[Discussion on the composition and implementation of diagnosis and treatment strategies for whole field pain management strategy].
Pain is the fifth major vital sign, and chronic pain is a large category of diseases that affects health seriously. At present, the incidence of chronic pain is high, but the overall treatment satisfaction is low. It is necessary to continuously optimize pain diagnosis and treatment strategies and improve the connotation of pain management. Based on the clinical practice of our pain center, combined with relevant literature, the article proposes a diagnosis and treatment strategy of "whole field pain management" should be carried out from the four dimensions of feeling, emotion, cognition, and behavior. Innovative digital pain diagnosis and treatment technologies such as VR/MR and brain-computer interface are used to regulate emotional, cognitive, and behavioral regulation, and combined with lifestyle changes, rehabilitation physiotherapy, drugs, and minimally invasive interventional therapy to constitute a " whole field pain management strategy" to explore the new development direction of further improving the management of chronic pain.


The Identification of Key Genes and Pathways in Glioma by Bioinformatics Analysis.
Glioma is the most common malignant tumor in the central nervous system. This study aims to explore the potential mechanism and identify gene signatures of glioma. The glioma gene expression profile GSE4290 was analyzed for differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied for the enriched pathways. A protein-protein interaction (PPI) network was constructed to find the hub genes. Survival analysis was conducted to screen and validate critical genes. In this study, 775 downregulated DEGs were identified. GO analysis demonstrated that the DEGs were enriched in cellular protein modification, regulation of cell communication, and regulation of signaling. KEGG analysis indicated that the DEGs were enriched in the MAPK signaling pathway, endocytosis, oxytocin signaling, and calcium signaling. PPI network and module analysis found 12 hub genes, which were enriched in synaptic vesicle cycling rheumatoid arthritis and collecting duct acid secretion. The four key genes CDK17, GNA13, PHF21A, and MTHFD2 were identified in both generation (GSE4412) and validation (GSE4271) dataset, respectively. Regression analysis showed that CDK13, PHF21A, and MTHFD2 were independent predictors. The results suggested that CDK17, GNA13, PHF21A, and MTHFD2 might play important roles and potentially be valuable in the prognosis and treatment of glioma.


Effect of track maintenance on mechanical properties of a dirt racetrack: a preliminary study.
When Thoroughbred racehorses experience catastrophic injuries, the track surface is often discussed as a factor. The present study investigated the mechanical properties of the surface and found that significant changes in a track occur during routine maintenance. Questions regarding the relative importance of track variability and hardness require further investigation.


Possible mechanisms by which the H-2Kbm3 mutation may decrease cytotoxic T-lymphocyte recognition of vesicular stomatitis virus nucleoprotein antigen.
Spleen cells from C57BL/6 (B6) mice generate a strong in vitro cytotoxic T-lymphocyte (CTL) response specific for vesicular stomatitis virus (VSV). Spleen cells from VSV-primed B6-H-2bm3 (bm3) mice, which have a mutation in H-2Kb, require approximately 10-fold more UV-inactivated VSV to generate in vitro secondary anti-VSV CTL, compared with spleen cells from primed B6 mice. Anti-VSV CTL elicited in both bm3 and B6 mice are primarily specific for the viral nucleocapsid protein (N protein), as demonstrated by using recombinant vaccinia viruses that express the VSV N protein. bm3 CTL were found to exhibit only a very low level of lytic activity when tested against autologous VSV-infected concanavalin A spleen cell blasts as well as several H-2b tumor cell lines. The weak anti-VSV response of bm3 CTL was found to be the result of a combination of inefficient recognition of VSV-infected target cells and decreased elicitation of secondary effector cells. VSV-infected bm3 target cells were not killed as well as B6 targets by either bm3 or B6 effectors. This is because of the inefficient recognition of targets, as demonstrated by the fact that VSV-infected bm3 cells were unable to competitively inhibit the lysis of VSV-infected B6 target cells by either bm3 or B6 effectors. By using cells from recombinant mice, it was shown that the CTL response restricted by H-2Kb was low in the bm3 mice, compared with that of the B6 mice. However, the H-2Db-restricted CTL activity was similarly low in both the B6 and bm3 mice. The possibility that the low response to VSV-infected bm3 cells is caused by differences between the bm3 and B6 cells in expression of either viral antigens or H-2K was investigated by radiolabeling and immunoprecipitation. VSV-infected B6 and bm3 cells were found to express equivalent levels of both viral antigens and H-2K. These results indicate that the bm3 mutation alters a functional site on the H-2Kb molecule that is involved in the recognition of VSV-infected cells. The observation that elicitation of bm3 CTL can occur at high antigen doses further suggests that the bm3 mutation results in a lower affinity of H-2K either for viral antigen or for receptor sites on the CTL.


Effect of oral iron supplementation during pregnancy on maternal and fetal iron status.
The known increased need for iron during pregnancy appears to be met only in part by increased iron absorption and amenorrhea. Considerable demands are made on maternal iron stores and, since many women lack sufficient storage iron, pregnancy may be expected to cause iron deficiency. This may lead to anemia in pregnancy and post partum and could also have a bearing on the iron status of the fetus and the neonate. Based on these considerations, prophylactic supplementation of dietary iron is advocated but remains a disputed issue. In the present controlled, prospective and longitudinal study changes in hematologic status, and in particular in iron stores, during pregnancy were investigated in 44 healthy Caucasian women with uncomplicated pregnancies and deliveries. They were randomly assigned to a study group (n = 21) receiving oral iron supplements from the 16th week of amenorrhea until 6 weeks post partum, and a control group (n = 23) without iron supplementation. Maternal concentrations of hemoglobin, serum iron, serum transferrin and serum ferritin were determined at 16, 28 and 36 weeks of amenorrhea, at delivery, and 6 and 12 weeks post partum. The same variables were determined in cord blood. Iron supplementation appeared to prevent the physiologic fall in hemoglobin and serum iron concentrations which occurred in the control group, but had little influence on the observed rise in transferrin concentrations. Ferritin levels in serum, which are known to reflect mobilisable iron stores, fell to 30% of the initial values in the control group and to 70% in the study group. Six and 12 weeks post partum ferritin levels were still low in the nonsupplemented group (Tab. I).(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of the levels of the 21S mitochondrial rRNA in derepressed and glucose-repressed Saccharomyces cerevisiae.
A cDNA preparation, synthesized by using Saccharomyces cerevisiae mitochondrial RNA as template and oligodeoxythymidylic acid as primer, was found to specifically hybridize to the mitochondrial 21S rRNA by the following criteria: (i) it hybridizes only to the 21S RNA species in mitochondrial RNA and not to RNA from a [rho0] mutant, and (ii) it hybridizes to fragments in restriction digests of mitochondrial DNA that contain the 21S rRNA gene but not to nuclear DNA. This cDNA was used as a probe to demonstrate that a 2.6-fold decrease in the cellular level of the mitochondrial large rRNA is associated with glucose repression of mitochondrial function in S. cerevisiae. A corresponding decrease in the level of mitochondrial DNA was not observed.


iGUIDE: an improved pipeline for analyzing CRISPR cleavage specificity.
Genome engineering methods have advanced greatly with the development of programmable nucleases, but methods for quantifying on- and off-target cleavage sites and associated deletions remain nascent. Here, we report an improvement of the GUIDE-seq method, iGUIDE, which allows filtering of mispriming events to clarify the true cleavage signal. Using iGUIDE, we specify the locations of Cas9-guided cleavage for four guide RNAs, characterize associated deletions, and show that naturally occurring background DNA double-strand breaks are associated with open chromatin, gene dense regions, and chromosomal fragile sites. iGUIDE is available from https://github.com/cnobles/iGUIDE .


