Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1).
The unique proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1) is reported to activate numerous cancer-driving pathways simultaneously, and aberrant Pin1 activation is present in many human cancers. Here, we identified a novel hit compound, ZL-Pin01, that covalently modified Pin1 at Cys113 with an half-maximal inhibitory concentration (IC50) of 1.33 ± 0.07 μM through screening an in-house library. Crystallographic study drove the process of structure-guided optimization and led to the potent inhibitor ZL-Pin13 with an IC50 of 0.067 ± 0.03 μM. We obtained four co-crystal structures of Pin1 complexed with inhibitors that elucidated the detailed binding mode of the derivatives with Pin1. Interestingly, the co-crystal of Pin1 with ZL-Pin13 obtained by co-crystallization revealed the conformational change of Gln129 induced by the inhibitor. Furthermore, ZL-Pin13 effectively inhibited the proliferation and downregulated the Pin1 substrates in MDA-MB-231 cells. Collectively, we developed a potent covalent inhibitor of Pin1, ZL-Pin13, which could be an effective probe for studying the functional roles of Pin1.


Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.
The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma.


Advanced Neuropsychological Diagnostics Infrastructure (ANDI): A Normative Database Created from Control Datasets.
In the Advanced Neuropsychological Diagnostics Infrastructure (ANDI), datasets of several research groups are combined into a single database, containing scores on neuropsychological tests from healthy participants. For most popular neuropsychological tests the quantity, and range of these data surpasses that of traditional normative data, thereby enabling more accurate neuropsychological assessment. Because of the unique structure of the database, it facilitates normative comparison methods that were not feasible before, in particular those in which entire profiles of scores are evaluated. In this article, we describe the steps that were necessary to combine the separate datasets into a single database. These steps involve matching variables from multiple datasets, removing outlying values, determining the influence of demographic variables, and finding appropriate transformations to normality. Also, a brief description of the current contents of the ANDI database is given.


Effect of Cr in irrigation water on germination and growth of French beans (Dolichos lablab L.).
The waters containing chromium (Cr) mainly from industries enter into the sewers, municipal treatment plant, streams and lakes that are used for irrigation purposes. The effect of Cr in irrigation water on seed germination and growth of French bean (Dolichos lablab L.) was investigated. Germination studies were conducted in the lab and field conditions. Seeds were treated with different concentrations (0 to 25 mg/1) of Cr in irrigation water. The percentage germination of seeds and plant growth showed a gradual decrease with increase in Cr concentration. Stimulatory effect in growth of plant was observed at lower concentration (1 to 2 mg/l). Accumulation of Cr was in the order of Root > Leaf > Stem > Pod. There was an increase in the total concentration of Cr content of soil with increase in Cr concentration in irrigation water.


Characterization of non-stoichiometric hydration and the dehydration behavior of sitafloxacin hydrate.
Sitafloxacin (STFX) hydrate is a non-stoichiometric hydrate. The hydration state of STFX hydrate varies non-stoichiometrically depending on the relative humidity and temperature, though X-ray powder diffraction (XRPD) of STFX hydrate was not affected by storing at low and high relative humidities. The detailed properties of crystalline water of STFX hydrate were estimated in terms of hygroscopicity, thermal analysis combined with X-ray powder diffractometry, crystallography and density functional theory (DFT) calculation. STFX hydrate changed the water contents continuously and reversibly from an equivalent amount of dihydrate through that of sesquihydrate depending on the relative humidity at 25°C. Thermal analysis and X-ray powder diffraction (XRPD) simultaneous measurement also revealed that STFX hydrate dehydrated into a hydrated state equivalent to monohydrate by heating up to 100°C, whereas XRPD patterns were slightly affected. This indicated that the crystal structure of STFX hydrate was retained at the dehydration level of monohydrate. Single-crystal X-ray structural analysis showed that two STFX molecules and four water molecule sites were contained in an asymmetric unit. STFX molecules formed a channel structure where water molecules were included. At the partially dehydrated state, at least two of four water molecules were considered to be disordered in occupancy and/or coordinates. Insight into the crystal structure of STFX hydrate stored at low and high relative humidities and geometry of the hydrogen bond were helpful to estimate the origin of non-stoichiometric hydration of STFX hydrate.


Chemotherapy in non-seminomatous testicular tumours stage I.
Chemotherapy improves the survival rate of patients with disseminated teratoid testicular tumours, but patients without evidence of metastatic spread are not usually given further treatment after retroperitoneal lymphadenectomy because of the high toxicity of most drugs; 10 to 20% of these patients die later with widespread disease. In an earlier series of 24 patients from our hospital the survival rate in stage I disease was below 70%. Since 1973, when we began to use adjuvant chemotherapy in this group, there have been no relapse.


Noninvasive CT determination of arterial blood concentration of meglumine iothalamate.
A quantity that often must be determined in physiological imaging studies is the blood concentration of the tracer over time. This is usually performed by direct arterial or venous blood sampling. We studied the relationship between the concentration of meglumine iothalamate in arterial blood and values determined from voxels containing large blood vessels in a series of CT images at the same location over time. After correction for volume averaging based on a single venous blood sample, there was an excellent correlation between the two blood curves. Differences between the curves were shown to be inconsequential by a simulation of transcapillary transport determinations. We thus conclude that determination of plasma concentration from CT images is a reliable technique for CT transcapillary transport studies.


Propagation of Cell Death During Myocardial Reperfusion.
During myocardial reperfusion, increased cytosolic Ca(2+) concentration may cause hypercontracture and cell death. Hypercontracture can propagate to adjacent cells by a gap junction-dependent mechanism. This propagation explains infarct geometry and increases the final extent of necrosis. Its prevention may represent a new therapeutic strategy for treating patients with myocardial infarction.


The comorbidity of bipolar disorder, diabetes mellitus, and autoimmune hypothyroidism in an adult woman with Turner's syndrome: a case report.
Turner's syndrome (TS) is the most common sex chromosome abnormality in females and characterized with short stature and ovarian dysgenesis. Patients with TS may also present many other physical diseases and mental disorders. In this case report, we present a 49-year-old woman with TS, who also met criteria for bipolar disorder, type 2 diabetes mellitus, and autoimmune hypothyroidism. The patient was admitted to the mental health center for depressive symptoms in 1991 and was misdiagnosed as hypopituitarism, which was not corrected until 2005 when her karyotype of 45, X/46, X, i(Xq) was identified. Due to the misdiagnosis and other specific reasons, the patient missed the optimal time for hormone replacement therapy.


Naturally occurring altered peptide ligands control Salmonella-specific CD4+ T cell proliferation, IFN-gamma production, and protective potency.
T cell activation required for host defense against infection is an intricately regulated and precisely controlled process. Although in vitro studies indicate that three distinct stimulatory signals are required for T cell activation, the precise contribution of each signal in regulating T cell proliferation and differentiation after in vivo infection is unknown. In this study, altered peptide ligands (APLs) derived from the protective Salmonella-specific FliC Ag and CD4+ T cells specific for the immune-dominant FliC(431-439) peptide within this Ag were used to determine how changes in TCR stimulation impact CD4+ T cell proliferation, differentiation, and protective potency. To explore the prevalence and potential use of altered TCR stimulation by bacterial pathogens, naturally occurring APLs containing single amino acid substitutions in putative TCR contact residues within the FliC(431-439) peptide were identified and used for stimulation under both noninfection and infection conditions. On the basis of this analysis, naturally-occurring APLs that prime proliferation of FliC-specific CD4+ T cells either more potently or less potently compared with the wild-type FliC(431-439) peptide were identified. Remarkably, despite these differences in proliferation, all of the APLs primed reduced IFN-gamma production by FliC(431-439)-specific CD4+ T cells after stimulation in vivo. Moreover, after expression of the parental FliC(431-439) peptide or each APL in recombinant Listeria monocytogenes, only CD4+ T cells stimulated with the wild-type FliC(431-439) peptide conferred significant protection against challenge with virulent Salmonella. These results reveal important and unanticipated roles for TCR stimulation in controlling pathogen-specific CD4+ T cell proliferation, differentiation, and protective potency.


Navigated micropulse laser for central serous chorioretinopathy: Efficacy, safety, and predictive factors of treatment response.
There is no widely accepted treatment for persistent/chronic central serous chorioretinopathy. The present study aimed to evaluate the efficacy, safety, and factors associated to treatment response to navigated micropulse laser in chorioretinopathy. Retrospective observational case series including consecutive patients presenting with symptomatic persistent and chronic chorioretinopathy. All patients were treated with 5% navigated micropulse laser with the Navilas system (Navilas®, OD-OS GmBH, Teltwo, Germany), by overlying fluorescein angiography, indocyanine green angiography and/or spectral domain-optical coherence tomography images of visible leaking points and/or choroidal hyperpermeability/subretinal fluid to plan the laser treatment. Thirty-nine eyes of 36 consecutive patients (29 men and 7 women, with a mean age of 51.87 years) were included. Logarithm of the minimum angle of resolution (LogMar) best-corrected visual acuity increased from 0.39 ± 0.24 at baseline to 0.24 ± 0.22 at 3 months (p < 0.0001) and to 0.20 ± 0.07 at 6 months (p < 0.0001). Subretinal fluid decreased from 166.82 ± 111.11 micron at baseline to 52.33 ± 78.97 micron (p < 0.0001) at 3 months and 34.12 ± 67.56 micron at 6 months (p < 0.0001). The presence of a hot spot on fluorescein angiography and a focal choroidal hyperpermeability on indocyanine green angiography, but not the duration of symptoms correlated significantly with the resolution of subretinal fluid at month 3 (p = 0.023 and p = 0.001). Navigated micropulse laser laser treatment was found to be effective and safe for the treatment of chorioretinopathy, with significant improvement in visual and anatomical outcomes, unaccompanied by any adverse event at 3 and 6 months follow-up. Factors associated to subretinal fluid resolution may allow a better selection of likely responders to navigated micropulse laser treatment.


