontaneous locomotor activity of the rats was measured and then the animals were killed and their brain extracted. We quantified the mRNA expression of markers of the striatal direct and indirect pathways as well as the nigral expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH) mRNA. We also carried out an immunohistochemistry for the striatal TH protein expression. As expected, the unilateral 6-OHDA rats presented a tendency to an ipsilateral head turning and a low locomotor velocity. In 6-OHDA rats only, we observed a significant and positive correlation between locomotor velocity and both D1-class dopamine receptor (D1R) (direct pathway) and enkephalin (ENK) (indirect pathway) mRNA in the lesioned striatum, as well as between D1R and ENK mRNA. Our results demonstrate a strong relationship between both direct and indirect pathways and spontaneous locomotor activity in the parkinsonian rat model. We suggest a synergy between both pathways which could play a role in compensatory mechanisms and may contribute to the delayed appearance of bradykinesia in PD.


Trastuzumab in combination with heregulin-activated Her-2 (erbB-2) triggers a receptor-enhanced chemosensitivity effect in the absence of Her-2 overexpression.
The decision for treating breast cancer patients with trastuzumab is based on HER-2 amplification and/or overexpression. Using MCF-7 cells (Her-2 +/-) engineered to overexpress heregulin (MCF-7/HRG), a ligand for the Her-2/3/4 network, we investigated whether HRG-induced transactivation of Her-2 affected breast cancer cell sensitivity to chemotherapy and whether trastuzumab trigger receptor-enhanced chemosensitivity (REC) when combined with chemotherapy without Her-2 overexpression. MCF-7/HRG cells were more than 10-fold resistant to the alkylating agent cisplatin (CDDP), while trastuzumab coexposure completely reversed HRG-promoted CDDP resistance. A synergistic interaction between trastuzumab in combination with CDDP (paclitaxel or vincristine) was obtained in MCF-7/HRG cells. Trastuzumab prevented activation of the antiapoptotic and proliferative cascades and inhibited HRG-induced Her-2/3 phosphorylation. CDDP efficacy was enhanced by trastuzumab in cells expressing endogenously high levels of HRG. Conversely, trastuzumab coexposure was ineffective in enhancing chemotherapy efficacy in cells that did not secrete HRG, such as MCF-7 cells overexpressing a structural mutated HRG isoform. Therefore, trastuzumab-induced REC, in the absence of Her-2 overexpression, occurs through the kinase activity of Her-2/3. Interestingly, HRG expression in tumor biopsies from invasive breast carcinomas (n = 189) revealed that, whereas the minority (12%) of Her-2 positive tumors (n = 60; 32%) demonstrated Her-2 phosphorylation, the majority (67%) of HRG-overexpressing and Her-2 tumors (n = 57; 30%) were in active Her-2 status. We demonstrate that assessment of HRG expression and Her-2 activation define a particular breast cancer patient population for which trastuzumab plus CDDP or taxol are extremely efficient without Her-2 overexpression.