Inhibition of labile aggregation-stimulating substance (LASS) and platelet aggregation in diabetes mellitus.
Irreversible second-phase aggregation of platelets in diabetic patients is prevented in vitro by 5, 8, 11, 14-eicosatetraynoic acid (TYA), a competitive inhibitor of the labile aggregation-stimulating substance (LASS) which is formed from arachidonic acid. Thus, inhibition of prostaglandin synthesis inhibits platelet aggregation in diabetic subjects. These findings indicate that platelets from diabetics are subject to control by intracellular mechanisms operative in the regulation of platelet function in normal individuals.


How Much Is Too Much? Exploring Pseudohyperaldosteronism in Glycyrrhizic Acid Toxicity From Chronic Licorice Root Consumption.
Licorice has been around for centuries and has been commercialized in the food, tobacco, and healthcare industry. Historically, its therapeutic benefits have been reaped in countless ways, including as a thirst sensation suppressor in battlefields, flavoring agent in medicinal preparations, antacid for gastric discomfort and peptic ulcers, and even as an estrogenic agent in postmenopausal women. Licorice and its derivatives are recognized safe by the US Food and Drug Administration (FDA). Though FDA recognized the licorice to be a food additive in certain concentrations, it has issued warnings against its use in at-risk group and in larger amount. However, it is a lesser known fact that glycyrrhizic acid, the active component in licorice, can cause a metabolic syndrome presenting as pseudohyperaldosteronism. Chronic consumption leads to the development of hypertension, metabolic alkalosis, and hypokalemia. We present a patient who developed a sinus pause on telemetry and subsequent syncope after presenting for evaluation of hypertension and hypokalemia. The patient had been ingesting a significant quantity of deglycyrrhizinated licorice for many years to alleviate postprandial epigastric pain. Although seemingly benign electrolyte disturbance, it is crucial to recognize that chronic consumption of licorice without strict regulation can lead to supraventricular and ventricular ectopics and tachyarrhythmias with the potential to develop life-threatening arrhythmias including ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.


Rheology of polymer brush under oscillatory shear flow studied by nonequilibrium Monte Carlo simulation.
The rheological behaviors of polymer brush under oscillatory shear flow were investigated by nonequilibrium Monte Carlo simulation. The grafted chain under oscillatory shear flow exhibited a waggling behavior like a flower, and the segments were found to have different oscillatory phases along the chain contour. Stress tensor was further obtained based on the statistics of sampled configuration distribution functions. The simulation reproduced the abrupt increase of the first normal stress difference N(1) with the flow velocity over a critical value, as observed in the experiment of Klein et al. [Nature (London) 352, 143 (1991)]. However, our simulation did not reproduce the brush thickening with shear velocity increased, which was suggested to be responsible for the abrupt increase of N(1) in the above-mentioned paper. This simulation demonstrates that the increase of normal stress might be an inherent behavior of polymer brush due to chain deformation under flow.


Early experience with telemanipulative robot-assisted laparoscopic cholecystectomy using da Vinci.
In the past decade, robot-assisted surgery has become increasingly used to assist in minimally invasive surgical procedures. In this article we review the evolution of robotic devices, from the first use of an industrial robot for stereotactic biopsies to pioneering work with robots used for hip and prostate surgery, to the development of robotic guidance systems that enabled solo endoscopic surgery, to telemanipulative surgery with master-servant computer-enhanced robotic devices. In addition, we review our early experience with da Vinci Robotic Surgical Systems (Intuitive Surgical, Inc., Mountain View, CA, U.S.A.), which we used to perform robot-assisted laparoscopic cholecystectomies.


Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method.
This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR). Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation. For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR. We successfully constructed a multi-study-derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.


[Herpes simplex encephalitis in newborns. Treatment with 5-iodo-2'-deoxyuridin? (author's transl)].
Premature twins both affected with generalized herpes simplex infection including CNS involvement were treated with 5-Iodo-2'-deoxyuridin (IDU). Therapy was started 6 days and 5 days, respectively, after appearance of the first symptoms. Nevertheless both babies died, twin A at the age of 24 and twin B at the age of 28 days. Herpes virus was cultured from all organs in twin A. The literature shows a decrease in mortality in children treated with IDU for herpes simplex encephalitis. The percentage of survivors with ultimate severe CNS damage, however, is very high and remains in treated or untreated patients the same. The institution of IDU therapy in neonates with manifest HSV encephalitis is therefore not unequivocally justified.


Genetics and molecular biology of beta-lactam-resistant pneumococci.
Penicillin-resistant pneumococci have been reported with increasing frequency in recent years. Isolates with high-level resistance are now found in many countries, and in some countries they constitute a substantial proportion of all isolates. A worrying development is the recent emergence of pneumococci with high-level resistance to third-generation cephalosporins. Resistance to beta-lactam antibiotics in pneumococci is due entirely to the development of altered forms of the high-molecular-weight penicillin-binding proteins (PBPs) that have decreased affinity for the antibiotics. High-level resistance to third-generation cephalosporins has occurred by the development of altered forms of PBP1a and 2x, whereas high-level penicillin resistance additionally requires alterations of PBP2b. Altered PBPs are encoded by mosaic genes that have emerged by recombinational events between the pbp genes of pneumococci and their homologs in closely related streptococcal species. Horizontal gene transfer, presumably mediated by genetic transformation, has also resulted in the dissemination of altered pbp genes, and possibly capsular biosynthetic genes, between different pneumococcal lineages to produce new resistant clones.


The captivating role of calcium in plant-microbe interaction.
Plant immune response is fascinating due to the complete absence of a humoral system. The adaptive immune response in plants relies on the intracellular orchestration of signalling molecules or intermediates associated with transcriptional reprogramming. Plant disease response phenomena largely depend on pathogen recognition, signal perception, and intracellular signal transduction. The pathogens possess specific pathogen-associated molecular patterns (PAMP) or microbe-associated molecular patterns (MAMP), which are first identified by pattern recognition receptors (PRRs) of host plants for successful infection. After successful pathogen recognition, the defence response is initiated within plants. The first line of non-specific defence response is called PAMP-triggered immunity (PTI), followed by the specific robust signalling is called effector-triggered immunity (ETI). Calcium plays a crucial role in both PTI and ETI. The biphasic induction of reactive oxygen species (ROS) is inevitable in any plant-microbe interaction. Calcium ions play crucial roles in the initial oxidative burst and ROS induction. Different pathogens can induce calcium accumulation in the cytosol ([Ca2+]Cyt), called calcium signatures. These calcium signatures further control the diverse defence-responsive proteins in the intracellular milieu. These calcium signatures then activate calcium-dependent protein kinases (CDPKs), calcium calmodulins (CaMs), calcineurin B-like proteins (CBLs), etc., to impart intricate defence signalling within the cell. Decoding this calcium ionic map is imperative to unveil any plant microbe interplay and modulate defence-responsive pathways. Hence, the present review is unique in developing concepts of calcium signature in plants and their subsequent decoding mechanism. This review also intends to articulate early sensing of calcium oscillation, signalling events, and comprehensive mechanistic roles of calcium within plants during pathogenic ingression. This will accumulate and summarize the exciting roles of calcium ions in plant immunity and provide the foundation for future research.


Serum fluoxetine and norfluoxetine concentrations and antidepressant response.
A high-performance liquid chromatography assay for fluoxetine and its major metabolite, norfluoxetine, was established. Serum concentrations of the two were measured in 13 depressed outpatients following a 6-week trial of the drug. No significant correlations were obvious between clinical improvement as measured by the Hamilton Rating Scale for Depression and the Clinical Global Impression scores and the serum concentrations of fluoxetine and its major metabolite, norfluoxetine, according to these initial pilot data.


Antiproliferative activity of cardenolides isolated from Streptocaulon juventas.
Sixteen cardenolides, two hemiterpenoids, two phenylpropanoids and a phenylethanoid isolated from the roots of Streptocaulon juventas (LOUR.) MERR. were examined for their antiproliferative activity toward three human-derived (HT-1080 fibrosarcoma, lung A549 adenocarcinoma, cervix HeLa adenocarcinoma) and three murine-derived (colon 26-L5 carcinoma, Lewis lung carcinoma, B16-BL6 melanoma) cell lines. The cardenolides selectively and strongly inhibited proliferation of the HT-1080 (IC(50) values, 0.054-1.6 microM) and A549 (IC(50), 0.016-0.65 microM) cell lines. The characteristic morphological changes and ladder-like DNA fragmentation in those cells treated with the cardenolides indicated the antiproliferative activity was due to the induction of apoptosis.


