Endothelial to Mesenchymal Transition in the Cardiogenesis and Cardiovascular Diseases.
Today, cardiovascular diseases remain a leading cause of morbidity and mortality worldwide. Endothelial to mesenchymal transition (EndMT) does not only play a major role in the course of development but also contributes to several cardiovascular diseases in adulthood. EndMT is characterized by down-regulation of the endothelial proteins and highly up-regulated fibrotic specific genes and extracellular matrix-forming proteins. EndMT is also a transforming growth factor- β-driven (TGF-β) process in which endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype with expression of α-smooth muscle actin (α-SMA), fibroblastspecific protein 1, etc. EndMT is a vital process during cardiac development, thus disrupted EndMT gives rise to the congenital heart diseases, namely septal defects and valve abnormalities. In this review, we have discussed the main signaling pathways and mechanisms participating in the process of EndMT such as TGF-β and Bone morphogenetic protein (BMP), Wnt#, and Notch signaling pathway and also studied the role of EndMT in physiological cardiovascular development and pathological conditions including myocardial infarction, pulmonary arterial hypertension, congenital heart defects, cardiac fibrosis, and atherosclerosis. As a perspective view, having a clear understanding of involving cellular and molecular mechanisms in EndMT and conducting Randomized controlled trials (RCTs) with a large number of samples for involving pharmacological agents may guide us into novel therapeutic approaches of congenital disorders and heart diseases.


Risperidone-induced hepatotoxicity in children and adolescents? A chart review study.
Risperidone is an atypical antipsychotic drug that has been used in the treatment of numerous psychiatric disorders in children and adolescents. The question of whether risperidone-induced weight gain is associated with steatohepatitis has recently been raised. The purpose of this chart review was to ascertain: (1) the rate of liver dysfunction observed during risperidone treatment in children and adolescents; and (2) the clinical factors associated with liver dysfunction. For purposes of this chart review study, abnormal liver function was defined by serum transaminase or bilirubin values falling outside the normal laboratory ranges. Chart reviews were completed on 38 youths with ages ranging from 5-17 years with a variety of psychiatric diagnoses. The mean length of risperidone treatment was 15.2 months at a mean dose of 2.5 mg/day. It was found that 37 of the 38 youths treated with risperidone had no liver enzyme abnormalities at the end of study. One subject had an alanine aminotransferase (ALT) level of 46 U/L which was 7 U/L above the upper limit of normal for this laboratory test. This isolated value was not considered clinically significant. These data were noted in spite of weight gain and the use of numerous concomitant psychotropic medications. These findings suggest that risperidone in short term treatment does not commonly lead to evidence of abnormal liver function at therapeutic doses in children and adolescents. Larger-scale, prospective studies are needed in order to confirm these findings.


Identification of the Transcriptional Regulatory Role of RUNX2 by Network Analysis in Lung Cancer Cells.
The use of a new bioinformatics pipeline allowed the identification of deregulated transcription factors (TFs) coexpressed in lung cancer that could become biomarkers of tumor establishment and progression. A gene regulatory network (GRN) of lung cancer was created with the normalized gene expression levels of differentially expressed genes (DEGs) from the microarray dataset GSE19804. Moreover, coregulatory and transcriptional regulatory network (TRN) analyses were performed for the main regulators identified in the GRN analysis. The gene targets and binding motifs of all potentially implicated regulators were identified in the TRN and with multiple alignments of the TFs' target gene sequences. Six transcription factors (E2F3, FHL2, ETS1, KAT6B, TWIST1, and RUNX2) were identified in the GRN as essential regulators of gene expression in non-small-cell lung cancer (NSCLC) and related to the lung tumoral process. Our findings indicate that RUNX2 could be an important regulator of the lung cancer GRN through the formation of coregulatory complexes with other TFs related to the establishment and progression of lung cancer. Therefore, RUNX2 could become an essential biomarker for developing diagnostic tools and specific treatments against tumoral diseases in the lung after the experimental validation of its regulatory function.


Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol.
Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.


Otitis media in young Aboriginal children from remote communities in Northern and Central Australia: a cross-sectional survey.
Middle ear disease (otitis media) is common and frequently severe in Australian Aboriginal children. There have not been any recent large-scale surveys using clear definitions and a standardised middle ear assessment. The aim of the study was to determine the prevalence of middle ear disease (otitis media) in a high-risk population of young Aboriginal children from remote communities in Northern and Central Australia. 709 Aboriginal children aged 6-30 months living in 29 communities from 4 health regions participated in the study between May and November 2001. Otitis media (OM) and perforation of the tympanic membrane (TM) were diagnosed by tympanometry, pneumatic otoscopy, and video-otoscopy. We used otoscopic criteria (bulging TM or recent perforation) to diagnose acute otitis media. 914 children were eligible to participate in the study and 709 were assessed (78%). Otitis media affected nearly all children (91%, 95%CI 88, 94). Overall prevalence estimates adjusted for clustering by community were: 10% (95%CI 8, 12) for unilateral otitis media with effusion (OME); 31% (95%CI 27, 34) for bilateral OME; 26% (95%CI 23, 30) for acute otitis media without perforation (AOM/woP); 7% (95%CI 4, 9) for AOM with perforation (AOM/wiP); 2% (95%CI 1, 3) for dry perforation; and 15% (95%CI 11, 19) for chronic suppurative otitis media (CSOM). The perforation prevalence ranged from 0-60% between communities and from 19-33% between regions. Perforations of the tympanic membrane affected 40% of children in their first 18 months of life. These were not always persistent. Overall, 1 in every 2 children examined had otoscopic signs consistent with suppurative ear disease and 1 in 4 children had a perforated tympanic membrane. Some of the children with intact tympanic membranes had experienced a perforation that healed before the survey. In this high-risk population, high rates of tympanic perforation were associated with high rates of bulging of the tympanic membrane.


Boosting MS1-only Proteomics with Machine Learning Allows 2000 Protein Identifications in Single-Shot Human Proteome Analysis Using 5 min HPLC Gradient.
Proteome-wide analyses rely on tandem mass spectrometry and the extensive separation of proteolytic mixtures. This imposes considerable instrumental time consumption, which is one of the main obstacles in the broader acceptance of proteomics in biomedical and clinical research. Recently, we presented a fast proteomic method termed DirectMS1 based on ultrashort LC gradients as well as MS1-only mass spectra acquisition and data processing. The method allows significant reduction of the proteome-wide analysis time to a few minutes at the depth of quantitative proteome coverage of 1000 proteins at 1% false discovery rate (FDR). In this work, to further increase the capabilities of the DirectMS1 method, we explored the opportunities presented by the recent progress in the machine-learning area and applied the LightGBM decision tree boosting algorithm to the scoring of peptide feature matches when processing MS1 spectra. Furthermore, we integrated the peptide feature identification algorithm of DirectMS1 with the recently introduced peptide retention time prediction utility, DeepLC. Additional approaches to improve the performance of the DirectMS1 method are discussed and demonstrated, such as using FAIMS for gas-phase ion separation. As a result of all improvements to DirectMS1, we succeeded in identifying more than 2000 proteins at 1% FDR from the HeLa cell line in a 5 min gradient LC-FAIMS/MS1 analysis. The data sets generated and analyzed during the current study have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD023977.


Transposon-mediated gene transfer into adult and induced pluripotent stem cells.
Transposon technology is a particularly attractive non-viral gene delivery paradigm that allows for efficient genomic integration into a variety of different cell types. In particular, transposon-mediated gene transfer is a promising tool for stem cell research, by virtue of its ability to efficiently and stably transfer genes into adult and induced pluripotent stem (iPS) cells. Moreover, transposons open up new perspectives for non-viral-mediated stem cell-based gene therapy. Several transposon systems, especially the Sleeping Beauty (SB), the piggyBac (PB) and Tol2, have been optimized for gene transfer into mammalian cells. In particular, SB resulted in stable gene transfer into various adult stem cells including human CD34(+) hematopoietic stem cells (HSCs), myoblasts and mesenchymal stem cells (MSCs). This has been confirmed with PB, yielding stable gene transfer in human CD34(+) HSCs. Recently, PB transposons were used to deliver the genes encoding the reprogramming factors into somatic cells making it an attractive technology for generating iPS cells. Subsequent de novo expression of the PB transposase resulted in traceless excision of the reprogramming cassette. This prevented inadvertent re-expression of the reprogramming factors obviating some of the concerns associated with the use of integrating vectors. Transposons have also been used as a novel non-viral paradigm to coax differentiation of iPS cells into their desired target cells by forced expression of specific differentiation factors. This review focuses on the emerging potential of transposons for gene transfer into stem cells and its implications for gene therapy and regenerative medicine.


The molecular appearance of native TRPM7 channel complexes identified by high-resolution proteomics.
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed membrane protein consisting of ion channel and protein kinase domains. TRPM7 plays a fundamental role in the cellular uptake of divalent cations such as Zn2+, Mg2+, and Ca2+, and thus shapes cellular excitability, plasticity, and metabolic activity. The molecular appearance and operation of TRPM7 channels in native tissues have remained unresolved. Here, we investigated the subunit composition of endogenous TRPM7 channels in rodent brain by multi-epitope affinity purification and high-resolution quantitative mass spectrometry (MS) analysis. We found that native TRPM7 channels are high-molecular-weight multi-protein complexes that contain the putative metal transporter proteins CNNM1-4 and a small G-protein ADP-ribosylation factor-like protein 15 (ARL15). Heterologous reconstitution experiments confirmed the formation of TRPM7/CNNM/ARL15 ternary complexes and indicated that complex formation effectively and specifically impacts TRPM7 activity. These results open up new avenues towards a mechanistic understanding of the cellular regulation and function of TRPM7 channels.