Construction of a circRNA-miRNA-mRNA Regulated Pathway Involved in EGFR-TKI Lung Adenocarcinoma Resistance.
Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.


Evaluation of attitudes towards telemedicine as a basis for successful implementation: A cross-sectional survey among postgraduate trainees in family medicine in Germany.
By comparison with other countries of the European Union Germany is only middle-ranking in terms of telemedicine usage. There is a relevant gap between the legal framework and the actual state of implementation. Healthcare providers play an important role in this implementation process as they are increasingly confronted with the application of telemedical scenarios. Therefore, the aim of this survey was to determine attitudes towards telemedicine of postgraduate trainees in Family Medicine (FM) in Germany. A cross-sectional survey was conducted between July and October 2016 among postgraduate trainees in FM throughout Germany. The questionnaire covered four topics: attitudes towards telemedicine, barriers for the implementation of telemedicine, assessment of useful telemedical applications and telemedicine scenarios. A descriptive approach was used to analyze the data in order to derive determinants for the implementation of telemedicine. In total, 388 postgraduate trainees from 13 of the 16 federal states in Germany answered the survey. Seventy-eight percent were female. Participants' mean age was 36 years. The majority of participants believed that only a fraction of the already existing technology in telemedicine is being used (70 %). The largest perceived barrier to telemedicine was data safety concerns. More than half of the participants (54 %) believed that telemedicine would change the doctor-patient relationship. 51 % of the participants were interested in training in telemedicine. In this respect, it is important to note that 27 % of the postgraduate trainees said their willingness to practice in rural areas might be facilitated through the availability of telemedical backup for family physicians. Participating trainees in FM in Germany think that the potential for telemedicine is not yet fully exploited. Based on the results of this survey the next steps to be taken for the implementation of telemedicine applications can be addressed.


Immunohistochemical detection of tumor suppressor gene p53 protein in feline injection site-associated sarcomas.
Sarcomas associated with injection sites are a rare but important problem in cats. Immunohistochemical detection of p53 protein may correlate to mutation of the p53 tumor suppressor gene, a gene known to be important in oncogenesis. The expression of nuclear p53 protein in 40 feline injection site-assocated sarcomas was examined by immunohistochemical staining. In 42.5% (17/40), tumor cell nuclei were stained darkly; in 20% (8/40), tumor cell nuclei were stained palely; and in 37.5% (15/40), tumor cell nuclei were unstained. Immunohistochemical detection of p53 protein in a proportion of injection site-associated sarcomas suggests that mutation of the p53 gene may play a role in the pathogenesis of these tumors.


The legal outlook for physician-hospital relationships.
Legal developments that could affect the relationship between hospitals and physicians include: Enforcement of fraud and abuse laws. Tighter billing rules. Emphasis on value-based purchasing. Renewed interest in alternative delivery models that reward quality, efficiency, and cost savings.


New insights in hepatocellular carcinoma: from bench to bedside.
Hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant transformation of the hepatocyte. The liver is one of the main targets for different metastatic foci, but it represents an important and frequent locus of degeneration in the course of chronic disease. In fact, Hepatocellular carcinoma (HCC) represents the outcome of the natural history of chronic liver diseases, from the condition of fibrosis, to cirrhosis and finally to cancer. HCC is the sixth most common cancer in the world, some 630,000 new cases being diagnosed each year. Furthermore, about the 80% of people with HCC, have seen their clinical history developing from fibrosis, to cirrhosis and finally to cancer. The three main causes of HCC development are represented by HBV, HCV infection and alcoholism. Moreover, metabolic disease [starting from Non Alcoholic Fatty Liver Disease (NAFLD), Non Alcoholic Steatohepatitis (NASH)] and, with reduced frequency, some autoimmune disease may lead to HCC development. An additional rare cause of carcinogenetic degeneration of the liver, especially developed in African and Asian Countries, is represented by aflatoxin B1. The mechanisms by which these etiologic factors may induce HCC development involve a wide range of pathway and molecules, currently under investigation. In summary, the hepatocarcionogenesis results from a multifactorial process leading to the common condition of genetic changes in mature hepatocytes mainly characterized by uncontrolled proliferation and cell death. Advances in understanding the mechanism of action are fundamental for the development of new potential therapies and results primarily from the association of the research activities coming from basic and clinical science. This review article analyzes the current models used in basic research to investigate HCC activity, and the advances obtained from a basic and clinical point of view.


Multi-Scale Graph Representation Learning for Autism Identification With Functional MRI.
Resting-state functional MRI (rs-fMRI) has been widely used for the early diagnosis of autism spectrum disorder (ASD). With rs-fMRI, the functional connectivity networks (FCNs) are usually constructed for representing each subject, with each element representing the pairwise relationship between brain region-of-interests (ROIs). Previous studies often first extract handcrafted network features (such as node degree and clustering coefficient) from FCNs and then construct a prediction model for ASD diagnosis, which largely requires expert knowledge. Graph convolutional networks (GCNs) have recently been employed to jointly perform FCNs feature extraction and ASD identification in a data-driven manner. However, existing studies tend to focus on the single-scale topology of FCNs by using one single atlas for ROI partition, thus ignoring potential complementary topology information of FCNs at different spatial scales. In this paper, we develop a multi-scale graph representation learning (MGRL) framework for rs-fMRI based ASD diagnosis. The MGRL consists of three major components: (1) multi-scale FCNs construction using multiple brain atlases for ROI partition, (2) FCNs representation learning via multi-scale GCNs, and (3) multi-scale feature fusion and classification for ASD diagnosis. The proposed MGRL is evaluated on 184 subjects from the public Autism Brain Imaging Data Exchange (ABIDE) database with rs-fMRI scans. Experimental results suggest the efficacy of our MGRL in FCN feature extraction and ASD identification, compared with several state-of-the-art methods.


Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease.
Families bearing mutations in the presenilin 1 (PS1) gene develop early onset familial Alzheimer's disease (FAD). Further, some PS1 mutants enhance secretion of the longer form of amyloid beta protein (Abeta42). We constructed cDNAs encoding human PS1 harboring 28 FAD-linked mutations, and examined the effects of the expressed PS1 mutants on Abeta42 secretion in beta amyloid precursor producing COS-1 cells. All the mutants significantly enhanced the ratio of Abeta42 to total Abeta compared with wild-type PS1. However, the increase in Abeta42 ratio in cells with each PS1 mutation did not correlate with the reported age of onset of FAD caused by that mutation. These results suggest that increased Abeta42 secretion is important for the development of Alzheimer's disease (AD), but may not be the only factor contributing to the onset of AD.


Highly effective synthesis and photoluminescence of Sr2Si5N8:Eu2+ red-emitting phosphor for LEDs.
We developed a highly effective and self-sustaining route for synthesizing Sr(2)Si(5)N(8):Eu(2+) red-emitting phosphor particles for use in light emitting diodes (LEDs). The phosphors thus synthesized showed excellent emission characteristics under a blue excitation wavelength of 450 nm, had a uniform particle size distribution, and showed high performance in LED packages.


Evolving networks with disadvantaged long-range connections.
We consider a growing network, whose growth algorithm is based on the preferential attachment typical for scale-free constructions, but where the long-range bonds are disadvantaged. Thus, the probability of getting connected to a site at distance d is proportional to d(-alpha), where alpha is a tunable parameter of the model. We show that the properties of the networks grown with alpha<1 are close to those of the genuine scale-free construction, while for alpha>1 the structure of the network is quite different. Thus, in this regime, the node degree distribution is no longer a power law, and it is well represented by a stretched exponential. On the other hand, the small-world property of the growing networks is preserved at all values of alpha.


Detection of loss of heterozygosity of p53 gene in paraffin-embedded breast cancers by non-isotopic PCR-SSCP.
A rapid non-isotopic PCR-SSCP (polymerase chain reaction-single-stranded conformation polymorphism) method was developed in this study to detect polymorphism and loss of heterozygosity (LOH) of p53 in formalin-fixed and paraffin-embedded samples of normal breast tissue and of breast cancer. p53 expression was also examined by immunohistochemistry. In 35 paired samples, heterozygosity in exon 4 of p53 was detected in 17 cases (49 per cent) and LOH of the p53 gene in breast cancer tissues was observed in 7 out of 15 informative cases (47 per cent). The correlation of LOH of p53 with positive p53 immunostaining did not reach statistical significance, but all immunostaining-positive tumours among informative cases had LOH of p53. The results support the hypothesis that in most cases the allelic deletion of p53 may uncover the 'recessive mutation' in the remaining allele. However, LOH of p53 was more frequent than positive immunostaining and was significantly associated with poor differentiation of breast cancer (P < 0.05). The results suggest that the allelic deletion of p53 may also contribute to the development and progression of breast cancer by reducing the amount of normal p53 protein. These results show that non-isotopic PCR-SSCP is a simple, fast, and effective method for detecting polymorphism and LOH of the p53 gene, which is especially useful for retrospective studies.