Effects of Multiple Injection of Bone Marrow Mononuclear Cells on Spinal Cord Injury of Rats.
The effects of multiple injection of bone marrow mononuclear cells (BMNCs) on spinal cord injury (SCI) were compared with those of single injection in rats. BMNCs separated by density-gradient centrifugation from a bone marrow perfusate were injected three times (once weekly) through the cerebrospinal fluid (CSF) via the fourth ventricle, and the locomotor improvement and tissue recovery, including axonal regeneration, were compared with those of single injection. While the single-injection group showed a steep elevation of the Basso-Beattie-Bresnahan (BBB) score 1 week after transplantation, the multiple-injection group maintained a similar steep elevation for 2 weeks after transplantation, and the BBB scores of the multiple-injection group remained thereafter at a level approximately 2-3 points higher than those of the single-injection group until the end of the experiment. There were significant differences between the single- and multiple-injection groups at 3, 4, and 8 weeks after transplantation. The difference in BBB scores at 8 weeks after transplantation suggested that there was a marked difference in the quality of locomotor behaviors between the single-and multiple-injection groups at this stage. An extensive outgrowth of regenerating axons through the astrocyte-devoid areas and a marked reduction of cavity formation were found in both the single- and multiple-injection groups. There were, however, no significant differences in the density of regenerating axons or volumes of cavities between the single- and multiple-injection groups. These results showed that although tissue recoveries were similar between single and multiple injection, the multiple injection of BMNCs was more beneficial for locomotor improvement than single injection for the treatment of SCI. Considering the technically simple and low-cost procedures for the preparation and injection of BMNCs, multiple injection of BMNCs by lumbar puncture has an advantage over single injection on clinical application.


Maternal Effects of Respiratory Syncytial Virus Infection during Pregnancy.
Given the illness and deaths caused by respiratory syncytial virus (RSV) infection during the first year of life, preventing infant RSV infections through maternal vaccination is intriguing. However, little is known about the extent and maternal effects of RSV infection during pregnancy. We describe 3 cases of maternal RSV infection diagnosed at a US center during winter 2014. Case-patient 1 (26 years old, week 33 of gestation) received a diagnosis of RSV infection and required mechanical ventilation. Case-patient 2 (27 years old, week 34 of gestation) received a diagnosis of infection with influenza A(H1N1) virus and RSV and required mechanical ventilation. Case-patient 3 (21 years old, week 32 of gestation) received a diagnosis of group A streptococcus pharyngitis and RSV infection and was monitored as an outpatient. Clarifying the effects of maternal RSV infection could yield valuable insights into potential maternal and fetal benefits of an effective RSV vaccination program.


Characteristics of tyrosinase in AOT-isooctane reverse micelles.
Isooctane-AOT-H(2)O is a suitable system for studying enzyme behavior in organic solvents. Tyrosinase was able to catalyze a well-known reaction in aqueous medium: oxidation of 4-methylcatechol to yield 4-methyl-o-benzoquinone. This reaction was studied using the preceding ternary system with adequate amounts of each component to make up reverse micelles. 4-Methyl-o-benzoquinone stability was demonstrated in isooctane even at alkaline pH values. Apparent K(m) and V(max) were similar to those in water, but substrate inhibition was more evident. The pH and temperature appear to be shifted toward high and low values, respectively. Characteristic parameters of reverse micelles, omega(0) (= H(2)O/AOT) and percentage of H(2)O (v/v), were investigated. The results obtained showed that the steady-state rate varies either with omega(0) or with percentage of H(2)O. The variation observed with omega(0) showed an optimal value while an increase in percentage of H(2)O can lead to decreased or increased activity depending on substrate concentration.


Frequent milk and soybean consumption are high risks for uterine leiomyoma: A prospective cohort study.
This study aims to retrospectively analyze the potential risk factors for uterine leiomyoma and prospectively examine whether these risk factors can increase the incidence of uterine leiomyoma.Women who attended our outpatient department from January 1, 2010 to December 31, 2010 were enrolled. General demographical characteristics, personal information, and living habits were collected. Univariate and multivariate logistic regression analyses were used to identify the potential risk factors. Follow-up was regularly conducted to complete the prospective analysis.A total of 1273 women were enrolled including 213 uterine leiomyomas (case group) and 1060 nonuterine leiomyoma women (control group). No statistical differences were found on the age, marital status, number and complication of pregnancy, frequent physical exercise, frequent alcohol consumption, and family history of uterine diseases between two groups (all P > .05). Mean body mass index (P = .043), high school education (P = .041), frequent smoking (P = .030), frequent caffeine consumption (P = .019), frequent milk or soybean consumption (P = .025), and frequent oral contraceptive use (P = .034) were statistically correlated with the onset of uterine leiomyoma. Multivariate analysis verified that frequent milk or soybean consumption (7.349 [5.081-9.454]; P = .039] and frequent oral contraceptive use (8.103 [4.486-12.583]; P = .018] were the independent risk factors for uterine leiomyoma.Frequent milk or soybean consumption and frequent oral contraceptive use are associated with a high risk of uterine leiomyoma, and proper education on the prevention of uterine leiomyoma is highly recommended in clinical practice.


Liver-Oriented Acute Metabolic Effects of A Low Dose of L-Carnitine under Fat-Mobilizing Conditions: Pilot Human Clinical Trial.
The acute metabolic effect of low dosages of L-carnitine under fat-mobilizing conditions was investigated. Healthy subjects (Study 1: n=5; Study 2: n=6) were asked to fast overnight. Then, 30 min of aerobic exercise on a cycle ergometer was performed after supplementation, followed by a 3.5-h sedentary recovery phase. The following ingestion patterns were used: Study 1 (i) noningestion, (ii) 750 mg of L-carnitine (LC), and (iii) 750 mg of LC+50 g of carbohydrate (CHO); Study 2 (iv) noningestion, (v) 500 mg of LC, (vi) 30 mg of CoQ10, and (vii) 500 mg of LC+30 mg of CoQ10. The energy expenditure (EE) and nonprotein respiratory quotient (npRQ) were measured during the pre-exercise, postexercise, and recovery periods. Serum free carnitine, acetylcarnitine, total carnitine (Study 1 and 2), and ketone bodies (Study 2) were measured. The 750 mg LC treatment significantly facilitated fat oxidation during the recovery phases (p<0.05) without elevating EE. The higher fat oxidation associated with LC was completely suppressed by CHO. CoQ10 affected neither npRQ nor EE. npRQ was significantly correlated with the serum total ketone bodies (R=-0.68, p<0.001) and acetylcarnitine (R=-0.61--0.70, p<0.001). The highest correlation was found between acetylcarnitine and total ketone bodies immediately after exercise (R=0.85, p<0.001). In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.


The landscape of metastatic progression patterns across major human cancers.
The majority of patients with solid malignancies die from metastatic burden. However, our current understanding of the mechanisms and resulting patterns of dissemination is limited. Here, we analyzed patterns of metastatic progression across 16 major cancer types in a cohort of 1008 patients with metastatic cancer autopsied between 2000 and 2013 to assess cancer specific progression patterns of disease and related risk predictions. The frequency and location of metastases were evaluated in and across 1) 16 major cancers, 2) smoking- and non-smoking-related cancers and 3) adeno- and squamous cell carcinoma. Associations between primary and secondary sites were analyzed by the fractional and the relative risk methods. We detected significantly different cancer specific patterns of metastatic progression with specific relative risk profiles for secondary site involvement. Histology and smoking etiology influenced these patterns. Backward analysis showed that metastatic patterns help to predict unknown primary sites. Solid malignancies maintain a unique and recurrent organ tropism to specific secondary sites which does not appear to be strongly influenced by advances in cancer medicine as shown by comparison with previous data sets. The delineated landscape of metastatic progression patterns is a comprehensive data resource to both clinical and basic scientists which aids fostering new hypotheses for cancer research and cancer therapies.


Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting.
Colon cancer (COAD) is a leading cause of cancer mortality in the world. Most patients with COAD die as a result of cancer cell metastasis. However, the mechanisms underlying the metastatic phenotype of COAD remain unclear. Instead, particular features of the tumor microenvironment (TME) could predict adverse outcomes including metastasis in patients with COAD, and the role of TME in governing COAD progression is undeniable. Therefore, exploring the role of TME in COAD may help us better understand the molecular mechanisms behind COAD progression which may improve clinical outcomes and quality of patients. Here, we identified a Specific TME Regulatory Network including AEBP1, BGN, POST, and FAP (STMERN) that is highly involved in clinical outcomes of patients with COAD. Comprehensive in silico analysis of our study revealed that the STMERN is highly correlated with the severity of COAD. Meanwhile, our results reveal that the STMERN might be associated with immune infiltration in COAD. Importantly, we show that dihydroartemisinin (DHA) potentially interacts with the STMERN. We suggest that DHA might contribute to immune infiltration through regulating the STMERN in COAD. Taken together, our data provide a set of biomarkers of progression and poor prognosis in COAD. These findings could have potential prognostic and therapeutic implications in the progression of COAD.


[Number of apolipoprotein(a) kringle IV repeats and mobility of isoforms in PAGE].
Serum apo(a) isoform sizes were determined by SDS-polyacryl amide gel electrophoretic (PAGE) method, followed by a high sensitive immunoblotting. The relation between the number of apo(a) kringle IV encoding sequences in the apo(a) gene, as assessed by pulsed field gel electrophoresis and genomic blotting (genotype), and the apo(a) isoforms (phenotype) in SDS-PAGE was evaluated in 78 individuals. The correlation of apo(a) allele number between phenotype and genotype method was high (r = 0.513) in 178 expressed apo(a) alleles. This nomenclature is achieved by using standard serum of kringle IV repeats. We conclude that this method is an approach to genotyping to designate the phenotypes by kringle IV repeats.


Theoretical study of the relativistic molecular rotational g-tensor.
An original formulation of the relativistic molecular rotational g-tensor valid for heavy atom containing compounds is presented. In such formulation, the relevant terms of a molecular Hamiltonian for non-relativistic nuclei and relativistic electrons in the laboratory system are considered. Terms linear and bilinear in the nuclear rotation angular momentum and an external uniform magnetic field are considered within first and second order (relativistic) perturbation theory to obtain the rotational g-tensor. Relativistic effects are further analyzed by carrying out the linear response within the elimination of the small component expansion. Quantitative results for model systems HX (X=F, Cl, Br, I), XF (X=Cl, Br, I), and YH(+) (Y=Ne, Ar, Kr, Xe, Rn) are obtained both at the RPA and density functional theory levels of approximation. Relativistic effects are shown to be small for this molecular property. The relation between the rotational g-tensor and susceptibility tensor which is valid in the non-relativistic theory does not hold within the relativistic framework, and differences between both molecular parameters are analyzed for the model systems under study. It is found that the non-relativistic relation remains valid within 2% even for the heavy HI, IF, and XeH(+) systems. Only for the sixth-row Rn atom a significant deviation of this relation is found.


NiO Nanofibers as a Candidate for a Nanophotocathode.
p-type NiO nanofibers have been synthesized from a simple electrospinning and sintering procedure. For the first time, p-type nanofibers have been electrospun onto a conductive fluorine doped tin oxide (FTO) surface. The properties of the NiO nanofibers have been directly compared to that of bulk NiO nanopowder. We have observed a p-type photocurrent for a NiO photocathode fabricated on an FTO substrate.


Triphasic EEG pattern in bilateral paramedian thalamic infarction.
Two cases of bilateral paramedian thalamic infarction (BPTI) showing triphasic waves (TWs) on the electroencephalogram (EEG) at acute stage are presented in this study. BPTI is a rare syndrome with decreased level of consciousness, gaze abnormalities and cognitive deterioration. TWs are nonspecific EEG findings occurring in both metabolic and nonmetabolic conditions. The TWs in BPTI might be related to level of consciousness and does not always predict a poor prognosis in BPTI.


The synthesis of hyaluronic acid by sheep and rabbit articular cartilage in vitro.
Standard methods of glycosaminoglycan separation were used to confirm the presence of hyaluronic acid in sheep and rabbit articular cartilage. During incubation of carilage in vitro in the presence of [1-14 C]acetate, cartilage cells synthesize this macromolecule and, under the conditions used, it appears to have a shorter turnover time than chondroitin suplhate in the same tissue. The possible functions of hyaluronic acid in cartilage are discussed.


6-Bromo-3-{2-[2-(diphenyl-methyl-ene)hydrazin-yl]-1,3-thia-zol-5-yl}-2H-chromen-2-one chloro-form monosolvate.
In the title compound, C(25)H(16)BrN(3)O(2)S·CHCl(3), the thia-zole ring is approximately planar [maximum deviation = 0.002 (3) Å] and makes dihedral angles of 10.75 (14) and 87.75 (15)/2.80 (14)° with the pyran ring system and the two terminal phenyl rings, respectively. The solvent mol-ecule is disordered over two sets of sites, with refined occupancies of 0.639 (7) and 0.361 (7). In the crystal, mol-ecules are connected via pairs of weak C-H⋯O inter-actions, forming centrosymmetric dimers. An intra-molecular C-H⋯O hydrogen bond generates an S(6) ring motif.


Rituximab mediates loss of CD19 on B cells in the absence of cell death.
To evaluate loss of the B cell-specific marker CD19 after the addition of rituximab (RTX) to healthy donor blood and to determine the role of complement-mediated cytotoxicity in these cells. Whole blood and peripheral blood mononuclear cells (PBMCs) from healthy donors were evaluated for the loss of CD19 in the presence of RTX using flow cytometry. The effect of complement on CD19 loss was examined using serum-free media, C3- and C5-deficient sera, and a C5-blocking antibody. Evidence of B cell death was evaluated by measuring messenger RNA (mRNA) levels as well as by flow cytometry. Transfer of CD19 antigen to monocytes and neutrophils was evaluated by flow cytometry and confocal microscopy. RTX induced a rapid decrease in CD19 count (mean 51%; n = 37) in PBMCs. This reduction occurred in the absence of complement. Despite the decrease in CD19 expression, B cell death did not occur, as evidenced by a lack of change in CD19 or CD20 mRNA levels and a lack of change in CD19 levels determined by intracellular staining and through the use of viability dyes. The CD19 antigen was shown to be transferred to monocytes and neutrophils in an Fc-dependent manner. Our findings indicate that the addition of RTX to healthy donor PBMCs in vitro results in complement-independent loss of CD19 without causing B cell death. CD19 is transferred from B cells to monocytes and neutrophils during shaving of the RTX-CD20 complex in an Fc-dependent manner. These data suggest that monitoring the effect of RTX by measuring the CD19+ cell count may be compromised by this activity.