Signatures of human European Palaeolithic expansion shown by resequencing of non-recombining X-chromosome segments.
Human genetic diversity in Europe has been extensively studied using uniparentally inherited sequences (mitochondrial DNA (mtDNA) and the Y chromosome), which reveal very different patterns indicating sex-specific demographic histories. The X chromosome, haploid in males and inherited twice as often from mothers as from fathers, could provide insights into past female behaviours, but has not been extensively investigated. Here, we use HapMap single-nucleotide polymorphism data to identify genome-wide segments of the X chromosome in which recombination is historically absent and mutations are likely to be the only source of genetic variation, referring to these as phylogeographically informative haplotypes on autosomes and X chromosome (PHAXs). Three such sequences on the X chromosome spanning a total of ~49 kb were resequenced in 240 males from Europe, the Middle East and Africa at an average coverage of 181 ×. These PHAXs were confirmed to be essentially non-recombining across European samples. All three loci show highly homogeneous patterns across Europe and are highly differentiated from the African sample. Star-like structures of European-specific haplotypes in median-joining networks indicate past population expansions. Bayesian skyline plots and time-to-most-recent-common-ancestor estimates suggest expansions pre-dating the Neolithic transition, a finding that is more compatible with data on mtDNA than the Y chromosome, and with the female bias of X-chromosomal inheritance. This study demonstrates the potential of the use of X-chromosomal haplotype blocks, and the utility of the accurate ascertainment of rare variants for inferring human demographic history.


Short Communication: Nonprogressive HIV-1 Infection Is Associated with Expansion of IL-21R Expressing Class-Switched Memory B Cells.
HIV perturbs the functionality of B cells resulting in defective humoral responses. As efficient humoral immune responses are important in controlling HIV-disease progression, we characterized the memory B cell population for its subsets and their activation (CD38 expression) and functional [interleukin (IL)-21R expression] profile in individuals with nonprogressive [long-term nonprogressors (LTNPs), N = 16] and progressive HIV disease (progressors, N = 16) along with 10 HIV uninfected healthy controls (HCs). The frequencies of total memory B cells were similar in HCs and HIV-infected individuals, whereas the frequencies of unswitched memory B (UMB) cells and CD38+ UMB cells were significantly higher in progressors than LTNPs and HCs (p < .03). LTNPs showed higher frequencies of class-switched memory B (SMB) cells and IL-21R expressing SMB cells than seen in progressors (p = .019), which were similar to that seen in HCs. The %UMB cells correlated inversely (p = .0002, r = -0.6053) and %SMB cells correlated positively (p = .0005, r = 0.5804) with CD4 count. IL-21/IL-21R interaction is required for class switching of B cells and differentiation into antibody-secreting plasma cells. The higher expression of IL-21R on class SMB cells from LTNPs might be resulting in efficient plasma cell differentiation and the functional humoral immune response that might be responsible for mounting efficient antibody response against the encountered infections. The more insights in this area might be required to further understand the role of IL-21R expressing class SMB cells in HIV infection.


Chiari network--case report and brief literature review.
Chiari networks are present in the right atrium in a minority of the population and are usually of no clinical significance. On the other hand it may associate some pathological changes, as patent foramen ovale, intraatrial thrombus or atrial arrhythmias. We present the case of an asymptomatic young woman diagnosed with Chiari network during a routine echocardiography.


Inhaled nitric oxide for acute chest syndrome in people with sickle cell disease.
Acute chest syndrome has been defined as a new infiltrate visible on chest radiograph associated with one or more symptoms, such as fever, cough, sputum production, tachypnea, dyspnea, or new-onset hypoxia. Symptoms and complications of this syndrome, whether of infectious or non-infectious origin, vary quite widely in people with sickle cell disease. Lung infection tends to predominate in children, whilst infarction appears more common in adults. However, these are often interrelated and may occur concurrently. The differences in clinical course and severity are suggestive of multiple causes for acute chest syndrome. Successful treatment depends principally on high-quality supportive care. The syndrome and its treatment have been extensively studied, but the response to antibiotics, anticoagulants, and other conventional therapies remains disappointing. The potential of inhaled nitric oxide as a treatment option has more recently provoked considerable interest. Nitric oxide appears to play a major role in both the regulation of vascular muscle tone at the cellular level and in platelet aggregation (clumping). Much of the pathophysiology of sickle cell disease is consistent with a mechanism of nitric oxide depletion and although there has been extensive research on the pathophysiology of acute chest syndrome, the possible therapeutic role of inhaled nitric oxide for acute chest syndrome in sickle cell disease is still to be determined. To assess the effectiveness of inhaled nitric oxide for treating acute chest syndrome by comparing improvement in symptoms and clinical outcomes against standard care. We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. In July 2007 the following clinical trials registers were searched: ClinicalTrials.gov (www.clinicaltrials.gov/); the WHO International Clinical Trials Registry Platform (www.who.int/trialsearch/); Current Controlled Trials (www.controlled-trials.com/) and CLINICALTRIALS.COM (www.clinicaltrials.com/). Most recent search of the Trials Register: November 2007. All randomised or quasi-randomised controlled trials of people with sickle cell disease suffering from acute chest syndrome, comparing the use of inhaled nitric oxide to placebo or standard care for any single or multiple treatment and over any time period. No studies identified were eligible for inclusion. No studies identified were eligible for inclusion. There is a need for well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of this form of treatment as an adjunct to established therapies.


[Cavinton in the prevention of the convulsive syndrome in children after birth injury].
The authors studied the efficacy of cavinton as an agent helpful in preventing neurologic disorders in the newborn with hypoxic ischemic encephalopathy due to intracranial birth trauma. The short-term results of the treatment were elucidated in 61 children. In group I including 20 persons given conventional therapy, the disappearance of seizures was recorded in 6 patients; out of 41 children (group II) given additionally cavinton, in 27. Twenty-nine children were followed up for a year. In group I, convulsive paroxysms recurred in 4 patients, whereas in the group II children, no convulsive syndrome was recorded on the follow-up. The group II children also showed a decrease of the phenomena of intracranial hypertension and normalization of the psychomotor development. The preventive effect of cavinton seen in children with a history of birth trauma may be accounted for by its capacity of normalizing cerebrovascular disorders and by its own anticonvulsive properties.


Toward novel inhibitors against KdsB: a highly specific and selective broad-spectrum bacterial enzyme.
KdsB (3-deoxy-manno-octulosonate cytidylyltransferase) is a highly specific and selective bacterial enzyme that catalyzes KDO (3-Deoxy-D-mano-oct-2-ulosonic acid) activation in KDO biosynthesis pathway. Failure in KDO biosynthesis causes accumulation of lipid A in the bacterial outer membrane that leads to cell growth arrest. This study reports a combinatorial approach comprising virtual screening of natural drugs library, molecular docking, computational pharmacokinetics, molecular dynamics simulation, and binding free energy calculations for the identification of potent lead compounds against the said enzyme. Virtual screening demonstrated 1460 druglike compounds in a total of 4800, while molecular docking illustrated Ser13, Arg14, and Asp236 as the anchor amino acids for recognizing and binding the inhibitors. Functional details of the enzyme in complex with the best characterized compound-226 were explored through two hundred nanoseconds of MD simulation. The ligand after initial adjustments jumps into the active cavity, followed by the deep cavity, and ultimately backward rotating movement toward the initial docked site of the pocket. During the entire simulation period, Asp236 remained in contact with the ligand and can be considered as a major catalytic residue of the enzyme. Radial distribution function confirmed that toward the end of the simulation, strengthening of ligand-receptor occurred with ligand and enzyme active residues in close proximity. Binding free energy calculations via MM(PB/GB)SA and Waterswap reaction coordinates, demonstrated the high affinity of the compound for enzyme active site residues. These findings can provide new avenues for designing potent compounds against notorious bacterial pathogens.


Camel Milk Has Beneficial Effects on Diabetes Mellitus: A Systematic Review.
Controlling diabetes, a worldwide metabolic disease, by effective alternative treatments is currently a topic of great interest. Camel milk is believed to be a suitable hypoglycemic agent in experimental animals and patients with diabetes. The current systematic review aimed at evaluating the effect of camel milk on diabetes. A comprehensive search was dine in PubMed and Scopus for all clinical trials and animal studies documented up to 2015, which focused on the effect of camel milk on diabetes markers. Studies which assessed the effects of camel milk, with no dose limit, on glucose parameters and lipid profiles in animals or humans with diabetes, were included. The quality of the included clinical trials was evaluated by the Delphi score checklist. The initial search yielded 73 articles. After screening abstracts and full texts, 22 articles were included consisting of 11 animal studies and 11 clinical trials, 8 of which focused on type 1 diabetes and the other three on type 2diabetes. All animal studies except for 1 showed significant reductions in at least 1 of the diabetes parameters such as blood glucose, insulin resistance, glycated hemoglobin, and lipid profile. In most of the clinical trials, the recommended dose of camel milk was 500 mL/day, which led to improvement of diabetes markers even after 3 months in patients with diabetes. Most of the studies in the current systematic review demonstrated the favorable effects of camel milk on diabetes mellitus by reducing blood sugar, decreasing insulin resistance and improving lipid profiles.


High initial frequency of TCR-transgenic CD8 T cells alters inflammation and pathogen clearance without affecting memory T cell function.
In adoptive transfer experiments, the initial frequency of naïve TCR-transgenic T cells impacts CD8 T cell phenotype after acute infections. The exact reasons for the observed changes, however, are unclear and it is unknown whether alterations in phenotype translate into impaired memory T cell function as well. Here we perform in vivo comparisons of effector and memory CD8 T cells generated from high or low numbers of naïve precursors. We show that high numbers of adoptively transferred T cells exhibit effector functions that alter systemic inflammation and pathogen abundance in the initial days after infection. While these altered environmental conditions resulted in profound changes in primary effector and memory CD8 T cell phenotype, memory T cells derived from both high and low numbers of naïve precursors protected equally well against re-infection and generated secondary effector and memory T cells that were similar in numbers and phenotype. Our results confirm the necessity to use low numbers of naïve precursors to mimic endogenous immune responses but show at the same time that memory CD8 T cell function in adoptive transfers is independent of input numbers.