Detection and analysis by dual-laser flow cytometry of bacteriophage T4 DNA inside Escherichia coli.
Bacteriophage T4 DNA was detected and analyzed inside E. coli by dual-laser flow cytometry using a dye combination of Hoechst 33258 (H33258) and chromomycin A3 (CA3) which bind to A-T- and G-C-rich regions of DNA, respectively. An exponentially-growing culture of E. coli ATCC 11303 was infected with T4 bacteriophage at a 1:1 multiplicity of infection. Samples were taken immediately and at 5 min intervals and placed on ice to interrupt viral replication. The samples were then centrifuged, ethanol-fixed, stained with H33258 and CA3, and analyzed by flow cytometry. Twenty-five minutes post-infection, a population of cells which contained T4 DNA began to appear on both a bivariate contour plot and a frequency histogram plot of the data. By 35 min, T4 DNA-containing cells could be distinguished from E. coli cells containing little or no T4 DNA. The ratio of CA3:H33258 fluorescence was then used to calculate the % G + C value for T4 DNA inside E. coli. A value of 35.6 +/- 0.2% was obtained, which agrees with % G + C values determined by traditional methods. These results demonstrate that dual-laser flow cytometry can be used to study viral DNA inside the bacterial host.


JCAHO issues call-to-action over nursing shortage.
The issue of nursing shortages, of course, is not new. But, the Joint Commission on Accreditation of Healthcare Organizations notes in a newly released white paper that the problem is not likely to improve any time soon unless radical changes are implemented at the cultural, workplace, educational, and leadership levels.


Partial thrombosis of the corpus cavernosum - a malignancy mimicker.
Partial thrombosis of the corpus cavernosum is a rare condition, typically seen in young patients. Etiology, physiopathology and treatment are still not entirely understood. The authors report a case of a 49-year-old male with gastric cancer, who successfully treated a thrombosis of the corpus cavernosum conservatively. Diagnostic considerations and treatment options are discussed.


A brief history of ultrasound in rheumatology: where we were.
Ultrasonography in the '70s was a well-known and widely used method within several medical specialties but not in rheumatology. Initial development of the field was led by radiologists who mainly investigated the potential of ultrasound in the assessment of large joints. In the late '80s, the first studies supporting the role of ultrasound in the detection of soft tissue changes and bone erosions in the hands of patients with rheumatoid arthritis were published. In the '90s, the dramatic improvement of spatial resolution due to the new generation high frequency probes opened up new avenues for the exploration of otherwise undetectable anatomical details. Ultrasound research during this period was enhanced by the growing use of colour Doppler and power Doppler and by the first prototypes of three dimensional ultrasound. Over the last 10 years, the buzz words in ultrasound research in rheumatology have been standardisation, early diagnosis and therapy monitoring.


Repair of chronic distal biceps brachii tendon rupture using free autogenous semitendinosus tendon.
Distal biceps brachii tendon ruptures occur much less frequently than do their proximal counterparts. Distal tendon ruptures usually are associated with considerable function deficits and may require surgical treatment. Repair of chronic distal biceps brachii ruptures are extremely unusual. A free autogenous semitendinosus tendon graft was used to reconstruct the distal biceps tendon by reattaching the graft to the radial tuberosity via a 2-incision technique in a patient with symptoms and a chronic injury.


Transgenic mouse lines that are immunologically tolerant and nontolerant to herpes simplex virus glycoprotein D.
A construct containing the gene for glycoprotein D of herpes simplex virus (HSV-gD), under the control of the simian virus 40 early promoter, was microinjected into single-cell embryos, and four transgenic mouse lines were established. Three were homozygous (lines 75, 111, and 113) and one was hemizygous (line 108) for the HSV-gD gene. Examination of sera revealed that only one of the lines (line 75) spontaneously produced antibody to HSV-gD. Immunization of the other three lines with vaccinia virus-HSV-gD showed that one of them (line 113) responded by making antibody to HSV-gD, whereas the other two (lines 108 and 111) appeared to be immunologically tolerant. Evidence that tolerance was not absolute was obtained by immunization with infectious HSV, which resulted in an antibody response to HSV-gD in some of the animals from line 111. Examination of organs for HSV-gD mRNA revealed transcripts in the tolerant line (line 108) and in the partially tolerant line (line 111), but not in the nontolerant line (line 113), suggesting that the development of immunological tolerance requires active expression of the HSV-gD gene.


"Reframing" dopamine signaling at the intersection of glial networks in the aged Parkinsonian brain as innate Nrf2/Wnt driver: Therapeutical implications.
Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/β-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.


H3K36 demethylase JMJ710 negatively regulates drought tolerance by suppressing MYB48-1 expression in rice.
The homeostasis of histone methylation is maintained by histone methyltransferases and demethylases, which are important for the regulation of gene expression. Here, we report a histone demethylase from rice (Oryza sativa), Jumonji C domain-containing protein (JMJ710), which belongs to the JMJD6 group and plays an important role in the response to drought stress. Overexpression of JMJ710 causes a drought-sensitive phenotype, while RNAi and clustered regularly interspaced short palindromic repeats (CRISPR)-knockout mutant lines show drought tolerance. In vitro and in vivo assays showed that JMJ710 is a histone demethylase. It targets to MYB TRANSCRIPTION FACTOR 48 (MYB48-1) chromatin, demethylates H3K36me2, and negatively regulates the expression of MYB48-1, a positive regulator of drought tolerance. Under drought stress, JMJ710 is downregulated and the expression of MYB48-1 increases, and the subsequent activation of its downstream drought-responsive genes leads to drought tolerance. This research reports a negative regulator of drought stress-responsive genes, JMJ710, that ensures that the drought tolerance mechanism is not mis-activated under normal conditions but allows quick activation upon drought stress.


Effect of prostaglandins E2 and 15-methyl F2 alpha on human pregnant and non-pregnant cervix.
Forty-two women of reproductive age were studied in two equal groups (group I, first-trimester pregnant; group II, non-pregnant). Each group included three equal sub-groups; subgroup A received intra-cervical 15-Me PGF2 alpha gel, B received intracervical PGE2 gel and C received intra-cervical gel alone as placebo. Three different staining techniques were employed to study the histological picture and histochemical alterations of cervical biopsies. These showed that PG-treated cervices presented significant changes compared to placebo in terms of more widely dissociated connective tissue bundles that are separated by clear spaces and an increase in the amount of ground substance. Moreover, the observed changes in pregnant sub-groups were more evident than in the corresponding non-pregnant cases.


UHPLC-MS/MS-Based Metabolomics and Clinical Phenotypes Analysis Reveal Broad-Scale Perturbations in Early Pregnancy Related to Gestational Diabetes Mellitus.
Gestational diabetes mellitus (GDM) is the most common metabolic disturbance during pregnancy, with adverse effects on both mother and fetus. The establishment of early diagnosis and risk assessment model is of great significance for preventing and reducing adverse outcomes of GDM. In this study, the broad-scale perturbations related to GDM were explored through the integration analysis of metabolic and clinical phenotypes. Maternal serum samples from the first trimester were collected for targeted metabolomics analysis by using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Statistical analysis was conducted based on the levels of the 184 metabolites and 76 clinical indicators from GDM women (n =60) and matched healthy controls (n =90). Metabolomics analysis revealed the down-regulation of fatty acid oxidation in the first trimester of GDM women, which was supposed to be related to the low serum level of dehydroepiandrosterone.While the significantly altered clinical phenotypes were mainly related to the increased risk of cardiovascular disease, abnormal iron metabolism, and inflammation. A phenotype panel established from the significantly changed serum indicators can be used for the early prediction of GDM, with the area under the receiver-operating characteristic curve (ROC) 0.83. High serum uric acid and C-reaction protein levels were risk factors for GDM independent of body mass indexes, with ORs 4.76 (95% CI: 2.08-10.90) and 3.10 (95% CI: 1.38-6.96), respectively. Predictive phenotype panel of GDM, together with the risk factors of GDM, will provide novel perspectives for the early clinical warning and diagnosis of GDM.


The Causal and Force Perception and Their Perceived Asymmetries in Flight Collisions.
The present study was to investigate causal perception and force perception in ecological objects. Four experiments were designed to compare the perceived causality and force of one of the two objects on the other by changing the property of one or both of the objects involved in the launching effect. Our results support causal asymmetry and force asymmetry, in which the launcher has a greater causal effect and exerts more force on the target. Furthermore, we also found that, the ecological object, which is the airplane in this study, had a greater causal effect and exerted more force, resulting in strengthened asymmetries when the airplane acted as the launcher and weakened asymmetries when the airplane acted as the target. The properties of the object also impacted causal perception by attenuating the effect of the temporal gap on causality. Those results indicate that the airplane is perceived as the main cause for a collision compared with an abstract object. The influence of conceptual knowledge of the object and the sense of agency on changing the degree of perceived causality and force in a particular motion pattern was discussed.