First and second transmembrane segments of alpha3, alpha4, beta2, and beta4 nicotinic acetylcholine receptor subunits influence the efficacy and potency of nicotine.
The first three transmembrane segments (M1-M3) of human nicotinic acetylcholine receptors (nAChRs) have been implicated in determining the efficacy of nicotine by studies of alpha3/alpha4 subunit chimeras. Nicotine has full efficacy on the alpha4beta2 nAChR and partial efficacy on the alpha3beta2 nAChR. Now, we have exchanged individually three amino acids between the alpha4 and the alpha3 subunits at positions 226(M1), 258(M2), and 262(M2). Also, similar exchanges were made in the beta2 and beta4 subunits at positions 224(M1), 226(M1), and 254(M2) (using alpha subunit numbering). Expression of these mutated nAChRs in Xenopus laevis oocytes showed that the mutated M1 amino acids were important in influencing the potency of ACh and nicotine. It is hypothesized that these M1 amino acids affect the stability between the resting and activated states of the nAChR. M2 amino acids altered the efficacy of nicotine, usually without altering its potency. When the residue located at position 258 in the M2 region of the alpha subunit was valine (as in the alpha3 subunit), the resulting nAChR exhibited partial efficacy for nicotine that was voltage-dependent. Therefore, we believe that these M2 amino acids contribute to the formation of a binding site for nicotine in the alpha3beta2 nAChR channel, which results in a low-affinity channel block, causing the lower efficacy of nicotine on this nAChR.


Expression of normal and mutagenized apolipoprotein CII in procaryotic cells. Structure-function relationship.
A full-length human apo CII cDNA clone has been constructed by completing the 5' end of an incomplete cDNA with a 44 bp long synthetic oligonucleotide. This apo CII cDNA insert was cloned into the pSP19 expression vector and transcribed and translated in vitro. Its N-terminal signal sequence (23 amino-acid residues) was accurately cleaved during cotranslational translocation through endoplasmic reticulum membranes to yield the mature apo CII. Mature apo CII was expressed on a preparative scale as fusion protein apo CII-beta-galactosidase with the full-length apo CII cDNA integrated into the pUR291 vector. Furthermore it was expressed in E. coli transformed with the pKK233-2 apo CII clone. The preform was accurately processed by the host cell. C-Terminal apo CII deletion mutants generated by partial Bal31 digestion of the pKK233-2 apo CII vector yielded well-defined truncated apo CII polypeptides on a preparative scale which allowed the determination of the polypeptide domain responsible for the activation of the serum lipoprotein lipase.


Of cholescintigraphy, sonography, and great bears. A view on modern biliary imaging.
We review the discrepancies and the reasons for them, in two articles in this issue of the Journal to conclude that clinical findings hold the key to selection of the proper imaging test in biliary obstruction. Cholescintigraphy is a more rewarding approach in detecting low grade obstruction, as by common duct stones, whereas in the patient with prolonged painless jaundice, and the high likelihood of a malignancy, computed tomography or ultrasound will yield the best results. Because of the potential for noninvasive imaging to miss choledocholithiasis and because of ever increasing therapeutic options, direct cholangiography will continue to be the mainstay in definition evaluation of the biliary tract.


Existence of HbF Enhancer Haplotypes at HBS1L-MYB Intergenic Region in Transfusion-Dependent Saudi β-Thalassemia Patients.
Background and Objectives. β-Thalassemia and sickle cell disease are genetic disorders characterized by reduced and abnormal β-globin chain production, respectively. The elevation of fetal hemoglobin (HbF) can ameliorate the severity of these disorders. In sickle cell disease patients, the HbF level elevation is associated with three quantitative trait loci (QTLs), BCL11A, HBG2 promoter, and HBS1L-MYB intergenic region. This study elucidates the existence of the variants in these three QTLs to determine their association with HbF levels of transfusion-dependent Saudi β-thalassemia patients. Materials and Methods. A total of 174 transfusion-dependent β-thalassemia patients and 164 healthy controls from Eastern Province of Saudi Arabia were genotyped for fourteen single nucleotide polymorphisms (SNPs) from the three QTL regions using TaqMan assay on real-time PCR. Results. Genotype analysis revealed that six alleles of HBS1L-MYB QTL (rs9376090C p = 0.0009, rs9399137C p = 0.008, rs4895441G p = 0.004, rs9389269C p = 0.008, rs9402686A p = 0.008, and rs9494142C p = 0.002) were predominantly associated with β-thalassemia. In addition, haplotype analysis revealed that haplotypes of HBS1L-MYB (GCCGCAC p = 0.022) and HBG2 (GTT p = 0.009) were also predominantly associated with β-thalassemia. Furthermore, the HBS1L-MYB region also exhibited association with the high HbF cohort. Conclusion. The stimulation of HbF gene expression may provide alternative therapies for the amelioration of the disease severity of β-thalassemia.


[Hypogonadism in patients with testicular tumors and prostate cancer].
Hypogonadism is defined as an array of symptoms arising from a deficiency of androgens. It is caused by a hormonal and spermatogenic dysfunction of the testes. It results in impaired fertility and has a negative impact on the functions of multiple organs and systems, physical well-being, sexual functions and also mental state. Particularly patients with a history of cancer have a high risk of developing hypogonadism as a result of not only the nature of the disease, but mainly its treatment. While leaving the patient with cancer without treatment does not fall within the concept of the art of medicine and the ethical canon of a physician, the symptoms of hypogonadism are often ignored and left untreated. Among urological patients special attention should be given to those with testicular tumors and prostate cancer.


Central nervous system capillary haemangioblastoma: the pathologist's viewpoint.
Haemangioblastomas are rare neoplasms of uncertain histogenesis. They represent 1.5-2.5% of intracranial tumours. While the cerebellum is by far the most frequent site, these lesions also tend to occur in the medulla and spinal cord. Most haemangioblastomas are sporadic but up to one quarter are associated with Von Hippel-Lindau disease (VHL). Although a fairly good number of haemangioblastomas were reported, a lack of side-by-side analysis of these reports has resulted in tentative conclusions that merely offer a first glimpse at their clinicopathologic diversity and histogenesis. To remedy this issue, this study presents a literature review concerning these lesions. Medline literature including both relevant monographs and clinicopathological case series. Haemangioblastomas occur either as a part of VHL disease (25-30%, inherited mutation of VHL gene on 3p25-26 chromosome) or as sporadic tumours (often with somatic mutation of VHL gene). They have diverse clinicopathologic presentations with cerebellar lesions having a better prognosis than their brainstem counterparts. Immunostaining is important for separation of haemangioblastomas from other tumours with similar histology. The rich vascularity of haemangioblastomas is due to overexpression of vascular endothelial growth factors. Moreover, 'stromal' cells represent the neoplastic cells of haemangioblastomas and are capable of forming blood islands with extramedullary haematopoiesis.


Asymmetry, commitment and inhibition in the GroE ATPase cycle impose alternating functions on the two GroEL rings.
The ATPase cycle of GroE chaperonins has been examined by transient kinetics to dissect partial reactions in complexes where GroEL is asymmetrically loaded with nucleotides. The occupation of one heptameric ring by ADP does not inhibit the loading of the other with ATP nor does it prevent the consequent structural rearrangement to the "open" state. However, ADP binding completely inhibits ATP hydrolysis in the asymmetric complex, i.e. ATP cannot by hydrolysed when ADP is bound to the other ring. This non-competitive inhibition of the ATPase by ADP is consistent with a ring-switching, or "two-stroke", mechanism of the type: ATP:GroEL --> ADP:GroEL --> ADP:GroEL:ATP --> GroEL:ATP --> GroEL:ADP, i.e. with respect to the GroEL rings, ATP turns over in an alternating fashion. When the ATP-stabilized, "open" state is challenged with hexokinase and glucose, to quench the free ATP, the open state relaxes slowly (0.44 s-1) back to the apo (or closed) conformation. This rate, however, is three times faster than the hydrolytic step, showing that bound ATP is not committed to hydrolysis. When GroES is bound to the GroEL:ATP complex and the system is quenched in the same way, approximately half of the bound ATP undergoes hydrolysis on the chaperonin complex showing that the co-protein increases the degree of commitment. Thus, non-competitive inhibition of ATP hydrolysis, combined with the ability of the co-protein to block ligand exchange between rings has the effect of imposing a reciprocating cycle of reactions with ATP hydrolysing, and GroES binding, on each of the GroEL rings in turn. Taken together, these data imply that the dominant, productive steady state reaction in vivo is: GroEL:ATP:GroES --> GroEL:ADP:GroES --> ATP:GroEL:ADP:GroES --> ATP:GroEL:ADP --> GroES:ATP:GroEL:ADP --> GroES:ATP:GroEL for a hemi-cycle, and that significant inhibi tion of hydrolysis may arise through the formation of a dead-end ADP:GroEL:ATP:GroES complex.


Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke.
Cadmium is a cumulative nephrotoxicant that is absorbed into the body from dietary sources and cigarette smoking. The levels of Cd in organs such as liver and kidney cortex increase with age because of the lack of an active biochemical process for its elimination coupled with renal reabsorption. Recent research has provided evidence linking Cd-related kidney dysfunction and decreases in bone mineral density in nonoccupationally exposed populations who showed no signs of nutritional deficiency. This challenges the previous view that the concurrent kidney and bone damage seen in Japanese itai-itai disease patients was the result of Cd toxicity in combination with nutritional deficiencies, notably, of zinc and calcium. Further, such Cd-linked bone and kidney toxicities were observed in people whose dietary Cd intakes were well within the provisional tolerable weekly intake (PTWI) set by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives of 1 microg/kg body weight/day or 70 microg/day. This evidence points to the much-needed revision of the current PTWI for Cd. Also, evidence for the carcinogenic risk of chronic Cd exposure is accumulating and Cd effects on reproductive outcomes have begun to emerge.


Primary in situ extracorporeal shock wave lithotripsy for ureteral calculi.
The use of a second generation lithotriptor (Siemens Lithostar) for ESWL treatment of 199 consecutively referred patients with ureteral calculi is evaluated. Follow up data were available in all patients. In 79 patients the calculus was located in the upper third of the ureter, in 43 patients in the middle third and in 77 patients in the lower third of the ureter. In situ ESWL was performed in 187 patients (94%) under local infiltration analgesia, if invasive procedures in conjunction with ESWL were not planned. The overall stone free rates for all patients after 1, 3 and 6 months were 62.3%, 82.4% and 89.9% respectively. The size of the calculus influenced the outcome of treatment, the number of treatments and number of shock waves given. The stone free rates 3 and 6 months after ESWL in patients with upper ureteral calculi were 86.1% and 91.1%; the number of treatments per patient was 1.2. The corresponding rates for patients with mid or lower ureteral calculi were 76.7%, 86.0% (1.0 treatment) and 81.8%, 90.9% (1.2 treatment) respectively. ESWL alone failed to clear calculi in 4 patients with upper ureteral stones, 6 patients with mid-ureteral calculi and 14 patients with lower ureteral calculi. The number of additional procedures post-ESWL was significantly higher among patients with calculi in the lower third of the ureter. It is concluded, that ESWL in situ with a second generation lithotriptor using X-ray localization is an effective and noninvasive method to treat ureteral calculi. In situ ESWL is recommended as first line treatment for ureteral calculi in the upper and mid-thirds.(ABSTRACT TRUNCATED AT 250 WORDS)


Direct inhibitory effect of estradiol on pituitary luteinizing hormone responsiveness to luteinizing hormone releasing hormone is specific and of rapid onset.
We have employed a perifusion technique to explore the time course and specificity of 17 beta-estradiol (E2) effects directly upon luteinizing hormone (LH) release from the isolated rat anterior pituitary under pulsatile luteinizing hormone releasing hormone (LHRH) stimulation. We first characterized the perifusion system and fitted the data to a simple dose-response model. Multiple perifusion studies were then performed with pulses of LHRH at approximately half-maximal response concentration (10(-8) M); LH responses to an initial LHRH pulse (#1) were compared with LH responses to a second LHRH pulse (#2) given at variable times after addition of E2, antiestrogen (LY 117018), and/or 17 alpha-estradiol (17 alpha-E2). Using this approach, we found that the direct inhibitory effect of E2 upon LH responsiveness to LHRH was rapid and specific. The ratio of LH secretion in response to LHRH pulse #2 to that in response to LHRH pulse #1 (LH secretion ratio) decreased steadily during 1 h of exposure to E2. This inhibition was significant (P less than 0.01) by 36 min of E2 exposure. It represented more than the removal of a LHRH self-priming effect because the LH secretion ratios were significantly less than 1.0 [0.80 +/- 0.05 (SEM), P less than 0.01] within 36 min of E2 exposure. The inhibitory effect was not seen when LY 117018 was added with E2, nor when 17 alpha-E2 replaced E2. The specificity of this rapid E2 inhibitory effect upon pituitary LH responsiveness to LHRH strongly suggests that it is receptor mediated. The rapidity of this apparent receptor-mediated estrogen effect suggests that it is a very rapid consequence of nuclear translocation of the E2-receptor complex.


Enhancing the evidence base for HIV/AIDS control in India.
An optimum evidence base is necessary for the effective control of HIV/AIDS in India, as the lack of an adequate evidence base on critical issues leads to controversy and hurdles. To assess the trends in the HIV/AIDS evidence base for India, a PubMed literature search for publications from India in 2002 and 2003 on HIV/AIDS was done, and abstracts from India in one major international HIV/AIDS conference in 2002, and presentations at one major HIV/AIDS conference in India in 2003 were reviewed. The PubMed search revealed 145 papers with abstracts on HIV/AIDS from India during this period, which was 1.4% of the worldwide HIV/AIDS publications. Of these 145 publications, 124 (85.5%) were based on original research and, of these, 27.4% were in the basic sciences, 62.9% in the clinical sciences, and 9.7% in the public health sciences; 53.2% of the original research papers were published in journals with impact factors ranging from 0 to 1. Many vital issues for HIV control, such as validation of the methods used to assess HIV burden in the population, large-scale impact assessment of HIV prevention programmes, cost-effectiveness of HIV interventions, and critical evidence-to-policy issues, were not covered. Of the 8824 abstracts accepted for presentation at the XIV International AIDS Conference 2002 at Barcelona, 8% were from India--a fair representation given that India has about 10% of the world's HIV burden. However, the utility of this information is severely limited with the majority of it not getting translated into detailed papers in the peer-reviewed literature for widespread scrutiny and use. The views expressed by many experts at the Fourth International Conference on AIDS India 2003 at Chennai were impressive, but the presentation and discussion on original research data from India were sparse. From these various sources, it is estimated that the available evidence base for HIV/AIDS control in India is suboptimal. Using certain assumptions, it is estimated that to provide an adequate evidence base for the control of HIV/AIDS in India, quality original HIV/AIDS research in India would have to double in the basic and clinical sciences, and increase by more than 5 times for the public health sciences. Enhancingthis evidence base to an optimum level would require optimizing its demand, systematically planning its supply locally in India and creating an environment suitable for its development. To effectively control HIV/AIDS in India, strategic planning is needed to develop an evidence base that covers all critical areas where information is needed. Formation of a Society for HIV/AIDS Research in India by involving all the major stakeholders could help build up momentum towards establishing a comprehensive, relevant, dynamic and long-term evidence base that provides rigorous and timely information needed for HIV/AIDS control.


Structural characterization combined with the first principles simulations of barium/strontium cobaltite/ferrite as promising material for solid oxide fuel cells cathodes and high-temperature oxygen permeation membranes.
Mixed ionic-electronic conducting perovskite type oxides with a general formula ABO(3) (where A = Ba, Sr, Ca and B = Co, Fe, Mn) often have high mobility of the oxygen vacancies and exhibit strong ionic conductivity. They are key materials that find use in several energy related applications, including solid oxide fuel cell (SOFC), sensors, oxygen separation membranes, and catalysts. Barium/strontium cobaltite/ferrite (BSCF) Ba(0.5)Sr(0.5)Co(0.8)Fe(0.2)O(3-delta) was recently identified as a promising candidate for cathode material in intermediate temperature SOFCs. In this work, we perform experimental and theoretical study of the local atomic structure of BSFC. Micro-Raman spectroscopy was performed to characterize the vibrational properties of BSCF. The Jahn-Teller distortion of octahedral coordination around Co(4+) cations was observed experimentally and explained theoretically. Different cations and oxygen vacancies ordering are examined using plane wave pseudopotential density functional theory. We find that cations are completely disordered, whereas oxygen vacancies exhibit a strong trend for aggregation in L-shaped trimer and square tetramer structure. On the basis of our results, we suggest a new explanation for BSCF phase stability. Instead of linear vacancy ordering, which must take place before the phase transition into brownmillerite structure, the oxygen vacancies in BSCF prefer to form the finite clusters and preserve the disordered cubic structure. This structural feature could be found only in the first-principles simulations and can not be explained by the effect of the ionic radii alone.