New Technologies in Rice Derivatives.
In this research the incapsulation of ferulic acid (FA) in advanced systems of protection with the aim of improving its stability and photostability was studied. Lipoparticles and polymeric microparticles as incapsulation systems were prepared and characterized. Lipoparticles were completely of natural origin, while microparticles were obtained using chitosan as natural polymer. In both systems FA stability was greatly increased and its organoleptic properties in the emulsions did not change.


Influence of leg muscle vibration on human walking.
We studied the effect of vibratory stimulation of different leg muscles [bilateral quadriceps (Q), hamstring (HS) muscles, triceps surae (TS), and tibialis anterior (TA)] in seven normal subjects during 1) quiet standing, 2) stepping in place movements, and 3) walking on the treadmill. The experiments were performed in a dimly illuminated room, and the subjects were given the instruction not to resist the applied perturbation. In one condition the velocity of the treadmill was controlled by a feedback from the subject's current position. In normal standing, TA vibration elicited a prominent forward body tilt, whereas HS and TS vibration elicited backward trunk or whole body inclination, respectively. Q vibration had little effect. During stepping in place, continuous HS vibration produced an involuntary forward stepping at about 0.3 m s(-1) without modifying the stepping frequency. When the subjects (with eyes closed) kept a hand contact with an external still object, they did not move forward but perceived an illusory forward leg flexion relative to the trunk. Q, TS, and TA vibration did not cause any systematic body translation nor illusory changes in body configuration. In treadmill locomotion, HS vibration produced an involuntary steplike increase of walking speed (by 0.1-0.6 m.s(-1)). Continuous vibration elicited larger speed increments than phasic stimulation during swing or stance phase. For phasic stimulation, HS vibration tended to be more effective when applied during swing than during stance phase. Q, TA, and TS vibration had little if any effect. Vibration of thigh muscles altered the walking speed depending on the direction of progression. During backward locomotion, the walking speed tended to decrease after HS vibration, whereas it significantly increased after Q vibration. Thus the influence of leg muscle vibration on stepping in place and locomotion differed significantly from that on normal posture. We suggest that the proprioceptive input from thigh muscles may convey information about the velocity of the foot movement relative to the trunk.


Arabidopsis ACYL-ACTIVATING ENZYME 9 (AAE9) encoding an isobutyl-CoA synthetase is a key factor connecting branched-chain amino acid catabolism with iso-branched wax biosynthesis.
Iso-branched wax compounds are well known in plants, but their biosynthetic pathways are still mostly unknown. It has been speculated that branched waxes are derived from branched-chain amino acid (BCAA) catabolism, but the evidence for this is very limited. Gas chromatography-flame ionisation detection (GC-FID) analysis revealed that mutations in two subunits of the branched-chain ketoacid dehydrogenase (BCKDH) complex, a key enzyme complex in the degradation of BCAAs, significantly decreased the amounts of branched wax compounds, indicating that BCAA degradation may be integral to the synthesis of iso-branched wax. Substrate feeding studies further revealed that the metabolic precursor of iso-branched wax compounds is isobutyric acid (iBA), which is derived from valine degradation in Arabidopsis. We also isolated a novel mutant and found that its branched wax deficient phenotype could not be rescued by iBA. Map-based cloning together with complementation analysis revealed that mutation in ACYL-ACTIVATING ENZYME 9 (AAE9) is responsible for this phenotype. Genetic and enzyme activity analysis demonstrated that AAE9 is located downstream of the BCAA degradation pathway, and that it activates iBA to isobutyryl-CoA for use on branched wax synthesis. Taken together, our study demonstrates that AAE9 is a key factor connecting BCAA catabolism with branched wax biosynthesis.


Organocatalytic asymmetric spirocyclization reactions of cyclic 2,4-dienones with cyanoketones: synthesis of spiro-dihydropyrano cyclohexanones.
The first organocatalytic asymmetric synthesis of spiro-dihydropyrano cyclohexanones has been developed via the cascade reaction between cyanoketones and cyclic 2,4-dienones. A cinchona alkaloid-derived bifunctional primary amine catalyst in combination with N-Boc-tleucine was found to be the most effective for this spirocyclization reaction and provided the desired products in moderate to good yields with high enantioselectivities.


Transcriptional Targeting of Dendritic Cells Using an Optimized Human Fascin1 Gene Promoter.
Deeper knowledge about the role of the tumor microenvironment (TME) in cancer development and progression has resulted in new strategies such as gene-based cancer immunotherapy. Whereas some approaches focus on the expression of tumoricidal genes within the TME, DNA-based vaccines are intended to be expressed in antigen-presenting cells (e.g., dendritic cells, DCs) in secondary lymphoid organs, which in turn induce anti-tumor T cell responses. Besides effective delivery systems and the requirement of appropriate adjuvants, DNA vaccines themselves need to be optimized regarding efficacy and selectivity. In this work, the concept of DC-focused transcriptional targeting was tested by applying a plasmid encoding for the luciferase reporter gene under the control of a derivative of the human fascin1 gene promoter (pFscnLuc), comprising the proximal core promoter fused to the normally more distantly located DC enhancer region. DC-focused activity of this reporter construct was confirmed in cell culture in comparison to a standard reporter vector encoding for luciferase under the control of the strong ubiquitously active cytomegalovirus promoter and enhancer (pCMVLuc). Both plasmids were also compared upon intravenous administration in mice. The organ- and cell type-specific expression profile of pFscnLuc versus pCMVLuc demonstrated favorable activity especially in the spleen as a central immune organ and within the spleen in DCs.


Antioxidant drugs to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: What does evidence suggest?
To determine whether or not the use of antioxidant supplementation aids in the prevention of post- endoscopic retrograde cholangiopancreatography pancreatitis. A systematic review of randomized controlled trials (RCTs) was made to evaluate the preventive effect of prophylactic antioxidant supplementation in post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The inclusion criteria included: acute post-endoscopic retrograde cholangiopancreatography pancreatitis in adults; randomized clinical trials with the use of any antioxidant as an intervention compared with placebo, to reduce PEP. The outcome measure was the incidence and severity of PEP. Twelve RCTs involving 3110 patients since 1999 were included. The antioxidants used were selenite, β-carotene, and pentoxifylline (each one in one trial), N-acetylcysteine (NAC) in three trials, and allopurinol in six trials. The group of patients treated with NAC received different doses; either oral or intravenous, and allopurinol-treated patients received five different oral doses in two different administration periods. The results are expressed with raw numbers, proportions, as well as mean and standard deviations. The incidence of pancreatitis between groups was analyzed with Pearson's χ(2) test or Fisher's exact test (F). The main outcome is expressed as relative risks and 95%CI. The incidence of pancreatitis in all antioxidant treatment groups was 8.6%, whereas it was 9.7% in the control group. The antioxidants used were selenite, β-carotene, and pentoxifylline (each one in one trial), NAC in three trials, and allopurinol in six trials. In allopurinol trials, three different dosifications were used; two trials reported a low dosage (of less than 400 mg), two trials reported a moderate dose (600 mg) and the remaining two employed higher doses (more than 900 mg). Supplementation was not associated with a significant reduction in the incidence of PEP [relative risk (RR) = 0.93; 95%CI: 0.82-1.06; P = 0.28]. In addition, the incidences of PEP in patients treated with allopurinol and those treated with other antioxidants were similar to that observed in patients who received the placebo (RR for trials with allopurinol, 0.92; 95%CI: 0.78-1.08; P = 0.31) and, with the use of other antioxidants, the incidence of PEP was 8.9%, whereas it was 9.7% in the control group (RR = 0.95; 95%CI: 0.77-1.18; P = 0.19). Antioxidant supplementation shows no beneficial effect on the incidence of PEP. There is a lack of robust trials to support the use of antioxidants for prevention.


Robust pose estimation which guarantees positive depths.
In the area of 3D computer vision, the ability to estimate pose between two cameras under high noise levels while maintaining small reprojection errors reflects the robustness of such pose estimation algorithms. Moreover, maintaining positive depth constraint is another challenging task. Unfortunately, current pose estimation algorithms are often sensitive to noise/outliers and do not always guarantee positive depths. As a standalone task, these algorithms perform a positive sign check and simply discard the points with negative depths after the algorithms are executed. These algorithms do not integrate positive depth constraints into the algorithms themselves. Instead, they do it afterwards. Here, from a comprehensive mathematical derivation, we propose a novel pose estimation algorithm that integrates positive depth constraint into the algorithm itself by estimating the depths directly. The algorithm was competitive in producing small reprojection errors when compared to the state-of-the-art algorithms under both synthetic and real-world tests, while most importantly guaranteeing positive depths.


The German Hypertension League (Deutsche Hochdruckliga) Quality Seal Protocol for blood pressure-measuring devices: 15-year experience and results from 105 devices for home blood pressure control.
The German Hypertension League (Deutsche Hochdruckliga) established a program to assess the accuracy and reliability of blood pressure (BP)-measuring devices in 1999 (Quality Seal Protocol). Here, we report on the results of a testing series of 105 devices designed for BP self-measurement. The test protocol for the validation of upper-arm, wrist, and finger devices was developed to compare device to conventional Riva-Rocci measurements based on five criteria: mean systolic and mean diastolic differences, their standard deviations, and a point score representing the correlation of systolic and diastolic errors of individual comparisons. The results of this testing are summarized. From 1999 to 2014, a total of 105 BP devices for self-measurement were tested according to the Quality Seal Protocol. Of these, 47.6% fulfilled all five validation criteria, 55.7% of the upper-arm devices (39 of 71) and 32.4% (11 of 34) of the wrist devices. Finger devices were not offered for testing. Forty-four devices (41.9%) failed multiple test criteria of the validation procedure. A subanalysis with 51 devices tested showed that a stricter definition of the passing point score with a limit of at least 55% would slightly increase the consistency with the conventional criteria in comparison with a point score criterion of at least 50%. It was therefore introduced in 2007. The results indicate the importance of a rigorous testing of a BP-measuring device used for home BP measurement to prevent patients from making erroneous treatment decisions.