There is a Role in Detection of SARS-CoV-2 in Conjunctiva and Tears: a comprehensive review.
Data on the involvement of the ocular surface and its relationship with Coronavirus disease 2019 (COVID- 19) are still minimal and not univocal. The respiratory tract is the structure most affected by COVID-19, and the serious form of the disease is characterized by severe pneumonia, acute respiratory distress syndrome and hypercoagulation. However, accumulating evidence shows that other organs could be reached by the virus, thus causing further comorbidities. To date, the exact route/routes of transmission of COVID-19 are still unclear. The respiratory tract is probably not the only route of transmission for this viral infection and some authors have also speculated that COVID-19 droplets, or infected hands, could contaminate the conjunctiva, which could therefore represent the initial site of an infection spread. Theoretically, the role of the ocular surface, a biological site still relatively unexplored, appears scientifically relevant in understanding the Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) infection. The purpose of this paper is to summarize the current literature in order to elucidate the potential role of tear and conjunctival sampling to detect SARS-CoV-2 for the diagnosis of COVID-19 and to monitor patients during follow-up.


Percutaneous left atrial to femoral arterial bypass pumping for circulatory support in high-risk coronary angioplasty.
Left atrial to femoral arterial bypass was evaluated as a means of supporting patients who were considered to be at high risk for the performance of percutaneous transluminal coronary angioplasty. A 20 French drainage catheter was inserted percutaneously into the left atrium via a modified transseptal technique. Blood was withdrawn from the left atrium and returned through a femoral arterial cannula using a roller pump. Thirteen patients were treated in this fashion with excellent circulatory support. Pump flows varied from 1.5 to 3 liters per minute and bypass time ranged from 27 to 106 min (mean = 43 +/- 17). Aortic mean pressure was well supported during balloon inflation. No significant complications were encountered. Neither an oxygenator nor a perfusionist is required. The ability to obtain direct left ventricular decompression offers a major potential advantage. Further evaluation of this technique for the support of such patients is indicated.


Development of an In Vitro Drug Release Method to Enable In Vitro-In Vivo Correlation of Potassium Chloride Extended-Release Tablets.
An in vitro drug release test was developed to establish a level A in vitro-in vivo correlation (IVIVC) for predicting the in vivo performance of potassium chloride extended-release (ER) matrix tablets. Three ER formulations of potassium chloride with different in vitro release rates were designed using the USP dissolution test, and their urinary pharmacokinetic profiles were evaluated in healthy subjects. Due to the lack of IVIVC with the USP method, experiments were designed to investigate the effects of in vitro test conditions on drug release in order to match in vitro drug release with in vivo behaviors of different formulations. The evaluated in vitro variables included the type of USP apparatus, surfactant, and ionic strength of the dissolution medium. Based on the study findings and data analysis, a discriminatory drug release method was successfully developed that enabled the establishment and validation of a level A IVIVC model of the potassium chloride ER tablet using urinary pharmacokinetic data. This method uses USP apparatus I at 50 rpm in 900 mL of 150 mM NaCl solution containing 40 mM sodium dodecyl sulfate at 37 °C. The current study highlights the value of investigating test conditions in developing a predictive in vitro test method for establishing IVIVC.


Combined thermotherapy and cryotherapy for efficient virus eradication: relation of virus distribution, subcellular changes, cell survival and viral RNA degradation in shoot tips.
Accumulation of viruses in vegetatively propagated plants causes heavy yield losses. Therefore, supply of virus-free planting materials is pivotal to sustainable crop production. In previous studies, Raspberry bushy dwarf virus (RBDV) was difficult to eradicate from raspberry (Rubus idaeus) using the conventional means of meristem tip culture. As shown in the present study, it was probably because this pollen-transmitted virus efficiently invades leaf primordia and all meristematic tissues except the least differentiated cells of the apical dome. Subjecting plants to thermotherapy prior to meristem tip culture heavily reduced viral RNA2, RNA3 and the coat protein in the shoot tips, but no virus-free plants were obtained. Therefore, a novel method including thermotherapy followed by cryotherapy was developed for efficient virus eradication. Heat treatment caused subcellular alterations such as enlargement of vacuoles in the more developed, virus-infected cells, which were largely eliminated following subsequent cryotherapy. Using this protocol, 20-36% of the treated shoot tips survived, 30-40% regenerated and up to 35% of the regenerated plants were virus-free, as tested by ELISA and reverse transcription loop-mediated isothermal amplification. Novel cellular and molecular insights into RBDV-host interactions and the factors influencing virus eradication were obtained, including invasion of shoot tips and meristematic tissues by RBDV, enhanced viral RNA degradation and increased sensitivity to freezing caused by thermotherapy, and subcellular changes and subsequent death of cells caused by cryotherapy. This novel procedure should be helpful with many virus-host combinations in which virus eradication by conventional means has proven difficult.


Differential cross-seeding properties of tau and α-synuclein in mouse models of tauopathy and synucleinopathy.
Co-occurrence of tau and α-synuclein pathologies in a subset of Alzheimer's disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer's disease neurodegenerative cascade. To understand the aetiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant α-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of tau fibrils or α-synuclein fibrils, and to a lesser extent tau + α-synuclein copolymer fibrils prepared from co-incubating individual recombinant monomers, induced robust phosphorylated tau pathology in PS19 mice relative to control mice. Though the tau + α-synuclein copolymer fibrils did not modulate induction of pathologies at the site of injection, examination of the whole brain showed that these copolymers exacerbated neuroanatomic transmission of seeded tau pathology compared to tau fibril-injected mice. Only α-synuclein fibrils, but not tau alone or tau + α-synuclein copolymers, triggered modest levels of endogenous phosphorylated α-synuclein pathology. Overall, data from the PS19 mice suggest that human α-synuclein fibrils can efficiently cross-seed human tau and have a modest priming effect on mouse α-synuclein, and the presence of tau fibrils does not exacerbate the priming process. In M20 mice, unilateral hippocampal injection of α-synuclein fibrils or tau fibrils induced robust bilateral phosphorylated α-synuclein pathology, while tau + α-synuclein copolymer injection resulted in restricted phosphorylated α-synuclein pathology predominantly in the ipsilateral cortex. This suggests that human tau fibrils can also induce human α-synuclein pathogenesis, and the presence of combinatorial seeds is not synergistic. None of these aggregates induced phosphorylated tau pathology in M20 mice, showing that mouse tau cannot be primed efficiently by human tau fibrils or human α-synuclein fibrils. Neuropathological analysis of the whole brain of M20 mice showed that tau + α-synuclein copolymer-injected mice had lower abundance of bilaterally transmitted α-synuclein pathologies relative to α-synuclein fibril-injected mice. Thus, the tau + α-synuclein copolymer fibrils show robust transmission properties preferentially in rodent model of tauopathies but not in synucleinopathy, probably signifying an enhanced cooperative relationship between tau and α-synuclein in the tau seeding process. Together, our data highlight the unique cross-seeding properties of tau and αSyn in neurodegenerative proteinopathies.


Analysis of Clinical Related Factors of Severe Mycoplasma pneumoniae Pneumonia in Children Based on Imaging Diagnosis.
Severe pneumonia is a common acute respiratory disease in children, and it has a rapid onset and violent onset, which often affects the whole body. Moreover, typical clinical manifestations and signs often cannot be taken seriously or covered up in clinical work. Due to the short time for treatment, it is easy to cause improper diagnosis and treatment, aggravate the disease and further deteriorate, and even threaten the life of the child. In order to achieve early intervention and treatment of severe Mycoplasma pneumoniae pneumonia in children, reduce or shorten the course of the disease, and improve the cure rate, this paper combines the imaging diagnosis to study the analysis of clinical related factors of severe Mycoplasma pneumoniae pneumonia in children. In addition, this paper analyzes the experimental data with hospital case samples, conducts statistical research on the analysis of clinical related factors of severe Mycoplasma pneumoniae pneumonia in children, and proposes effective coping strategies.


Interventions for treating pain and disability in adults with complex regional pain syndrome.
There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used. To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS). We identified Cochrane reviews and non-Cochrane reviews through a systematic search of the following databases: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Ovid MEDLINE, Ovid EMBASE, CINAHL, LILACS and PEDro. We included non-Cochrane systematic reviews where they contained evidence not covered by identified Cochrane reviews. The methodological quality of reviews was assessed using the AMSTAR tool.We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes of quality of life, emotional well being and participants' ratings of satisfaction or improvement. Only evidence arising from randomised controlled trials was considered. We used the GRADE system to assess the quality of evidence. We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable.There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events.There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control.For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn. There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult.


Shyness and informal help-seeking behavior.
The present study examined whether shy individuals are more reluctant to seek help than less shy individuals. A sample of 48 undergraduates (46% men, Mage=20.6 yr.) were selected from a pool of 72 students based on their relatively high or low scores on the Social Interaction Anxiety Scale. They were then exposed to a situation involving an impossible task, on which they had the option of seeking assistance. Analysis indicated that participants scoring high on Shyness took significantly more time to seek help than participants scoring low. This result suggests that even when help is readily available, shy individuals may refrain from seeking it. Presumably, shy people may be reluctant to seek help because that often requires them to initiate a social interaction.