Using variable rate models to identify genes under selection in sequence pairs: their validity and limitations for EST sequences.
Using likelihood-based variable selection models, we determined if positive selection was acting on 523 EST sequence pairs from two lineages of sunflower and lettuce. Variable rate models are generally not used for comparisons of sequence pairs due to the limited information and the inaccuracy of estimates of specific substitution rates. However, previous studies have shown that the likelihood ratio test (LRT) is reliable for detecting positive selection, even with low numbers of sequences. These analyses identified 56 genes that show a signature of selection, of which 75% were not identified by simpler models that average selection across codons. Subsequent mapping studies in sunflower show four of five of the positively selected genes identified by these methods mapped to domestication QTLs. We discuss the validity and limitations of using variable rate models for comparisons of sequence pairs, as well as the limitations of using ESTs for identification of positively selected genes.


Adaptive neural PD control with semiglobal asymptotic stabilization guarantee.
This paper proves that adaptive neural plus proportional-derivative (PD) control can lead to semiglobal asymptotic stabilization rather than uniform ultimate boundedness for a class of uncertain affine nonlinear systems. An integral Lyapunov function-based ideal control law is introduced to avoid the control singularity problem. A variable-gain PD control term without the knowledge of plant bounds is presented to semiglobally stabilize the closed-loop system. Based on a linearly parameterized raised-cosine radial basis function neural network, a key property of optimal approximation is exploited to facilitate stability analysis. It is proved that the closed-loop system achieves semiglobal asymptotic stability by the appropriate choice of control parameters. Compared with previous adaptive approximation-based semiglobal or asymptotic stabilization approaches, our approach not only significantly simplifies control design, but also relaxes constraint conditions on the plant. Two illustrative examples have been provided to verify the theoretical results.


Inhibitory effect of Gardenblue blueberry (Vaccinium ashei Reade) anthocyanin extracts on lipopolysaccharide-stimulated inflammatory response in RAW 264.7 cells.
Blueberries are a rich source of anthocyanins, which are associated with health benefits contributing to a reduced risk for many diseases. The present study identified the functional Gardenblue blueberry (Vaccinium ashei Reade) anthocyanin extracts (GBBAEs) and evaluated their capacity and underlying mechanisms in protecting murine RAW 264.7 cells from lipopolysaccharide (LPS)-stimulated inflammation in vitro. Enzyme-linked immunosorbent assay (ELISA) kit results showed that GBBAEs significantly inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), IL-1β, and interferon-γ (INF-γ). Real-time polymerase chain reaction (PCR) analysis indicated that the mRNA expression levels of IL-6, IL-1β, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase 2 (COX-2) were suppressed in LPS-stimulated RAW 264.7 cells. Additionally, Western blot analysis was used to evaluate the relative protein expression levels of COX-2 and nuclear factor-κB p65 (NF-κBp65). All these results suggested the potential use of GBBAEs as a functional food for the treatment of inflammatory diseases.


TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease.
Chronic iron overload results in heart and liver diseases and is a common cause of morbidity and mortality in patients with genetic hemochromatosis and secondary iron overload. We investigated the role of tissue inhibitor of metalloproteinase 3 (TIMP3) in iron overload-mediated tissue injury by subjecting male mice lacking Timp3 ( Timp3-/-) and wild-type (WT) mice to 12 wk of chronic iron overload. Whereas WT mice with iron overload developed diastolic dysfunction, iron-overloaded Timp3-/- mice showed worsened cardiac dysfunction coupled with systolic dysfunction. In the heart, loss of Timp3 was associated with increased myocardial fibrosis, greater Timp1, matrix metalloproteinase ( Mmp) 2, and Mmp9 expression, increased active MMP-2 levels, and gelatinase activity. Iron overload in Timp3-/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin. Loss of Timp3 enhanced the hepatic inflammatory response to iron overload, leading to greater neutrophil and macrophage infiltration and increased hepatic fibrosis. Expression of inflammation-related MMPs (MMP-12 and MMP-13) and inflammatory cytokines (IL-1β and monocyte chemoattractant protein-1) was elevated to a greater extent in iron-overloaded Timp3-/- livers. Gelatin zymography demonstrated equivalent increases in MMP-2 and MMP-9 levels in WT and Timp3-/- iron-overloaded livers. Loss of Timp3 enhanced the susceptibility to iron overload-mediated heart and liver injury, suggesting that Timp3 is a key protective molecule against iron-mediated pathology. NEW & NOTEWORTHY In mice, loss of tissue inhibitor of metalloproteinase 3 ( Timp3) was associated with systolic and diastolic dysfunctions, twofold higher hepatic iron accumulation (attributable to constituently lower levels of ferroportin), and increased hepatic inflammation. Loss of Timp3 enhanced the susceptibility to iron overload-mediated injury, suggesting that Timp3 plays a key protective role against iron-mediated pathology.


Activity of Amphotericin B and Anidulafungin Combined with Rifampicin, Clarithromycin, Ethylenediaminetetraacetic Acid, N-Acetylcysteine, and Farnesol against Candida tropicalis Biofilms.
We evaluated the activity of (1) amphotericin-B (AMB), combined with rifampicin (RIF), clarithromycin (CLA), N-acetylcysteine (NAC), ethylenediaminetetraacetic acid (EDTA), and farnesol (FAR) (1000, 1000, 1000, 4000, and 30,000 mg/L, and 300 µM, respectively), against Candida tropicalis biofilms formed on polytetrafluoroethylene (PTFE) and (2) anidulafungin (ANF) combined with the same compounds at 8, 10, 5, 40, and 30 mg/L, and 30 µM, respectively, against biofilms formed on titanium. Biofilm growth kinetics were performed in a CDC Biofilm Reactor (CBR). PTFE or titanium disks were removed from the CBR at 24, 48, 72, and 96 h to determine the Log10CFU/cm². Killing kinetics were performed by adding the drugs to 24-h-mature biofilms (time 0). Disks were removed after 24, 48, and 72 h of drug exposure to determine Log10CFU/cm². Viable cells in biofilms were 4.73 and 4.29 Log10CFU/cm² on PTFE and titanium, respectively. Maximum Log10 decreases in CFU/cm² depend on the combination and were: 3.53 (AMB + EDTA), 2.65 (AMB + RIF), 3.07 (AMB + NAC), 2.52 (AMB + CLA), 1.49 (AMB + FAR), 2.26 (ANF + EDTA), 2.45 (ANF + RIF), 2.47 (ANF + NAC), 1.52 (ANF + CLA), and 0.44 (ANF + FAR). In conclusion, EDTA, NAC, RIF, and CLA improve the activity of AMB and ANF against biofilms developed on both surfaces, which could be an effective strategy against C. tropicalis biofilm-related infections.


ChEC-seq kinetics discriminates transcription factor binding sites by DNA sequence and shape in vivo.
Chromatin endogenous cleavage (ChEC) uses fusion of a protein of interest to micrococcal nuclease (MNase) to target calcium-dependent cleavage to specific genomic loci in vivo. Here we report the combination of ChEC with high-throughput sequencing (ChEC-seq) to map budding yeast transcription factor (TF) binding. Temporal analysis of ChEC-seq data reveals two classes of sites for TFs, one displaying rapid cleavage at sites with robust consensus motifs and the second showing slow cleavage at largely unique sites with low-scoring motifs. Sites with high-scoring motifs also display asymmetric cleavage, indicating that ChEC-seq provides information on the directionality of TF-DNA interactions. Strikingly, similar DNA shape patterns are observed regardless of motif strength, indicating that the kinetics of ChEC-seq discriminates DNA recognition through sequence and/or shape. We propose that time-resolved ChEC-seq detects both high-affinity interactions of TFs with consensus motifs and sites preferentially sampled by TFs during diffusion and sliding.