Renal Tubular Acidosis in Patients with Primary Sjögren's Syndrome.
Primary Sjögren's syndrome (pSS) is characterized by lymphocytic infiltration of the exocrine glands resulting in decreased saliva and tear production. It uncommonly involves the kidneys in various forms, including tubulointerstitial nephritis, renal tubular acidosis, Fanconi syndrome, and rarely glomerulonephritis. Its clinical symptoms include muscle weakness, periodic paralysis, and bone pain due to metabolic acidosis and electrolyte imbalance. Herein, we describe the cases of two women with pSS whose presenting symptoms involve the kidneys. They had hypokalemia and normal anion gap metabolic acidosis due to distal renal tubular acidosis and positive anti-SS-A and anti-SS-B autoantibodies. Since one of them experienced femoral fracture due to osteomalacia secondary to renal tubular acidosis, an earlier diagnosis of pSS is important in preventing serious complications.


Hospitalisation in short-stay units for adults with internal medicine diseases and conditions.
Short-stay units are hospital units that provide short-term care for selected patients. Studies have indicated that short-stay units might reduce admission rates, time of hospital stays, hospital readmissions and expenditure without compromising the quality of care. Short-stay units are often defined by a target patient category, a target function, and a target time frame. Hypothetically, short-stay units could be established as part of any department, but this review focuses on short-stay units that provide care for participants with internal medicine diseases and conditions. To assess beneficial and harmful effects of short-stay unit hospitalisation compared with usual care in people with internal medicine diseases and conditions. We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to 13 December 2017 together with reference checking, citation searching and contact with study authors to identify additional studies. We also searched several grey literature sources and performed a forward citation search for included studies. We included randomised trials and cluster-randomised trials, comparing hospitalisation in a short-stay unit with usual care (hospitalisation in a traditional hospital ward or other services). We defined a short-stay unit to be a hospital ward where the targeted length of stay in hospital for patients was five days or less. We included both multipurpose and specialised short-stay units. Participants were adults admitted to hospital with an internal medicine disease or condition. We excluded surgical, obstetric, psychiatric, gynaecological, and ambulatory participants. Trials were included irrespective of publication status, date, and language. We used standard methodological procedures expected by Cochrane. Two review authors independently extracted data and assessed the risk of bias of each included trial. We measured intervention effect sizes by meta-analyses for two primary outcomes, mortality and serious adverse events, and one secondary outcome, hospital readmission. We narratively reported the following important outcomes: quality of life, activities of daily living, non-serious adverse events, and costs. We used risk ratio differences of 15% for mortality and of 20% for serious adverse events for minimal relevant clinical consideration. We rated the certainty of the evidence and the strength of recommendations of the outcomes using the GRADE approach. We included 19 records reporting on 14 randomised trials with a total of 2872 participants. One trial was ongoing. Thirteen trials evaluated short-stay unit hospitalisation for six specific conditions (acute decompensated heart failure (one trial), asthma (one trial), atrial fibrillation (one trial), chest pain (seven trials), syncope (two trials), and transient ischaemic attack (one trial)) and one trial investigated participants presenting with miscellaneous internal medicine disease and conditions. The components of the intervention differed among the trials as dictated by the trial participants' condition. All included trials were at high risk of bias.The certainty of the evidence for all outcomes was very low. Consequently, it is uncertain whether hospitalisation in short-stay units compared with usual care reduces mortality (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.47 to 1.15) 5 trials (seven additional trials reporting on 1299 participants reported no deaths in either group)); serious adverse events (RR 0.95, 95% CI 0.59 to 1.54; 7 trials (one additional trial with 108 participants reported no serious adverse events in either group)), and hospital readmission (RR 0.80, 95% CI 0.54 to 1.19, 8 trials (one additional trial with 424 participants did not report results for participants)). There was not enough information to confirm or refute that short-stay unit hospitalisation had relevant effects on quality of life, activities of daily living, non-serious adverse events, and costs. Overall, the quantity and the certainty of the evidence was very low. Consequently, it is uncertain whether there are any beneficial or harmful effects of short-stay unit hospitalisation for adults with internal medicine diseases and conditions - more trials comparing the effects of short-stay units with usual care are needed. Such trials ought to be conducted with low risk of bias and low risks of random errors to improve the overall confidence in the evidence.


Investigation of the structure of lipid A from Actinobacillus actinomycetemcomitans strain Y4 and human clinical isolate PO 1021-7.
The lipopolysaccharides of Actinobacillus actinomycetemcomitans strain Y4 and a human clinical isolate PO 1021-7 were examined by SDS/PAGE, deoxycholate/PAGE and mass spectrometry. PAGE analysis revealed an electrophoretic pattern similar to the SR-type lipopolysaccharide (LPS) of Salmonella. Deoxycholate/PAGE indicated the LPS of A. actinomycetemcomitans to consist of short sugar chains. Chemical analysis revealed the presence of thiobarbituric-acid-positive material (3-deoxy-D-manno-octulosonic acid equivalents) and four neutral sugars: glucose, galactose, D-glycero-D-manno-heptose and L-glycero-D-manno-heptose. Phosphate, glucosamine, glycine, and the fatty acids, 3-hydroxymyristic acid, myristic acid and palmitic acid, comprised the remainder of the molecule. The structure of the free lipid A revealed it to consist of a 1,6-glucosamine disaccharide esterified at C4' by a phosphomonoester. The hydroxyl group at C3 and the amide group of the non-reducing glucosamine were both acylated by 3-myristoylmyristic acid; analogous sites on the reducing glucosamine were acylated by 3-hydroxymyristic acid. Hydroxyl groups at C4 and C6' in the free lipid A were unsubstituted, with C6 being the proposed attachment site of the polysaccharide moiety. Chemical analysis revealed the presence of glycine in the intact LPS; its exact location in the A. actinomycetemcomitans LPS is still to be determined. Both intact LPS and free lipid A were highly lethal to galactosamine-sensitized mice, comparable to that of Salmonella.


Functional and molecular analysis of three distinct HLA-DR4 beta-chains responsible for the MLR between HLA-Dw4, Dw15, and DKT2.
Differences in structure and function of HLA-class II molecules between HLA-DR4-related HLA-D specificities HLA-Dw4, Dw15, and DKT2 were investigated. Anti-HLA-DR framework monoclonal antibody HU-4 completely inhibited the one-way mixed lymphocyte reaction (MLR) between these specificities. HU-4 precipitated a monomorphic alpha-chain and a polymorphic beta-chain of human class II molecules from each B lymphoblastoid cell line (BLCL) homozygous for these three HLA-D specificities. We established IL 2-dependent T cell lines specific for streptococcal cell wall (SCW) antigen from peripheral blood lymphocytes (PBL) from four DR4-positive donors: an HLA-Dw4/DKT2 heterozygote, an HLA-Dw4/Dw12 heterozygote, an HLA-DKT2/D-blank heterozygote, and an HLA-Dw15/D-blank heterozygote. These T cell lines showed a proliferative response to SCW antigen in the presence of autologous or allogeneic antigen-presenting cells (APC) when T cell donors and APC donors shared at least one of the HLA-D specificities. This cooperation between the T cell line and APC was completely blocked by HU-4. We conclude from these data that the T cells could distinguish three distinct DR4 molecules expressed on APC of HLA-Dw4, Dw15, and DKT2 as restriction molecules at the presentation of SCW antigen.


Assessment of Acute Pulmonary Embolism by Computer-Aided Technique: A Reliability Study.
BACKGROUND Acute pulmonary embolism is one of the most common cardiovascular diseases. Computer-aided technique is widely used in chest imaging, especially for assessing pulmonary embolism. The reliability and quantitative analyses of computer-aided technique are necessary. This study aimed to evaluate the reliability of geometry-based computer-aided detection and quantification for emboli morphology and severity of acute pulmonary embolism. MATERIAL AND METHODS Thirty patients suspected of acute pulmonary embolism were analyzed by both manual and computer-aided interpretation of vascular obstruction index and computer-aided measurements of emboli quantitative parameters. The reliability of Qanadli and Mastora scores was analyzed using computer-aided and manual interpretation. RESULTS The time costs of manual and computer-aided interpretation were statistically different (374.90±150.16 versus 121.07±51.76, P<0.001). The difference between the computer-aided and manual interpretation of Qanadli score was 1.83±2.19, and 96.7% (29 out of 30) of the measurements were within 95% confidence interval (intraclass correlation coefficient, ICC=0.998). The difference between the computer-aided and manual interpretation of Mastora score was 1.46±1.62, and 96.7% (29 out of 30) of the measurements were within 95% confidence interval (ICC=0.997). The emboli quantitative parameters were moderately correlated with the Qanadli and Mastora scores (all P<0.001). CONCLUSIONS Computer-aided technique could reduce the time costs, improve the and reliability of vascular obstruction index and provided additional quantitative parameters for disease assessment.


Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.
In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. National Institutes of Health Clinical Center. Seventeen of the original 18 patients with advanced Parkinson disease complicated by dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. Parkinsonian symptoms and dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.


Molecular aspects of glucose dehydration by chromium chlorides in ionic liquids.
A combined experimental and computational study of the ionic-liquid-mediated dehydration of glucose and fructose by Cr(II) and Cr(III) chlorides has been performed. The ability of chromium to selectively dehydrate glucose to 5-hydroxymethylfurfural (HMF) in the ionic liquid 1-ethyl-3-methyl imidazolium chloride does not depend on the oxidation state of chromium. Nevertheless, Cr(III) exhibits higher activity and selectivity to HMF than Cr(II) . Anhydrous CrCl(2) and CrCl(3)⋅6 H(2)O readily catalyze glucose dehydration with HMF yields of 60 and 72%, respectively, after 3 h. Anhydrous CrCl(3) has a lower activity, because it only slowly dissolves in the reaction mixture. The transformation of glucose to HMF involves the formation of fructose as an intermediate. The exceptional catalytic performance of the chromium catalysts is explained by their unique ability to catalyze glucose to fructose isomerization and fructose to HMF dehydration with high selectivity. Side reactions leading to humins by means of condensation reactions take predominantly place during fructose dehydration. The higher HMF selectivity for Cr(III) is tentatively explained by the higher activity in fructose dehydration compared to Cr(II) . This limits the concentration of intermediates that are involved in bimolecular condensation reactions. Model DFT calculations indicate a substantially lower activation barrier for glucose isomerization by Cr(III) compared to Cr(II) . Qualitatively, glucose isomerization follows a similar mechanism for Cr(II) and Cr(III) . The mechanism involves ring opening of D-glucopyranose coordinated to a single Cr ion, followed by a transient self-organization of catalytic chromium complexes that promotes the rate-determining hydrogen-shift step.