A note on "Optical motions as information for unsigned depth".
Farber and McConkie have questioned whether optical (or retinal) flows provide a basis for the accurate perception of relative distance (or filled depth, in Gibson, Gibson, Smith, & Flock's terms). Some of the analysis Farber and McConkie present is incorrect. In this article I identity some of the fallacies and discuss issues relevant to these fallacies. The critique does not concern the experiments presented by Farber and McConkie but rather the underlying analysis that culminated in the experiments.


Trends in postcoronary artery bypass graft sternal wound dehiscence in a provincial population.
It appears that the medical profile of patients undergoing coronary artery bypass graft (CABG) surgery has changed. The impact of this demographic shift on CABG outcomes, such as sternal wound dehiscence, is unclear. To quantify the incidence and trends of sternal wound dehiscence, quantify the demographic shift of those undergoing CABG and identify patient factors predictive of disease. A prospective analysis was performed on a historical cohort of consecutive patients who underwent CABG (without valve replacement) in Alberta between April 1, 2002 and November 30, 2009. The incidence and trends of sternal wound dehiscence were determined. In addition, the trend of the mean Charlson index score and European System for Cardiac Operative Risk Evaluation (EuroSCORE) (capturing patient comorbidities) was analyzed. Univariable analysis and multivariable models were performed to determine factors predictive of wound dehiscence. A total of 5815 patients underwent CABG during the study period. The incidence proportion of sternal wound dehiscence in Alberta was 1.86% and the incidence rate was 1.98 cases per 100 person-years. Although both the EuroSCORE and Charlson scores significantly increased over the study period, the incidence of sternal wound dehiscence did not change significantly. Factors predictive of sternal wound dehiscence were diabetes (OR 2.97 [95% CI 1.73 to 5.10]), obesity (OR 1.55 [95% CI 1.05 to 2.27]) and female sex (OR 1.90 [95% CI 1.26 to 2.87]). The incidence proportion of sternal wound dehiscence in Alberta was comparable with the incidence previously published in the literature. While patients undergoing CABG had worsening medical profiles, the incidence of sternal wound dehiscence did not appear to be increasing significantly.


Retention and strength of silicone-rubber catheters. A report of five cases of retention and analysis of catheter strength.
Five patients had a silicone-rubber catheter that broke during attempted removal. Mechanical testing was performed to determine the tensile strength of silicone-rubber as well as of polyvinyl chloride catheters. Silicone-rubber catheters were found to have a low tensile strength. The pull-out force of ten indwelling silicone-rubber catheters was also measured. The pullout force measured from a patient who had a cast was close to 40 per cent of the strength of the silicone-rubber catheters.


Physical Therapy for Benign Positional Vertigo of Posterior Canal: The Role of Alternated Epley and Semont Maneuvers.
To investigate if alternated Epley (EP) and Semont (ST) maneuvers could be more effective than repetition of the same in benign paroxysmal positional vertigo of posterior semicircular canal (pBPPV). We retrospectively reviewed the outcome of pBPPV patients treated with a second maneuver for the persistence of positional nystagmus. Forty-seven patients underwent 2 STs, 64 with 2 EPs, and 71 EPs followed by ST. Videonystagmography and Dizziness Handicap Inventory (DHI) questionnaire were performed. Absence of positional nystagmus was achieved after 2 maneuvers in 136 patients with pBPPV: 65.9% in the ST group, 70.3% in the EP group, and 84.5% in the EP-ST group. Alternated EP and ST were significantly more effective than repeated ST (P = .03), while we found no significant difference when compared with repeated EP (P = .07). At 1-month follow-up, 12 patients showed persistent positional nystagmus without difference between groups. After 1 month, the 46 patients with negative outcome had significantly higher DHI values (P = .01) than other 136 patients with pBPPV. Alternated EP and ST seemed more effective than repeating the same maneuver in treating pBPPV, and this should be confirmed in prospective clinical studies. Resolution of nystagmus after maneuvers was fundamental to reduce handicap deriving from dizziness as reported in DHI.


l-Cysteine-Terminated Triangular Silver Nanoplates/MXene Nanosheets are Used as Electrochemical Biosensors for Efficiently Detecting 5-Hydroxytryptamine.
5-Hydroxytryptamine (5-HT) is an important neurotransmitter, and its content in the human body is of great significance to human health. In this study, an l-cysteine-terminated triangular silver nanoplate loaded on a MXene (two-dimensional transition metal carbide or nitride) (Tri-AgNP/l-Cys/MXene) electrochemical sensor was used to detect 5-HT. As an electrically active amino acid with a sulfhydryl group, l-cysteine (l-Cys) forms a more stable Ag-S bond with silver nanoparticles, which can selectively substitute trisodium citrate (TSC) in TSC-capped triangular silver nanoplates (Tri-Ag-NP/TSC). Due to the good conductivity, biocompatibility, and large surface area, MXenes provide a good platform for loading Tri-AgNP/l-Cys. Under optimized conditions, the concentration range for detecting 5-HT with the sensor is 0.5-150 μM, and the limit of detection (LOD) is 0.08 μM (S/N = 3). For detecting 5-HT in actual serum samples, the sensor also showed a good recovery rate (95.38-102.3%), and the relative standard deviation was 2.2-3.4%.


A Rare Case of Penile Strangulation Managed by Orthopedic Jumbo Cutter.
Penile strangulation is not commonly encountered in orthopedic practice. Quick decision and immediate removal of the metallic ring with readily available instruments is the key to a successful outcome. Jumbo cutter is a commonly available instrument. It can be used with ease without causing any thermal or soft tissue damage, giving satisfactory results.


A Predictive Model for Nonsentinel Node Status after Sentinel Lymph Node Biopsy in Sentinel Lymph Node-Positive Chinese Women with Early Breast Cancer.
Axial lymph node dissection (ALND) is needed in patients with positive sentinel lymph node (SLN). ALND is easy to cause upper limb edema. Therefore, accurate prediction of nonsentinel lymph nodes (non-SLN) which may not need ALND can avoid excessive dissection and reduce complications. We constructed a new prognostic model to predict the non-SLN metastasis of Chinese breast cancer patients. We enrolled 736 patients who underwent sentinel lymph node biopsy (SLNB); 228 (30.98%) were diagnosed with SLNB metastasis which was determined by intraoperative pathological detection and further accepted ALND. We constructed a prediction model by univariate analysis, multivariate analysis, "R" language, and binary logistic regression in the abovementioned 228 patients and verified this prediction model in 60 patients. Based on univariate analysis using α = 0.05 as the significance level for type I error, we found that age (P=0.045), tumor size (P=0.006), multifocality (P=0.011), lymphovascular invasion (P=0.003), positive SLN number (P=0.009), and negative SLN number (P=0.034) were statistically significant. Age was excluded in multivariate analysis, and we constructed a predictive equation to assess the risk of non-SLN metastasis: Logit(P)=Ln(P/1 - P)=0.267∗a+1.443∗b+1.078∗c+0.471∗d - 0.618∗e - 2.541 (where "a" represents tumor size, "b" represents multifocality, "c" represents lymphovascular invasion, "d" represents the number of metastasis of SLN, and "e" represents the number of SLNs without metastasis). AUCs for the training group and validation group were 0.715 and 0.744, respectively. When setting the risk value below 22.3%, as per the prediction equation's low-risk interval, our model predicted that about 4% of patients could avoid ALND. This study established a model which demonstrated good prognostic performance in assessing the risk of non-SLN metastasis in Chinese patients with positive SLNs.


Measurement of bone mineral density as an efficacy marker in denosumab treatment of giant cell tumour of bone.
Three patients with giant cell tumour of bone (GCTB) in the lower extremity, where the only surgical treatment options were amputation or severe weakening of the bone, were treated with denosumab (D-mab) to strengthen the bone mass in the tumour. In order to quantify changes in bone mineral density (BMD) in the GCTB lesion during D-mab treatment, we did repeated dual-energy X-ray absorptiometry (DXA) scans. The patients underwent operation after 3, 4 and 8 months of D-mab treatment, respectively. The tumours in all three patients responded markedly to D-mab, and up to 50% BMD increase was observed. There was almost no BMD change in the control scans in the hip and spine of the same patients. DXA scans provide no information about local tumour response, but may be of value in evaluation of the time and size of the D-mab response in GCTB, and thereby aid in finding the best timing for surgery.


Engineering of Saccharomyces cerevisiae for 24-Methylene-Cholesterol Production.
24-Methylene-cholesterol is a necessary substrate for the biosynthesis of physalin and withanolide, which show promising anticancer activities. It is difficult and costly to prepare 24-methylene-cholesterol via total chemical synthesis. In this study, we engineered the biosynthesis of 24-methylene-cholesterol in Saccharomyces cerevisiae by disrupting the two enzymes (i.e., ERG4 and ERG5) in the yeast's native ergosterol pathway, with ERG5 being replaced with the DHCR7 (7-dehydrocholesterol reductase) enzyme. Three versions of DHCR7 originating from different organisms-including the DHCR7 from Physalis angulata (PhDHCR7) newly discovered in this study, as well as the previously reported OsDHCR7 from Oryza sativa and XlDHCR7 from Xenopus laevis-were assessed for their ability to produce 24-methylene-cholesterol. XlDHCR7 showed the best performance, producing 178 mg/L of 24-methylene-cholesterol via flask-shake cultivation. The yield could be increased up to 225 mg/L, when one additional copy of the XlDHCR7 expression cassette was integrated into the yeast genome. The 24-methylene-cholesterol-producing strain obtained in this study could serve as a platform for characterizing the downstream enzymes involved in the biosynthesis of physalin or withanolide, given that 24-methylene-cholesterol is a common precursor of these chemicals.