Single-molecule nanopositioning: structural transitions of a helicase-DNA complex during ATP hydrolysis.
The conformational states of Escherichia coli Rep helicase undergoing ATP hydrolysis while bound to a partial-duplex DNA (pdDNA) were studied using single-molecule FRET. Crystallographic studies showed that Rep bound to single-stranded DNA can exist in open and closed conformations that differ in the orientation of the 2B subdomain. FRET measurements between eight Rep mutants donor-labeled at different residues and pdDNA acceptor-labeled at the junction were conducted at each of the four nucleotide states. The positions of donor-labeled residues, based on crystal structure, and FRET measurements between these donor molecules and the acceptor fluorophore at the DNA junction were used to predict the most likely position for the DNA junction using a triangulation algorithm. These predicted junction positions are compared with the crystal structure to determine whether the open or closed conformation is more consistent with the FRET data. Our data revealed that there are two distinct Rep-pdDNA conformations in the ATPγS and ADP states, an unexpected finding. The primary conformation is similar to that observed in nucleotide-free and ADP.Pi states, and the secondary conformation is a novel conformation where the duplex DNA and 2B subdomain moved as a unit by 13 Å relative to the rest of the protein. The primary conformation found in all nucleotide states is consistent with the closed conformation of the crystal structure however; the secondary conformation is a new conformation that has not been observed before. We discuss the possible implications of this newly observed conformation.


[Indications for 3 D laparoscopy in gynecology].
In a prospective randomised study we investigated the possibilities of a 3 D-video system in comparison to a 2 D-video system in operative laparoscopy. On 76 patients the following operations were performed: enucleation of fibroids, extirpation of ovarian cysts, fimbrioplasty, tubo-tubal anastomosis and Burch's procedure via preperitoneal access. For microsurgical procedures of the adnexae the new 3 D-technology shows advantages in compared to the standard 2 D-laparoscopy. In these operations the operating area is naturally limited, and hence the disadvantages of the 3 D-technology like limited depth of focus are not important. The 3 D-system allows a very good visualisation even of small structures and safe and exact handling. For surgery of the uterus or larger tumours of the adnexae, the new technology is unsuited.


Renal nerves are not necessary for onset or maintenance of DOC-salt hypertension in rats.
The effect of renal denervation on the onset and maintenance of mineralocorticoid-salt [deoxycorticosterone (DOC)-salt] hypertension was determined. A unilateral right nephrectomy was performed on all rats. Rats were divided into renal-denervated and sham-operated groups. All rats received 10 mg/wk of DOC pivalate and 0.9% saline to drink ad libitum. Renal denervation was repeated at 3-wk intervals to prevent renal nerve regeneration. Renal denervation had no effect on the onset or maintenance of DOC-salt hypertension. Hypertension developed over the same time course in both the renal-denervated and sham-operated rats regardless of the time frame of unilateral nephrectomy and renal denervation. Tail-cuff pressure measurements reached plateau levels of 187 +/- 5.7 mmHg in sham-operated and 183 +/- 4.6 mmHg in renal-denervated rats after 4 wk of DOC-salt administration. Mean arterial pressure averaged 197 +/- 10.3 mmHg in sham-operated and 200 +/- 7.9 mmHg in renal-denervated rats after 8 wk of treatment. Intact renal nerves are not necessary for the development or maintenance of DOC-salt hypertension in rats.


Nucleosome positioning and histone modifications define relationships between regulatory elements and nearby gene expression in breast epithelial cells.
The precise nature of how cell type specific chromatin structures at enhancer sites affect gene expression is largely unknown. Here we identified cell type specific enhancers coupled with gene expression in two different types of breast epithelial cells, HMEC (normal breast epithelial cells) and MDAMB231 (triple negative breast cancer cell line). Enhancers were defined by modified neighboring histones [using chromatin immunoprecipitation followed by sequencing (ChIP-seq)] and nucleosome depletion [using formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq)]. Histone modifications at enhancers were related to the expression levels of nearby genes up to 750 kb away. These expression levels were correlated with enhancer status (poised or active), defined by surrounding histone marks. Furthermore, about fifty percent of poised and active enhancers contained nucleosome-depleted regions. We also identified response element motifs enriched at these enhancer sites that revealed key transcription factors (e.g. TP63) likely involved in regulating breast epithelial enhancer-mediated gene expression. By utilizing expression data, potential target genes of more than 600 active enhancers were identified. These genes were involved in proteolysis, epidermis development, cell adhesion, mitosis, cell cycle, and DNA replication. These findings facilitate the understanding of epigenetic regulation specifically, such as the relationships between regulatory elements and gene expression and generally, how breast epithelial cellular phenotypes are determined by cell type specific enhancers.


Chemical Composition, Antioxidant, Anti-Inflammatory, and Antiproliferative Activities of the Plant Lebanese Crataegus Azarolus L.
BACKGROUND In the present study, phytochemical screening, antioxidant, anti-inflammatory, and antiproliferative capacities of 3 extracts from leaves of Lebanese Crataegus azarolus L. were evaluated. MATERIAL AND METHODS Fresh leaves were dissolved in 3 different solvents: distilled water, ethanol, and methanol. The chemical composition was determined using high-performance liquid chromatography (HPLC) and the content of essential oil of this plant was examined by gas chromatography (GC) coupled with mass spectrometry (MS). The antioxidant potential was evaluated using DPPH radical scavenging and Fe2+ chelating activity assays. Anti-inflammatory effect was investigated by measuring the secreted amounts of the proinflammatory mediator PGE2 using ELISA technique, as well as by assaying the mRNA levels of the proinflammatory cytokines (IL-α, IL-β, and Il-6), chemokines (CCL3 and CCL4) and inflammation-sensitive COX2 and iNOS enzymes using quantitative real-time PCR (qRT-PCR). The antiproliferative effect was evaluated using the XTT viability assay. RESULTS The obtained results show that alcohol (methanol and ethanol) extracts were rich in bioactive molecules with medical relevance and exerted substantial antioxidant, anti-inflammatory, and antiproliferative capacities. On the other hand, aqueous extract contained fewer chemical components and exhibited less therapeutic efficiency. CONCLUSIONS Our observations indicate that Crataegus azarolus L. could be used for treating diseases related to oxidative stress, inflammatory reactions, and uncontrolled cell growth.


HPV16 infection regulates RASSF1A transcription mediated by p53.
Human papillomavirus (HPV) 16 infection and RASSF1A expression play important roles in tumor development and progression. However, the precise mechanisms underlying their concerted function in the development of reproductive system tumors still remain to be elucidated. In the present study, we showed that HPV16-E6 selectively upregulates RASSF1A expression via degradation of p53, which interacts with the RASSF1A promoter and regulates apoptosis. Overexpression of p53 triggered a decrease in endogenous RASSF1A in SiHa cells, accompanied by apoptosis. Similarly, knockdown of endogenous HPV16-E6 in SiHa cells with RNA interference (RNAi) led to downregulation of RASSF1A mediated by p53 and the subsequent induction of apoptosis. These findings collectively suggest that HPV16 infection regulates p53-mediated RASSF1A expression and suppresses apoptosis. Moreover, RASSF1A may form an element of the negative autoregulatory feedback loops that act on the HPV16 response and are involved in p53-dependent apoptosis. Our results provide novel insights into the cellular mechanism of tumor development, and present a starting point for the development of novel strategies in cancer treatment and effective diagnosis.


No relative increase in intra-abdominal adipose tissue in healthy unstressed preterm infants at term.
Preterm infants may be at risk for altered adiposity, a known risk factor for unfavorable metabolic and cardiovascular outcomes. The aim was to compare body composition (total body fat mass (FM), subcutaneous and intra-abdominal adipose tissue (AT)) between infants born preterm and at term. We conducted an observational, cross-sectional study that involved 50 infants born preterm free from major co-morbidities and 34 term healthy breastfed infants. Anthropometric measurements, body composition (total body FM, subcutaneous and intra-abdominal AT) were assessed at 40-42 weeks postconceptional age for preterm infants and within 15 days of birth for term infants. Total body FM was assessed by an air displacement plethysmography system and subcutaneous abdominal and intra-abdominal AT were assessed by magnetic resonance imaging using a commercially available software program. Compared to term infants, mean (SD) total body FM (g) (636.7 (247) vs. 418.4 (253), p < 0.0001) and mean (SD) subcutaneous abdominal AT (g) (123 (36) vs. 98.9 (22), p < 0.001) were significantly higher in preterm infants but mean (SD) fat-free mass (g) (2,530 (420) vs. 2,965 (389), p < 0.0001) and mean (SD) intra-abdominal AT (10.9 (5.2) vs. 18.2 (13.2), p = 0.001) were significantly lower. In the absence of severe illness during the hospital stay, prematurity, although associated with increased total body FM, does not appear to be associated with a relative increase in intra-abdominal AT compared to term infants.


Ultrasonic head controller for powered wheelchairs.
This report describes an evaluation by the Department of Veterans Affairs, Rehabilitation Research and Development Service, Technology Transfer Section (TTS). The Ultrasonic Head Controller Unit (UHCU) is the result of research and development conducted by the Palo Alto VA Rehabilitation Research and Development Center, under sponsorship of the Paralyzed Veterans of America and the VA Rehabilitation Research and Development Service. The UHCU provides an alternative to currently available human/machine interfaces for severely disabled individuals. Unlike switches or proportional joysticks, the UHCU operates without physical contact between the unit and the user. The UHCU produces analog signals in direct response to changes in the head position of the user. These signals can be used to control a variety of communication, robotic, mobility, and recreational devices. This clinical evaluation explored the use of the UHCU for powered wheelchair control by quadriplegic individuals.


The Effect of Social Support on Treatment Adherence in Hypertension in China.
Treatment nonadherence is a major problem in the management of hypertension. There are many factors influencing the treatment adherence of hypertensive patients. The aim of this study was to examine the effect of social support on the treatment adherence in hypertension in China. A total of 453 patients with hypertension hospitalized in a tertiary hospital in Xi'an, China were invited to participate in this cross-sectional study. Data were collected by "modified Chinese Hill-Bone compliance to high blood pressure therapy scale" and "Chinese Family Support Scale". It was found that 31.1% of patients were adherent with their antihypertensive treatments. Gender, duration of antihypertensive drug used, number of antihypertensive drugs used and social support were independently associated with hypertensive treatment adherence. Social support was strongly and positively associated with the hypertensive treatment adherence (P<0.001, OR = 0.752, 95% CI: 0.678-0.833). Family social support was provided to hypertensive patients mainly through their nuclear family, that is spouses, partner or children. Treatment adherence of hypertensive patients was positively correlated to the three subgroups of social support. It was found that social support provided to patients from social resource (r=0.568) had greater impact on treatment adherence than that from kinship (r=0.364) and nuclear family (r=0.262). Treatment adherence of patients with hypertension was found to increase positively as their social support increased. In addition to the support given to patients from nuclear family members, other social support especially professional agencies and community organizations should also be promoted and strengthened.


Modeling upper eyelid kinematics during spontaneous and reflex blinks.
To test a mathematical model for measuring blinking kinematics. Spontaneous and reflex blinks of 23 healthy subjects were recorded with two different temporal resolutions. A magnetic search coil was used to record 77 blinks sampled at 200 Hz and 2 kHz in 13 subjects. A video system with low temporal resolution (30 Hz) was employed to register 60 blinks of 10 other subjects. The experimental data points were fitted with a model that assumes that the upper eyelid movement can be divided into two parts: an impulsive accelerated motion followed by a damped harmonic oscillation. All spontaneous and reflex blinks, including those recorded with low resolution, were well fitted by the model with a median coefficient of determination of 0.990. No significant difference was observed when the parameters of the blinks were estimated with the under-damped or critically damped solutions of the harmonic oscillator. On the other hand, the over-damped solution was not applicable to fit any movement. There was good agreement between the model and numerical estimation of the amplitude but not of maximum velocity. Spontaneous and reflex blinks can be mathematically described as consisting of two different phases. The down-phase is mainly an accelerated movement followed by a short time that represents the initial part of the damped harmonic oscillation. The latter is entirely responsible for the up-phase of the movement. Depending on the instantaneous characteristics of each movement, the under-damped or critically damped oscillation is better suited to describe the second phase of the blink.


myo-Inositol 1,4,5-trisphosphate mobilizes Ca2+ from isolated adipocyte endoplasmic reticulum but not from plasma membranes.
The effects of myo-inositol 1,4,5-trisphosphate (IP3) on Ca2+ uptake and release from isolated adipocyte endoplasmic reticulum and plasma membrane vesicles were investigated. Effects of IP3 were initially characterized using an endoplasmic reticulum preparation with cytosol present (S1-ER). Maximal and half-maximal effects of IP3 on Ca2+ release from S1-ER vesicles occurred at 20 microM- and 7 microM-IP3, respectively, in the presence of vanadate which prevents the re-uptake of released Ca2+ via the endoplasmic reticulum Ca2+ pump. At saturating IP3 concentrations, Ca2+ release in the presence of vanadate was 20% of the exchangeable Ca2+ pool. IP3-induced release of Ca2+ from S1-ER was dependent on extravesicular free Ca2+ concentration with maximal release occurring at 0.13 microM free Ca2+. At 20 microM-IP3 there was no effect on the initial rate of Ca2+ uptake by S1-ER. IP3 promoted Ca2+ release from isolated endoplasmic reticulum vesicles (cytosol not present) to a similar level as compared with S1-ER. Addition of cytosol to isolated endoplasmic reticulum vesicles did not affect IP3-induced Ca2+ release. The endoplasmic reticulum preparation was further fractionated into heavy and light vesicles by differential centrifugation. Interestingly, the heavy fraction, but not the light fraction, released Ca2+ when challenged with IP3. IP3 (20 microM) did not promote Ca2+ release from plasma membrane vesicles and had no effect on the (Ca2+ + Mg2+)-ATPase activity or on the initial rate of ATP-dependent Ca2+ uptake by these vesicles. These results support the concept that IP3 acts exclusively at the endoplasmic reticulum to promote Ca2+ release.


Effects of Peroneal Muscles Fatigue on Dynamic Stability Following Lateral Hop Landing: Time to Stabilization Versus Dynamic Postural Stability Index.
Dynamic stability is a necessary requirement in many sports competitions. Muscle fatigue, which can impair stability, may be occurred in many sports competitions in which lateral movements and landing repeated frequently. To assess the effects of peroneal muscles fatigue on dynamic stability following lateral hop landing through measuring time to stabilization (TTS) and dynamic postural stability index (DPSI). Quasi-experimental. Laboratory study. A total of 20 recreationally active, healthy males with no lower-extremity injury during the previous 6 months participated in this study. Participants performed a lateral hop on a force plate before and immediately after a fatigue intervention using a Biodex dynamometer. For inducing fatigue, the participant made a prolonged eversion effort with 40% of the maximal voluntary contraction. Fatigue was met when the eversion torque declined by 50% of the initial value. TTS and DPSI were calculated using sequential averaging method and relevant formulas, respectively. Premeasures and postmeasures of TTS in the anteroposterior, mediolateral and vertical directions, resultant vector of TTS, stability indices in the anteroposterior, mediolateral and vertical directions, and DPSI. Means of the DPSI or its components did not change significantly due to fatigue (P > .05). Means of the TTS in the anteroposterior and mediolateral directions, and the mean of the resultant vector of the TTS increased significantly after fatigue (P < .05). The question that the dynamic stability is affected or not affected by fatigue depends on which of the TTS or DPSI is used for analysis. The TTS may be a sensitive measure to detect subtle changes in postural stability due to fatigue. But, the DPSI which may be changed after a more strenuous fatigue may be related to actual fatiguing situations.


Molecular epidemiology of airway colonisation by Aspergillus fumigatus in cystic fibrosis patients.
A total of 109 sequential and multiple Aspergillus fumigatus isolates corresponding to 41 samples from seven cystic fibrosis (CF) patients was typed by random amplification of polymorphic DNA (RAPD) with the primer NS3 from the fungal ribosomal gene 18S subunit, and by sequence-specific DNA primer (SSDP) analysis. RAPD typing of the isolates revealed 10 different genotypes, whereas nine genotypes were identified by SSDP. Combination of the two typing methods permitted the differentiation of 25 overall genotypes. The colonisation typing patterns differed greatly between patients colonised for <1 year by A. fumigatus and long-term colonised patients. Two of three recently colonised patients presented a large number of types even in the same sample, unlike the chronically colonised patients, who harboured a limited number of genotypes. In the latter, the occurrence of a dominant genotype, usually the overall genotype 2, tended to reflect to the duration of colonisation. Moreover, anti-catalase antibodies to A. fumigatus appeared in most cases to be in response to genotype 2. These findings suggest that some strains of A. fumigatus may be selected during prolonged colonisation of the airways in CF patients.


The effect of nearby maskers on speech intelligibility in reverberant, multi-talker environments.
The extent to which informational masking (IM) is involved in real-world listening is not well understood. In the literature, IM effects of more than 8 dB are reported, but these experiments typically used simplified spatial configurations and speech materials with exaggerated confusions. Westermann and Buchholz [(2015b). J. Acoust. Soc. Am. 138, 584-593] considered a simulated cafeteria and found only substantial IM effects when the target and maskers were colocated and the same talker. The present study further investigates the relevance of IM in real-world environments, specifically distractions by nearby maskers and the effect of hearing impairment. Speech reception thresholds (SRTs) were measured with normal hearing (NH) and sensorineural hearing impaired (HI) listeners in a simulated cafeteria environment. Three different masker configurations were considered: (1) seven dialogues distributed in the cafeteria, (2) two monologues presented close to the listener with varying angular separation, and (3) a combination of (1) and (2). The contribution of IM was measured as the difference in SRTs between speech maskers and unintelligible vocoded maskers. No significant IM was found with the seven dialogues alone. Including nearby maskers resulted in substantial IM for both NH and HI listeners, suggesting that such maskers might result in IM in real-world environments.


Fine structure histopathology of labyrinthitis ossificans in the gerbil model.
Labyrinthitis ossificans (LO) is the pathological deposition of new bone within the lumen of the cochlea and labyrinth. This process occurs most commonly as a result of infection or inflammation affecting the otic capsule. Trauma and vascular compromise can also lead to neo-ossification within the otic capsule. The mechanism that regulates this process remains unestablished. This study details the end-stage histopathology in high-resolution plastic thin sections. Twenty Mongolian gerbils were infected by intrathecal injection of Streptococcus pneumoniae type 3 followed by subcutaneous penicillin G procaine (8 days) and were painlessly sacrificed 3 months later. The cochleas were serially divided and sectioned for light and electron microscopy. Sixteen of 20 animals (27 of 40 cochleas) demonstrated LO. Cochlear damage was most extensive in the vestibule and basal turn and decreased toward the apex, which often appeared normal. The histopathologic findings consisted of 1) new bone, calcospherites, osteoid, and fibrosis without dense connective tissue or osteoblasts extending from the endosteal wall into the lumen of the vestibule and scala tympani; 2) areas of dense connective tissue and osteoid enclosed by epithelial cells conjoined with the organ of Corti, stria vascularis, spiral ligament, and vestibular (Reissner's) membrane; and 3) partial to complete loss of the organ of Corti, spiral ligament cell bodies, stria vascularis, and spiral ganglion cells. Osteoblastic activity was not demonstrated in end-stage ossification in LO in the gerbil model. Neo-ossification appears to occur by calcospherite deposition along collagen-like fibrils within osteoid. The destruction of the organ of Corti, spiral ganglion cells, stria vascularis, and cells of Reissner's membrane and the spiral ligament occurs even in the absence of ossification of the cochlear duct.