Percutaneous recanalization of chronic total coronary occlusions: experience with the direct argon laser assisted angioplasty system (LASTAC).
The present study reports initial experience with the argon laser LASTAC system in patients with chronic coronary artery occlusion not amenable to recanalization with conventional systems. The LASTAC system conducts focused argon laser light through an optical fiber of 200 microns which is inserted through a multiple-lumen balloon catheter. The balloon serves the purpose of coaxially positioning the optical fiber. The balloon catheter is advanced by means of a guidewire to about 2 mm proximal to the occlusive lesion. After advancing the optical fiber, in three times 10 to 20 Joules are applied. Thereafter, the optical fiber is withdrawn, the balloon deflated, the catheter system repositioned and the sequence repeated. The integrity of the system with respect to temperature increase, energy loss and contact with tissue is monitored with lens fluorescence. In 29 patients with angina pectoris and documented ischemia, 30 complete occlusions were treated. In 18 (60%), there was successful recanalization with conventional balloon dilation thereafter. The total success rate for the right coronary artery was 55%, for the circumflex artery 71% and for the left anterior descending artery 67%. With regard to complications, in one patient there was nontransmural myocardial infarction, in seven there were asymptomatic dissections, one patient required defibrillation. The value of the LASTAC system for recanalization of chronically occluded coronary arteries has not yet been fully delineated. However, the success rate of 60% in previously treatment-refractory patients as well as the fact that no perforations were incurred, is encouraging. Further assessment will require analysis of long-term results as well as comparison of other methods.


Philadelphia chromosome positive precursor B-cell acute lymphoblastic leukemia with a translocation t(2;14)(p13;q32).
A female patient with precursor B-cell acute lymphoblastic leukemia (precursor B-ALL) was analyzed cytogenetically. Karyotyping of the leukemic cells showed a Philadelphia chromosome (Ph1), and also showed a translocation between 2p13 and 14q32, which is thought to be specific for children with B-cell chronic lymphocytic leukemia. DNA analysis with both conventional and pulsed-field gel electrophoresis revealed the rearrangement of the c-abl gene, the BCR gene outside the 5.8 kb breakpoint cluster region (bcr or M-BCR), and the comigration of an abnormal Not I pHabl 5' and 3'-bcr fragment, indicating the presence of BCR/c-abl recombination. The JH gene was rearranged, but the JK gene showed a germline configuration, as with previously reported cases with a t(2;14). This case is the first report of a patient with Ph1-positive precursor B-ALL, in whom a specific translocation t(2;14)(p13;q32) is found simultaneously.


Peritoneal dialysis therapy for patients with liver and renal failure with ascites.
Two patients with severe liver disease complicated with ascites were recently treated at our institution. Both rapidly developed renal failure. In one patient, liver disease was the result of alcohol abuse, and in the other, was due to malnutrition associated with obesity and acute weight loss. The only reasonable therapeutic approach for these patients was believed to be a course of peritoneal dialysis, along with other supportive measures. In both cases, the management was successful. Furthermore, it was possible to discontinue dialysis at the time of discharge. We conclude that peritoneal dialysis can be a life-saving procedure in patients with severe liver disease and ascites complicated by renal failure.


1993 progress report from the International Bone Marrow Transplant Registry. Advisory Committee of the International Bone Marrow Transplant Registry.
The International Bone Marrow Transplant Registry is an organization devoted to scientific research in BMT. More than 230 transplant teams worldwide contribute detailed information about recipients of allogeneic and syngeneic BMT for study. Results of analyses are published in medical journals and presented at national and international scientific meetings (more than 60 publications and more than 500 presentations in the past 4 years). This collaborative research program has grown rapidly with more than 2000 cases reported annually. This report summarizes results of several recent investigations and reviews the state of BMT in leukemia and aplastic anemia.


Demonstration of Both a Photosynthetic and a Nonphotosynthetic CO(2) Requirement for NH(4) Assimilation in the Green Alga Selenastrum minutum.
Nitrogen-limited and nitrogen-sufficient cell cultures of Selenastrum minutum (Naeg.) Collins (Chlorophyta) were used to investigate the dependence of NH(4) (+) assimilation on exogenous CO(2). N-sufficient cells were only able to assimilate NH(4) (+) maximally in the presence of CO(2) and light. Inhibition of photosynthesis with 3-(3,4-dichlorophenyl)-1,1-dimethylurea, diuron also inhibited NH(4) (+) assimilation. These results indicate that NH(4) (+) assimilation by N-sufficient cells exhibited a strict requirement for photosynthetic CO(2) fixation. N-limited cells assimilated NH(4) (+) both in the dark and in the light in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea, diuron, indicating that photosynthetic CO(2) fixation was not required for NH(4) (+) assimilation. Using CO(2) removal techniques reported previously in the literature, we were unable to demonstrate CO(2)-dependent NH(4) (+) assimilation in N-limited cells. However, employing more stringent CO(2) removal techniques we were able to show a CO(2) dependence of NH(4) (+) assimilation in both the light and dark, which was independent of photosynthesis. The results indicate two independent CO(2) requirements for NH(4) (+) assimilation. The first is as a substrate for photosynthetic CO(2) fixation, whereas the second is a nonphoto-synthetic requirement, presumably as a substrate for the anaplerotic reaction catalyzed by phosphoenolpyruvate carboxylase.


Osteosarcoma: then and now. A fifty year review at Royal Prince Alfred Hospital.
The purpose of this study is to review survival, treatment methods and criteria for diagnosis of osteosarcoma at Royal Prince Alfred Hospital during two periods in the last 50 years. The records of 22 patients diagnosed with osteosarcoma and nine with osteosarcoma in Paget's disease (from 1939 to 1950) were reviewed. All but one had died within three years. One patient survived six years. The second series was taken from 1983 to 1990. Forty-nine patients, including three with Paget's sarcoma, were studied. Probability of survival was estimated by actuarial analysis using Kaplan-Meier curves. Overall survival was estimated at 45%. Those patients who were free of metastatic disease at the conclusion of their treatment were estimated to have a probability of survival of 85%.


Development of an ethanolic two-phase system (ETPS) based on polypropylene glycol 2000 + ethylene glycol + ethanol for separation of hydrophobic compounds.
This work reports, for the first time, an Ethanolic Two-Phase System (ETPS) based on polypropylene glycol 2000 (PPG 2000), mono-, di-, tri-ethylene glycol, and ethanol. An ionic liquid (IL) (1-butyl-3-methylpyridinium chloride) was used as an adjuvant. This ETPS shows promising results for the extraction of highly hydrophobic compounds. Bixin (model of hydrophobic compounds) migrates completely to the PPG 2000-rich phase, while ascorbic acid (hydrophilic compound) migrated to the opposite phase.


Exchange of 20-kDa myosin light chain-bound phosphate during sustained contraction of arterial smooth muscle.
K(+)-contracted porcine carotid arterial muscles containing phosphorylated 20-kDa myosin light chains (LC) were exposed to carrier-free [32P]orthophosphate in K(+)-stimulating solution during sustained contraction. The covalently bound LC phosphate was completely replaced by [32P]phosphate, indicating that myosin light chain phosphatase and kinase have ready access to the bound phosphate during the sustained contraction. On average, 0.38 mol [32P]phosphate was incorporated per mole LC during the sustained K+ contraction. This value was about half of the maximal value for [32P]phosphate incorporation into LC, 0.74 mol/mol, in muscles contracted with K+ for 1 min. Assuming that sustained contraction involves the maximal number of cross-bridges attached to actin, the data suggest that half of the attached cross-bridges contain phosphorylated LC.


Indirect cost-effectiveness analyses of abatacept and rituximab in patients with moderate-to-severe rheumatoid arthritis in the United States.
To estimate the incremental cost per quality-adjusted life-years (QALYs) for abatacept and rituximab, in combination with methotrexate, relative to methotrexate alone in patients with active rheumatoid arthritis (RA). A patient-level simulation model was used to depict the progression of functional disability over the lifetimes of women aged 55-64 years with active RA and inadequate response to a tumor necrosis factor (TNF)-alpha antagonist therapy. Future health-state utilities and medical care costs were based on projected values of the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients were assumed to receive abatacept or rituximab in combination with methotrexate until death or therapy discontinuation due to lack of efficacy or adverse events. HAQ-DI improvement at month 6, after adjustments for control drug (methotrexate) response, was derived from two clinical trials. Costs of medical care and biologic drugs, discounted at 3% annually, were from the perspective of a US third-party payer and expressed in 2007 US dollars. Relative to methotrexate alone, abatacept/methotrexate and rituximab/methotrexate therapies were estimated to yield an average of 1.25 and 1.10 additional QALYs per patient, at mean incremental costs of $58,989 and $60,380, respectively. The incremental cost-utility ratio relative to methotrexate was $47,191 (95% CI $44,810-49,920) per QALY gained for abatacept/methotrexate and $54,891 (95% CI $52,274-58,073) per QALY gained for rituximab/methotrexate. At an acceptability threshold of $50,000 per QALY, the probability of cost effectiveness was 90% for abatacept and 0.0% for rituximab. Abatacept was estimated to be more cost effective than rituximab for use in RA from a US third-party payer perspective. However, head-to-head clinical trials and long-term observational data are needed to confirm these findings.