HER2 significance and treatment outcomes after radiotherapy for brain metastases in breast cancer patients.
The aim of this retrospective study was to examine the influence of HER2 status on outcome in breast cancer patients following whole brain radiotherapy (WBRT) for cerebral metastases. One hundred and eighty one patients with recordable HER2 status, who received WBRT at single institution were identified and stratified according to HER2 status. Eighty eight were HER2 positive (HER2+) (49%) and 93 HER2 negative (HER2-) (51%). A total of 72 (82%) HER2+ group developed brain metastases whilst on chemotherapy compared with 45 (48%) in HER2- group. Median survival after WBRT was 8 months (1-38) for HER2+ patients and 4 (1-64) for HER2- patients p=0.01. On brain metastasis progression, 18 (20%) of HER2+ patients received further local therapy compared with 6 (6%) in HER2- group. This study shows superior survival in HER2+ group following WBRT as compared to HER2- group and more aggressive management on disease progression in HER2+ group.


Development and application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE): Initial results from a multi-center study of adults with temporal lobe epilepsy.
[Correction Notice: An Erratum for this article was reported online in Neuropsychology on Sep 15 2022 (see record 2023-01997-001). In the original article, there was an error in Figure 2. In the box at the top left of the figure, the fourth explanation incorrectly stated, "Generalized impairment = At least one test < -1.0 or -1.5SD in three or more domains." The correct wording is "Generalized impairment = At least two tests < -1.0 or -1.5SD in each of three or more domains." All versions of this article have been corrected.] Objective: To describe the development and application of a consensus-based, empirically driven approach to cognitive diagnostics in epilepsy research-The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) and to assess the ability of the IC-CoDE to produce definable and stable cognitive phenotypes in a large, multi-center temporal lobe epilepsy (TLE) patient sample. Neuropsychological data were available for a diverse cohort of 2,485 patients with TLE across seven epilepsy centers. Patterns of impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) using two impairment thresholds (≤1.0 and ≤1.5 standard deviations below the normative mean). Cognitive phenotypes were derived across samples using the IC-CoDE and compared to distributions of phenotypes reported in existing studies. Impairment rates were highest on tests of language, followed by memory, executive functioning, attention/processing speed, and visuospatial ability. Application of the IC-CoDE using varying operational definitions of impairment (≤ 1.0 and ≤ 1.5 SD) produced cognitive phenotypes with the following distribution: cognitively intact (30%-50%), single-domain (26%-29%), bi-domain (14%-19%), and generalized (10%-22%) impairment. Application of the ≤ 1.5 cutoff produced a distribution of phenotypes that was consistent across cohorts and approximated the distribution produced using data-driven approaches in prior studies. The IC-CoDE is the first iteration of a classification system for harmonizing cognitive diagnostics in epilepsy research that can be applied across neuropsychological tests and TLE cohorts. This proof-of-principle study in TLE offers a promising path for enhancing research collaborations globally and accelerating scientific discoveries in epilepsy. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Tectal tumors of childhood: clinical and imaging follow-up.
This study was done to determine which clinical and imaging findings best correlate with outcome in children with tectal tumors. A retrospective review was done of the medical records and imaging studies of 32 children (16 boys and 16 girls; mean age, 8 years) with tectal tumors. Eight children had CT, 11 had MR imaging, and 13 had both CT and MR studies. Findings from surgical and pathologic reports as well as from follow-up examinations (mean follow-up period, 5 years; range, 3.6 months to 17 years) were included in the review. All patients had hydrocephalus and all but one required CSF diversion. The tectum was the center of the tumor in all cases and the majority of the tumors appeared isodense on CT scans, isointense on T1-weighted MR images, and hyperintense on T2-weighted images. Twenty patients required no further treatment. In this group, the mean maximum tumor diameter was 1.8 cm and enhancement occurred in two cases. At follow-up, 18 patients had stable tumor size, one had an increase in tumor size with cyst formation but no worsening of symptoms, and one had a decrease in tumor size. Twelve patients required further treatment (excision and/or radiotherapy) because of progression as indicated by either increased tumor size or worsening of symptoms. In this group, the mean maximum tumor diameter was 2.5 cm and contrast enhancement occurred in nine cases. Further follow-up in this group showed decreased tumor size in eight and stable residual tumor in three. Tectal tumors in childhood have variable behavior. MR imaging assists in the clinical determination of which children need treatment beyond CSF diversion. Larger tumor size and enhancement are radiologic predictors of the need for further treatment.


Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin.
Phytohemagglutinin, an extract of the kidney bean, Phaseolus vulgaris, induces in human leukocyte cultures an inhibitor of the cytopathic effects of Sindbis virus. The physicochemical and biological properties of this virus-inhibitor are similar to those of interferon induced by Newcastle disease virus, except for an instability at pH 2 and 10 and at 56 degrees C.


Creatine is Neuroprotective to Retinal Neurons In Vitro But Not In Vivo.
To investigate the neuroprotective properties of creatine in the retina using in vitro and in vivo models of injury. Two different rat retinal culture systems (one containing retinal ganglion cells [RGC] and one not) were subjected to either metabolic stress, via treatments with the mitochondrial complex IV inhibitor sodium azide, or excitotoxic stress, via treatment with N-methyl-D-aspartate for 24 hours, in the presence or absence of creatine (0.5, 1.0, and 5.0 mM). Neuronal survival was assessed by immunolabeling for cell-specific antigens. Putative mechanisms of creatine action were investigated in vitro. Expression of creatine kinase (CK) isoenzymes in the rat retina was examined using Western blotting and immunohistochemistry. The effect of oral creatine supplementation (2%, wt/wt) on retinal and blood creatine levels was determined as well as RGC survival in rats treated with N-methyl-D-aspartate (NMDA; 10 nmol) or high IOP-induced ischemia reperfusion. Creatine significantly prevented neuronal death induced by sodium azide and NMDA in both culture systems. Creatine administration did not alter cellular adenosine triphosphate (ATP). Inhibition of CK blocked the protective effect of creatine. Retinal neurons, including RGCs, expressed predominantly mitochondrial CK isoforms, while glial cells expressed exclusively cytoplasmic CKs. In vivo, NMDA and ischemia reperfusion caused substantial loss of RGCs. Creatine supplementation led to elevated blood and retinal levels of this compound but did not significantly augment RGC survival in either model. Creatine increased neuronal survival in retinal cultures; however, no significant protection of RGCs was evident in vivo, despite elevated levels of this compound being present in the retina after oral supplementation.


Evaluation of novel disposable bioreactors on pandemic influenza virus production.
Since 1997, the highly pathogenic influenza H5N1 virus has spread from Hong Kong. According to the WHO bulletin report, the H5N1 virus is a zoonotic disease threat that has infected more than 850 humans, causing over 450 deaths. In addition, an outbreak of another new and highly pathogenic influenza virus (H7N9) occurred in 2013 in China. These highly pathogenic influenza viruses could potentially cause a worldwide pandemic. it is crucial to develop a rapid production platform to meet this surge demand against any possible influenza pandemic. A potential solution for this problem is the use of cell-based bioreactors for rapid vaccine production. These novel bioreactors, used for cell-based vaccine production, possess various advantages. For example, they enable a short production time, allow for the handling highly pathogenic influenza in closed environments, and can be easily scaled up. In this study, two novel disposable cell-based bioreactors, BelloCell and TideCell, were used to produce H5N1 clade II and H7N9 candidate vaccine viruses (CVVs). Madin-Darby canine kidney (MDCK) cells were used for the production of these influenza CVVs. A novel bench-scale bioreactor named BelloCell bioreactor was used in the study. All culturing conditions were tested and scaled to 10 L industrial-scale bioreactor known as TideCell002. The performances of between BelloCell and TideCell were similar in cell growth, the average MDCK cell doubling time was slightly decreased to 25 hours. The systems yielded approximately 39.2 and 18.0 μg/ml of HA protein with the 10-liter TideCell002 from the H5N1 clade II and H7N9 CVVs, respectively. The results of this study not only highlight the overall effectiveness of these bioreactors but also illustrate the potential of maintaining the same outcome when scaled up to industrial production, which has many implications for faster vaccine production. Although additional studies are required for process optimization, the results of this study are promising and show that oscillating bioreactors may be a suitable platform for pandemic influenza virus production.


Elective cholecystectomy for the patient with sickle cell disease and asymptomatic cholelithiasis.
Experience with elective cholecystectomy in ten patients with sickle cell disease and one patient with sickle-thalassemia from 1977-1984 was reviewed. In contrast to an earlier review from our institution, the current series had a low morbidity. This improvement is attributed to careful perioperative care, especially preoperative transfusion, hydration, and oxygenation. Because of the increasing longevity of sickle cell patients, because of the incidence of eventual significant complications of even asymptomatic cholelithiasis, and in order to simplify medical management by eliminating the diagnostic confusion between acute cholecystitis and sickle cell hepatobiliary crisis, the authors believe that elective cholecystectomy is to be recommended for the sickle cell patient with asymptomatic gall stones.


Retentivity and enantioselectivity of uniformly sized molecularly imprinted polymers for d-chlorpheniramine and -brompheniramine in hydro-organic mobile phases.
Uniformly sized molecularly imprinted polymers (MIPs) for d-chlorpheniramine (CP) and -brompheniramine (BP) have been prepared by a multi-step swelling and polymerization method using methacrylic acid (MAA) or 2-(trifluoromethyl)acrylic acid (TFMAA) and ethylene glycol dimethacrylate (EDMA) as a functional monomer and cross-linker, respectively. The retentive and enantioselective properties of CP, BP and their structurally related compounds on the MIPs were evaluated using hydro-organic mobile phases. CP and BP enantiomers were retained the most as a monovalent cation on MAA-co-EDMA polymers and a divalent cation on TFMAA-co-EDMA polymers. Ion exchange and hydrophobic interactions could mainly work for the retention and enantioseparation of CP and BP on both MAA-co-EDMA and TFMAA-co-EDMA polymers in hydro-organic mobile phases. Though the respective MIPs gave the highest enantioselectivity for the template molecule, cross-reactivity for CP and BP was observed with them.