The use of recombinant human granulocyte colony-stimulating factor in combination with single or fractionated doses of ifosfamide and doxorubicin in patients with advanced soft tissue sarcoma.
Sixty patients with stage III-B and IV soft tissue sarcomas were randomized to receive either ifosfamide 5 g/m2xdx1 and doxorubicin 60 mg/m2xdx1 given every 3 weeks (arm A) or ifosfamide 1.8 g/m2xdx5 and doxorubicin 60 mg/m2xdx1 given every 4 weeks (arm B). Recombinant human granulocyte colony-stimulating factor (r-met Hu G-CSF: 250 micrograms/m2xd) was applied with a prophylactic intent to patients in arm A only. The response rate was higher in arm A patients (56% versus 33%, p = 0.03). In stage III patients, the complete response rate was significantly higher (53% versus, 13.3%, p = 0.01) and the duration of response was significantly longer in arm A (20 +/- 8.2 months versus, 13.4 +/- 7 months, p = 0.05). Chemotherapy related myelotoxicity and mucositis were also less frequent in this arm as a result of prophylactic r-met Hu G-CSF administration (p = 0.04, p = 0.003). It was concluded that single dose ifosfamide and doxorubicin combinations deserve further investigation under the cover of hematopoietic growth factors, particularly in patients with stage III soft tissue sarcomas.


Calcium hydroxide intracanal medication effects on pain and flare-up: a systematic review and meta-analysis.
This study aimed to systematically review the pain and flare-up effects of calcium hydroxide (CH) as intracanal medication (ICM) in non-vital mature teeth. Electronic-databases searching for published and grey literature and manual searching were conducted. Only randomized clinical trials (RCTs) were included comparing CH to other ICMs in non-vital mature teeth. The risk of bias was assessed using the RoB 2.0 Cochrane tool. The main outcomes were pain and flare-up. Qualitative and quantitative analysis, wherever applicable, was performed. The certainty of evidence (CoE) was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Sixteen articles were included in 6 comparisons at different time points for different outcomes. CH reduced pain risk than no ICM within the 1-14-days interval (p < 0.05) and than triple-antibiotic paste within the first day (p < 0.05) and was similar to corticosteroid/antibiotics combination (p > 0.05). Chlorhexidine (CHX) or CH/CHX, however, reduced pain levels than CH alone (p < 0.05). CH showed higher flare-up risk than CHX (p < 0.05). CoE, however, ranged from very low to moderate. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required. PROSPERO database Identifier: CRD42016041953.


Pollinator Foraging Strategies in Mixed Floral Arrays: Density Effects and Floral Constancy
The profitability of any foraging strategy may be in part dependent on the number of foragers adopting it, and so it can be viewed mathematically as a "game." We explore here the implications of a game-theoretic model of pollinators foraging on a mixed array of two flower species, with individual pollinators either specializing on one or the other, or else acting as generalists. We further allow for the possibility of specialist advantages in foraging efficiency. The predicted mixture of pollinator behavioral strategies depends on the overall floral density and the relative densities of the two flower species. Where floral resources are scarce, pollinators should behave as generalists whereas when resources are superabundant, specialization on the single most profitable flower type (all else being equal, the commonest one) is favored. At intermediate floral densities, a mix of floral specializations (floral constancy) is favored, so long as the rarer flower's density does not fall below some critical minimum level. Where the rarer flower is too rare, a mixture of generalists and common-species specialists is favored. Rare flowers are at a reproductive disadvantage in all cases, but their relative success is highest where their pollinators are flower constant.


Fluorescence in situ hybridization for detecting erbB-2 amplification in breast tumor fine needle aspiration biopsies.
To evaluate the feasibility of erbB-2 amplification analysis of fine needle aspiration (FNA) biopsies. FNA smears and dissociated nuclei from 58 breast cancer samples were examined by dual-labeling fluorescence in situ hybridization (FISH) with probes for centromere 17 and the erbB-2 gene. The results were compared with the outcome of erbB-2 immunohistochemistry. Tumors were categorized according to the erbB-2/centromere 17 signal ratio. There were 23 tumors with high-level amplification, four cases with a low-level erbB-2 gain and 27 tumors with normal erbB-2 content. Four tumors showed an erbB-2 deletion, all in patients < or = 42 years of age. ErbB-2 amplification was strongly associated with positive erbB-2 immunostaining (P < .0001). Comparison of FISH analysis on dissociated cells and on FNA biopsies showed high correspondence (P < .0001). FISH allows reliable detection of erbB-2 gene amplification on FNA biopsies.


Ischemic colitis masquerading as colonic tumor: case report with review of literature.
Ischemic colitis can mimic a carcinoma on computed tomographic (CT) imaging or endoscopic examination. A coexisting colonic carcinoma or another potentially obstructing lesion has also been described in 20% of the cases of ischemic colitis. CT scan can differentiate it from colon cancer in 75% of cases. However, colonoscopy is the preferred method for diagnosing ischemic colitis as it allows for direct visualization with tissue sampling. Varied presentations of ischemic colitis have been described as an ulcerated or submucosal mass or as a narrowed segment of colon with ulcerated mucosa on colonoscopy. Awareness and early recognition of such varied presentations of a common condition is necessary to differentiate from a colonic carcinoma, and to avoid unnecessary surgery and related complications.


Progression in neuronal processing for saccadic eye movements from parietal cortex area lip to superior colliculus.
Neurons in both the lateral intraparietal area (LIP) of the monkey parietal cortex and the intermediate layers of the superior colliculus (SC) are activated well in advance of the initiation of saccadic eye movements. To determine whether there is a progression in the covert processing for saccades from area LIP to SC, we systematically compared the discharge properties of LIP output neurons identified by antidromic activation with those of SC neurons collected from the same monkeys. First, we compared activity patterns during a delayed saccade task and found that LIP and SC neurons showed an extensive overlap in their responses to visual stimuli and in their sustained activity during the delay period. The saccade activity of LIP neurons was, however, remarkably weaker than that of SC neurons and never occurred without any preceding delay activity. Second, we assessed the dependence of LIP and SC activity on the presence of a visual stimulus by contrasting their activity in delayed saccade trials in which the presentation of the visual stimulus was either sustained (visual trials) or brief (memory trials). Both the delay and the presaccadic activity levels of the LIP neuronal sample significantly depended on the sustained presence of the visual stimulus, whereas those of the SC neuronal sample did not. Third, we examined how the LIP and SC delay activity relates to the future production of a saccade using a delayed GO/NOGO saccade task, in which a change in color of the fixation stimulus instructed the monkey either to make a saccade to a peripheral visual stimulus or to withhold its response and maintain fixation. The average delay activity of both LIP and SC neuronal samples significantly increased by the advance instruction to make a saccade, but LIP neurons were significantly less dependent on the response instruction than SC neurons, and only a minority of LIP neurons was significantly modulated. Thus despite some overlap in their discharge properties, the neurons in the SC intermediate layers showed a greater independence from sustained visual stimulation and a tighter relationship to the production of an impending saccade than the LIP neurons supplying inputs to the SC. Rather than representing the transmission of one processing stage in parietal cortex area LIP to a subsequent processing stage in SC, the differences in neuronal activity that we observed suggest instead a progressive evolution in the neuronal processing for saccades.


Psychological Distress in Healthcare Workers between the First and Second COVID-19 Waves: The Role of Personality Traits, Attachment Style, and Metacognitive Functioning as Protective and Vulnerability Factors.
The COVID-19 pandemic has impacted the mental health of healthcare workers (HCWs) since its outbreak, but little attention has been paid to person-level vulnerability and protective factors. This study aims to determine the prevalence of both general and pandemic-related psychological distress among HCWs between the first and second COVID-19 waves in Italy and analyze associations between psychological distress and personality traits, attachment style, and metacognitive functioning. Between June and October 2020, 235 Italian HCWs completed questionnaires concerning psychological stress, personality traits, attachment style, and metacognitive functioning; 26.5% of respondents presented with moderate to extremely severe levels of general psychological distress and 13.8% with moderate to extremely severe levels of pandemic-related psychological distress. After controlling for demographic and occupational variables, significant associations emerged among high emotional stability as a personality trait and both general (aOR: 0.58, 95% CI: 0.41-0.79) and pandemic-related psychological stress (aOR: 0.62, 95% CI: 0.41-0.90). Additionally, higher scores regarding one's ability to understand others' emotional states were associated with lower odds of developing psychological distress (aOR: 0.78, 95% CI: 0.63-0.93). Lastly, when comparing those with fearful attachment styles to those with secure attachments, the aOR for psychological distress was 4.73 (95% CI: 1.45-17.04). These results highlight the importance of conducting baseline assessments of HCWs' person-level factors and providing regular screenings of psychological distress.


Clinical features and molecular analysis of Hb H disease in Taiwan.
Thalassemia is highly prevalent in Taiwan, but limited data are available about the association between genotypes and clinical manifestations in Taiwanese patients with Hb H disease. Here, we studied α-globin gene abnormalities and clinical features in Taiwanese patients with Hb H disease. Of the 90 patients, sixty-four (71.1%) were deletional and twenty-six (28.9%) were nondeletional Hb H disease. The (- -(SEA)) type of α(0)-thalassemia mutation was detected in the majority of patients (>95%). The most common genotype was (- -(SEA)/-α(3.7)), followed by (- -(SEA)/α(cs)α). After further investigation of the genotype-phenotype correlation in 68 patients, we found that patients with nondeletional Hb H disease had more severe clinical features than those with deletional Hb H disease, including younger age at diagnosis, more requirement of blood transfusions, and larger proportion of patients with splenomegaly, hepatomegaly or jaundice. This is probably a consequence of the lower hemoglobin levels and the higher Hb H levels. The clinical severity was highly variable even among patients with an identical genotype, and the diversity was much more profound among patients with (- -/α(cs)α) genotype. Therefore, predicting the phenotype directly from the genotype in Hb H disease remains relatively difficult in Taiwan.


A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1.
In the unfolded protein response, the type I transmembrane protein Ire1 transmits an endoplasmic reticulum (ER) stress signal to the cytoplasm. We previously reported that under nonstressed conditions, the ER chaperone BiP binds and represses Ire1. It is still unclear how this event contributes to the overall regulation of Ire1. The present Ire1 mutation study shows that the luminal domain possesses two subregions that seem indispensable for activity. The BiP-binding site was assigned not to these subregions, but to a region neighboring the transmembrane domain. Phenotypic comparison of several Ire1 mutants carrying deletions in the indispensable subregions suggests these subregions are responsible for multiple events that are prerequisites for activation of the overall Ire1 proteins. Unexpectedly, deletion of the BiP-binding site rendered Ire1 unaltered in ER stress inducibility, but hypersensitive to ethanol and high temperature. We conclude that in the ER stress-sensory system BiP is not the principal determinant of Ire1 activity, but an adjustor for sensitivity to various stresses.


Micronutrient intake, from diet and supplements, and association with status markers in pre- and post-RYGB patients.
Roux-en-Y gastric bypass (RYGB) is associated with an increased risk for micronutrient deficiencies. This study aimed to assess total (dietary and supplement) intake and association with iron (including hepcidin), vitamin B12, vitamin C and zinc status markers before and after Roux-en-Y gastric bypass (RYGB). This prospective study included patients with a planned RYGB in University Hospitals Leuven, Belgium; who were followed until 12 months post-RYGB. Patients completed an estimated dietary record of two non-consecutive days before and 1, 3, 6 and 12 months post-RYGB and supplement/drug use was registered. Associations between total micronutrient intake and status markers were analyzed. Fifty-four patients (21 males; mean age: 48.0 [95%CI 46.6; 49.3] years; mean preoperative BMI: 40.4 [95%CI 39.4; 41.4] kg/m2) were included. One month post-RYGB, usual dietary intake of the studied micronutrients was significantly decreased compared to pre-RYGB, but gradually increased until 12 months post-RYGB, remaining below baseline values. By including micronutrient supplement intake, 12 months post-RYGB values were higher than baseline, except for zinc. Hemoglobin, ferritin, vitamin B12 and C-reactive protein serum concentrations were significantly decreased and transferrin saturation and mean corpuscular volume were significantly increased 12 months post-RYGB. Serum hepcidin concentration was significantly decreased 6 months post-RYGB. Medical nutritional therapy is essential following RYGB as dietary intake of iron, vitamin B12, vitamin C, copper and zinc was markedly decreased postoperatively and some patients still had an inadequate total intake one year post-RYGB.


A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo.
Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.


A deep transfer learning model with classical data augmentation and CGAN to detect COVID-19 from chest CT radiography digital images.
The Coronavirus disease 2019 (COVID-19) is the fastest transmittable virus caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). The detection of COVID-19 using artificial intelligence techniques and especially deep learning will help to detect this virus in early stages which will reflect in increasing the opportunities of fast recovery of patients worldwide. This will lead to release the pressure off the healthcare system around the world. In this research, classical data augmentation techniques along with Conditional Generative Adversarial Nets (CGAN) based on a deep transfer learning model for COVID-19 detection in chest CT scan images will be presented. The limited benchmark datasets for COVID-19 especially in chest CT images are the main motivation of this research. The main idea is to collect all the possible images for COVID-19 that exists until the very writing of this research and use the classical data augmentations along with CGAN to generate more images to help in the detection of the COVID-19. In this study, five different deep convolutional neural network-based models (AlexNet, VGGNet16, VGGNet19, GoogleNet, and ResNet50) have been selected for the investigation to detect the Coronavirus-infected patient using chest CT radiographs digital images. The classical data augmentations along with CGAN improve the performance of classification in all selected deep transfer models. The outcomes show that ResNet50 is the most appropriate deep learning model to detect the COVID-19 from limited chest CT dataset using the classical data augmentation with testing accuracy of 82.91%, sensitivity 77.66%, and specificity of 87.62%.


Clinical Outcomes in Older Patients Aged over 75 Years Who Underwent Early Surgical Treatment for Pyogenic Vertebral Osteomyelitis.
Older patients with pyogenic vertebral osteomyelitis (PVO) usually have more medical comorbidities compared with younger patients, and present with advanced infections from different causative organisms. To aid surgical decision-making, we compared surgical outcomes of older patients with PVO to those who underwent nonoperative treatment. We identified the risk factors for adverse post-operative outcomes, and analyzed the clinical risks from further spinal instrumentation. This retrospective comparative study included 439 patients aged ≥75 years with PVO. Multivariable analysis was performed to compare treatment outcomes among three groups: 194, 130, and 115 patients in the non-operative, non-instrumented, and instrumented groups, respectively. The risk factors for adverse outcomes after surgical treatment were evaluated using a logistic regression model, and the estimates of the multivariable models were internally validated using bootstrap samples. Recurrence and mortality of these patients were closely associated with neurologic deficits, and increased surgical invasiveness, resulting from additional spinal instrumentation, did not increase the risk of recurrence or mortality. We propose that surgical treatment for these patients should focus on improving neurologic deficits through immediate and sufficient removal of abscesses. Spinal instrumentation can be performed if indicated, within reasonable clinical risk.


Similarities between UDP-glucose and adenine nucleotide release in yeast: involvement of the secretory pathway.
Extracellular UDP-glucose is a natural purinergic receptor agonist, but its mechanisms of cellular release remain unclear. We studied these mechanisms in Saccharomyces cerevisiae, a simple model organism that releases ATP, another purinergic agonist. Similar to ATP, UDP-glucose was released by S. cerevisiae at a rate that was linear over time. However, unlike ATP release, UDP-glucose release was not dependent on glucose stimulation. This discrepancy was resolved by demonstrating the apparent glucose stimulation of ATP release reflected glucose-dependent changes in the intracellular pattern of adenine nucleotides, with AMP release dominating in the absence of glucose. Indeed, total adenine nucleotide release, like UDP-glucose release, did not vary with glucose concentration over the short term. The genetic basis of UDP-glucose release was explored through analysis of deletion mutants, aided by development of a novel bioassay for UDP-glucose based on signaling through heterologously expressed human P2Y 14 receptors. Using this assay, an elevated rate of UDP-glucose release was demonstrated in mutants lacking the putative Golgi nucleotide sugar transporter YMD8. An increased rate of UDP-glucose release in ymd8Delta was reduced by deletion of the YEA4 UDP- N-acetylglucosamine or the HUT1 UDP-galactose transporters, and overexpression of YEA4 or HUT1 increased the rate of UDP-glucose release. These findings suggest an exocytotic release mechanism similar to that of ATP, a conclusion supported by decreased rates of ATP, AMP, and UDP-glucose release in response to the secretory inhibitor Brefeldin A. These studies demonstrate the involvement of the secretory pathway in nucleotide and nucleotide sugar efflux in yeast and offer a powerful model system for further investigation.


Definition of the interacting interfaces of Apobec3G and HIV-1 Vif using MAPPIT mutagenesis analysis.
The host restriction factor Apobec3G is a cytidine deaminase that incorporates into HIV-1 virions and interferes with viral replication. The HIV-1 accessory protein Vif subverts Apobec3G by targeting it for proteasomal degradation. We propose a model in which Apobec3G N-terminal domains symmetrically interact via a head-to-head interface containing residues 122 RLYYFW 127. To validate this model and to characterize the Apobec3G-Apobec3G and the Apobec3G-Vif interactions, the mammalian protein-protein interaction trap two-hybrid technique was used. Mutations in the head-to-head interface abrogate the Apobec3G-Apobec3G interaction. All mutations that inhibit Apobec3G-Apobec3G binding also inhibit the Apobec3G-Vif interaction, indicating that the head-to head interface plays an important role in the interaction with Vif. Only the D128K, P129A and T32Q mutations specifically affect the Apobec3G-Vif association. In our model, D128, P129 and T32 cluster at the edge of the head-to-head interface, possibly forming a Vif binding site composed of two Apobec3G molecules. We propose that Vif either binds at the Apobec3G head-to-head interface or associates with an RNA-stabilized Apobec3G oligomer.


The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.
GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.