A human type 5 adenovirus-based tuberculosis vaccine induces robust T cell responses in humans despite preexisting anti-adenovirus immunity.
There is an urgent need to develop new tuberculosis (TB) vaccines to safely and effectively boost Bacille Calmette-Guérin (BCG)-triggered T cell immunity in humans. AdHu5Ag85A is a recombinant human type 5 adenovirus (AdHu5)-based TB vaccine with demonstrated efficacy in a number of animal species, yet it remains to be translated to human applications. In this phase 1 study, we evaluated the safety and immunogenicity of AdHu5Ag85A in both BCG-naïve and previously BCG-immunized healthy adults. Intramuscular immunization of AdHu5Ag85A was safe and well tolerated in both trial volunteer groups. Moreover, although AdHu5Ag85A was immunogenic in both trial volunteer groups, it much more potently boosted polyfunctional CD4(+) and CD8(+) T cell immunity in previously BCG-vaccinated volunteers. Furthermore, despite prevalent preexisting anti-AdHu5 humoral immunity in most of the trial volunteers, we found little evidence that such preexisting anti-AdHu5 immunity significantly dampened the potency of AdHu5Ag85A vaccine. This study supports further clinical investigations of the AdHu5Ag85A vaccine for human applications. It also suggests that the widely perceived negative effect of preexisting anti-AdHu5 immunity may not be universally applied to all AdHu5-based vaccines against different types of human pathogens.


Muscle wasting and survival following pre-operative chemoradiotherapy for locally advanced rectal carcinoma.
Neoadjuvant chemoradiotherapy (NACRT) has increased local control in locally advanced rectal cancer. Reduced skeletal muscle mass (sarcopenia), or ongoing muscle wasting, is associated with decreased survival in cancer. This study aims to assess the change in body composition during NACRT and its impact on outcome using computed tomography (CT) imaging in locally advanced rectal cancer (LARC) patients. LARC patients treated with NACRT were selected from a prospectively maintained database and retrospectively analyzed. One-hundred twenty-two patients who received treatment between 2004 and 2012 with available diagnostic CT imaging obtained before and after NACRT were identified. Cross-sectional areas for skeletal muscle was determined, and subsequently normalized for patient height. Differences between skeletal muscle areas before and after NACRT were computed, and their influence on overall and disease-free survival was assessed. A wide distribution in change of body composition was observed. Loss of skeletal muscle mass during chemoradiotherapy was independently associated with disease-free survival (HR0.971; 95% CI: 0.946-0.996; p = 0.025) and distant metastasis-free survival (HR0.942; 95% CI: 0.898-0.988; p = 0.013). No relation was observed with overall survival in the current cohort. Loss of skeletal muscle mass during NACRT in rectal cancer patients is an independent prognostic factor for disease-free survival and distant metastasis-free survival following curative intent resection.


Remote ischemic preconditioning has a neutral effect on the incidence of kidney injury after coronary artery bypass graft surgery.
Acute kidney injury (AKI) is a frequent complication of cardiac surgery and usually occurs in patients with preexisting chronic kidney disease (CKD). Remote ischemic preconditioning (RIPC) may mitigate the renal ischemia-reperfusion injury associated with cardiac surgery and may be a preventive strategy for postsurgical AKI. We undertook a randomized controlled trial of RIPC to prevent AKI in 86 patients with CKD (estimated glomerular filtration rate under 60 ml/min per 1.73 m(2)) undergoing coronary artery bypass graft (CABG) surgery. Forty-three patients each were randomized to receive standard care with or without RIPC consisting of three 5-minute cycles of forearm ischemia followed by reperfusion. The primary end point was the development of AKI defined as an increase in serum creatinine concentration over 0.3 mg/dl within 48 h of surgery. Secondary end points included a comparison between the study and control groups of several serum biomarkers of renal injury including cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18), and urinary biomarkers including NGAL, IL-18, and kidney injury molecule-1 measured at 6, 12, and 24 h after CABG, and the 72-h serum troponin T concentration area under the curve as a marker of myocardial injury. Clinical and operative characteristics were similar between the preconditioned and control groups. AKI developed in 12 patients in both groups within 48 h of CABG. There were no significant differences between the two groups in the concentrations of any of the serum or urinary biomarkers of renal or cardiac injury after CABG. Thus, RIPC induced by forearm ischemia-reperfusion had no effect on the frequency of AKI after CABG in patients with CKD.


The Influence of Carbides on Atomic-Scale Mechanical Properties of Carbon Steel: A Molecular Dynamics Study.
Pearlite is an important structure in carbon steel; however, the influence mechanism of carbides in pearlite on its mechanical properties and microstructure evolution has not yet been fully elucidated. In this work, a ferrite-carbide composite model with various carbide types was constructed to investigate the influence of carbide types via a uniaxial compression deformation using classical molecular dynamics simulations. It was found that the carbide type had little effect on the compressive elastic modulus, but a more obvious effect on the yield strain, yield stress, and flow stress. The maximum compressive elastic modulus was in the Fe2C model, with 300.32 GPa, while the minimum was found in the Fe4C model at 285.16 GPa; the error was 5.32%. There were significant differences in the yield stress, yield strain, and flow stress of the ferrite-carbide model according to the stress-strain curve. Secondly, the type of carbide used affected its elastic constant, especially the bulk modulus and Cauchy pressure. The maximum bulk modulus of the Fe4C model was 199.01 GPa, the minimum value of the Fe3C model was 146.03 GPa, and the difference was 52.98 GPa. The Cauchy pressure calculation results were consistent with the yield strain trend. Additionally, the effective elastic moduli of the composite system were used to verify the accuracy of the calculation results of this work. Thirdly, ferrite-carbide interfaces could act as a resource for dislocation emission. The initial stacking fault forms at ferrite-carbide interfaces and expands into ferrite. The dislocation type and segment in the ferrite-carbide model were significantly different due to the type of carbide used.


Estimation of error rates in classification of distorted imagery.
This correspondence considers the problem of matching image data to a large library of objects when the image is distorted. Two types of distortions are considered: blur-type, in which a transfer function is applied to Fourier components of the image, and scale-type, in which each Fourier component is mapped into another. The objects of the library are assumed to be normally distributed in an appropriate feature space. Approximate expressions are developed for classification error rates as a function of noise. The error rates they predict are compared with those from classification of artificial data, generated by a Gaussian random number generator, and with error rates from classification of actual data. It is demonstrated that, for classification purposes, distortions can be characterized by a small number of parameters.


Confluentibacter sediminis sp. nov., isolated from the junction between the ocean and a freshwater lake and emended description of the genus Confluentibacter.
A novel marine Gram-stain-negative, non-motile, aerobic and rod-shaped bacterium, designated strain DSL-48T, was isolated from tidal flat sediment sampled from the East China Sea and characterized phylogenetically and phenotypically. Bacterial optimal growth occurred at 35 °C (range, 4-37 °C), pH 6 (pH 5-10) and with 4 % (w/v) NaCl (0-7 %). The nearest phylogenetic neighbour was Confluentibacter citreus KCTC 52638T with 16S rRNA gene similarity of 97.1 %. The predominant respiratory quinone was menaquinone-6 (MK-6). The major polar lipids were phosphatidylethanolamine, three unidentified aminolipids and four unidentified lipids. The major fatty acids of strain DSL-48T were iso-C15 : 0, iso-C17 : 0 3-OH, anteiso-C15 : 0, iso-C15 : 0 3-OH and iso-C16 : 0 3-OH. The G+C content of the genomic DNA was 33.3 mol%. The combined genotypic and phenotypic data indicated that strain DSL-48T represents a novel species of the genus Confluentibacter, for which the name Confluentibacter sediminis sp. nov. is proposed, with the type strain DSL-48T (=KCTC 62648T=MCCC 1K03537T).


Production of chlorflavonin, an antifungal metabolite of Aspergillus candidus.
Production of chlorflavonin, a new antifungal antibiotic, by strains of Aspergillus candidus is described. Two wild strains of the fungus had distinctly different chlorflavonin-producing capabilities. One strain produced 25 mug of chlorflavonin per ml per 4 to 5 days in a pilot scale fermentor with stirring, using a medium containing corn steep liquor and glucose. Production of antibiotic was favored by high rates of agitation-aeration. Crude chlorflavonin was extracted from the whole brew with a hydrocarbon solvent and then purified by recrystallization from benzene and petroleum ether. The overall yield from fermentation brew to pure product was 50%.


A comprehensive study of oxidative stress in patients with somatic symptom disorder.
To investigate oxidative stress parameters [total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), paraoxonase (PON), arylesterase (ARE) and thiol-disulphide homeostasis] in patients who were diagnosed as having somatic symptom disorder in accordance with Diagnostic and Statistical Manual of Mental Disorders-5. The study included 41 medication-free patients with somatic symptom disorder and 47 age, sex, and sociodemographic-matched healthy individuals. The patients were administered the Patient Health Questionnaire-15, Somatic Symptom Amplification Scale, Beck Depression Inventory, and Beck Anxiety Inventory. TOS, TAS, OSI, PON, ARE thiol, disulphide levels, and routine biochemical parameters were compared between the two groups. TOS, OSI, disulphide levels, disulphide/native thiol, and disulphide/total thiol ratios were found significantly higher in the patient group compared with the control group (p < 0.001). There was no significant difference in PON, ARE, and TAS parameters between the two groups (p > 0.05). This study showed that the level of oxidants increased and oxidative balance was impaired in somatic symptom disorder. Oxidative stress may play a role in the aetiopathogenesis of this disorder. This is the first study to report an association between oxidative stress and somatic symptom disorder.