Measurement and calculation of the dose at large distances from brachytherapy sources: Cs-137, Ir-192, and Co-60.
In a small number of special cases it may be necessary to estimate the radiation dose to organs far away from the target volume of a patient receiving radiotherapy, e.g. the dose to the gonads or to the fetus of a pregnant patient. Previously, for external beam radiotherapy a model was developed, which enabled this estimation with acceptable accuracy for the range of photon beam energies from cobalt-60 to 25 MV, independent of the make of the treatment machines, for generally used techniques and for a wide range of distances from the beam axis and field sizes [Van der Giessen and Hurkmans, Int. J. Radiat. Oncol. Biol. Phys. 27, 717-724 (1993); van der Giessen, ibid. 30, 1239-1246 (1994); to appear in Int. J. Radiat. Oncol. Biol. Phys.]. In this paper, results of measurements and Monte Carlo calculations are reported for evaluation of the dose at large distances from some brachytherapy sources. This has resulted in information on the behavior of the tissue attenuation factor T(r) for commonly used sources: Co-60, Ir-192, and Cs-137, in the range of distances up to 60 cm from the source. The influence of the size of the phantom was investigated. A mathematical model, described earlier by Kornelsen and Young, proved to yield the best fit to the results [Br. J. Radiol. 54, 136 (1981)]. Parameters for this model are derived for these isotopes. A few experiments in a Rando Alderson phantom are presented to support the measurements and the calculations.


Arthroscopic-assisted retrograde mosaicplasty for an osteochondral defect of the femoral head without performing surgical hip dislocation.
Osteochondral autograft transplantation (mosaicplasty) for the osteochondral defects of the femoral head is generally performed with safe dislocation of the hip joint. Here, we present a 27-year-old male patient who had a symptomatic osteochondral defect of the femoral head and underwent mosaicplasty applied by hip arthroscopy without surgical hip dislocation. The preoperative radiological evaluation showed a focal osteochondral defect on the weight-bearing surface of the femoral head. With the assistance of hip arthroscopy, the defect area was reconstructed with osteochondral plug, which was taken from the ipsilateral knee, inserted in a retrograde fashion, and positioned with the spherical surface of the femoral head cartilage under fluoroscopic and arthroscopic control. At the final follow-up (26 months postoperatively), he had full range of motion (ROM) without pain and radiographic evaluation showed near complete incorporation of the graft with preservation of the native joint space. Mosaicplasty can be applied in a retrograde fashion with the assistance of hip arthroscopy without using surgical hip dislocation and may be an alternative treatment option for the osteochondral defects of the femoral head in young patients.


[Polysomnographic comparation between dexmedetomidine-induced sleep and natural sleep].
Objective: To compare the parameters of polysomnography (PSG) in sleep structure and respiratory events between dexmedetomidine-induced sleep and natural sleep. Methods: From April 2016 to September 2018, a total of 44 patients with obstructive sleep apnea (OSA) and 3 patients with simple snoring completed PSG monitor both in natural sleep and dexmedetomidine-induced sleep in Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tsinghua Changgung Hospital. The PSG parameters were statistically analysed with SPSS 22.0 software. Results: The average dose of dexmedetomidine was (104.60±27.93) μg, and there was no significant difference between the induced-sleep efficiency and the natural sleep efficiency (82.14%±16.66% vs. 86.50%±9.18%, t=-1.559, P>0.05). There was no rapid eye movement(REM) stages in all 47 subjects and only 1 case of them had non-rapid eye movement(NREM) stage 3 in induced sleep. The percentage of NREM1 in total sleep time was statistically different between the two groups (42.10%±26.71% vs. 17.47%±11.68%, t=5.997, P<0.001),but there was no significant difference in the percentage of NREM2 in total sleep time between the two groups (56.96%±26.0% vs. 62.95%±9.03%, t=-1.521, P=0.135). About respiratory events, there were significant differences in apnea hypopnea index ((46.29±20.23)/h vs. (39.67±25.41)/h), obstructive apnea index (25.20[10.50,45.40]/h vs. 16.20[3.30,35.20]/h) between induced-sleep and natural sleep (t=2.297, Z=-3.008, all P<0.05), these difference were more significant in mild-to-moderate OSA. There were no statistically significant differences in central apnea index (0.00[0.00,2.80]/h vs. 0.40[0.10,1.20]/h), mixed apnea index (0.00[0.00,6.20]/h vs. 0.00[0.00,3.40]/h, hypopnea index (4.20[0.00,3.30]/h vs. 12.00[5.20,17.40]/h), Z=-0.110,-0.508,-1.544, all P>0.05). There were statistical differences in the lowest oxygen saturation (84.77%±7. 59% vs. 80.21%±11.62%, t=2.558, P=0.014). Conclusions: There is no significant difference in sleep efficiency and NREM2 between dexmedetomidine induced sleep and natural sleep.NREM3 sleep is rare induced, but REM sleep is none of all. And dexmedetomidine induced sleep may aggravate obstructive sleep apnea, but not central apnea.


Expression of NK Cell Surface Receptors in Breast Cancer Tissue as Predictors of Resistance to Antineoplastic Treatment.
Currently, one of the most used strategies for the treatment of newly diagnosed patients with breast cancer is neoadjuvant chemotherapy based on the application of taxanes and anthracyclines. However, despite the high number of patients who develop a complete pathological clinical response, resistance and relapse following this therapy continue to be a clinical challenge. As a component of the innate immune system, the cytotoxic function of Natural Killer (NK) cells plays an important role in the elimination of tumor cells. However, the role of NK cells in resistance to systemic therapy in breast cancer remains unclear. The present project aims to evaluate the gene expression profile of human NK cells in breast cancer tissue resistant to treatment with taxanes-anthracyclines. Biopsies from tumor tissues were obtained from patients with breast cancer without prior treatment. Histopathological analysis and ex vivo exposure to antineoplastic chemotherapeutics were carried out. Alamar blue and lactate dehydrogenase release assays were performed for quantitative analysis of tumor viability. Gene expression profiles from tumor tissues without prior exposure to therapeutic drugs were analyzed by gene expression microarrays and verified by polymerase chain reaction. A significant decrease in gene expression of cell-surface receptors related to NK cells was observed in tumor samples resistant to antineoplastic treatment compared with those that were sensitive to treatment. A decrease in NK cell infiltration into tumor tissue might be a predictive marker for failure of chemotherapeutic treatment in breast cancer.


Oral health and medical conditions among Amish children.
The Amish are a growing population who live a traditional, rural way of life, which makes them less accepting of modernism. Most Amish live in poverty and are detached from modern health care. In addition, the recent change of their lifestyle has been reported, such as consuming a nontraditional diet and the usage of electronic devices. As a result, their lifestyle change may have impacted their oral health. However, since only a single report about oral health among Amish children has been published approximately three decades ago it has not yet been updated. This study describes oral health among Amish children and their medical conditions during visits to a mobile dental unit (MDU). The dental records of all patients (N=216) who visited a mobile dental unit were reviewed, which covers 1 year from May 20, 2011, the first date of service. The following factors were taken into consideration during the review process: parental perceptions of their children's oral health care, dental care experiences, and general health information. Fifty-four (27.8%) children, ages 3 to 17, have never received dental treatment before visiting the MDU; the average number of untreated decayed teeth was 6.8. In spite of this, most parents rated their children's oral health as good or very good (87.7%). The high cost and long distance travel associated with routine, professional dental care makes it difficult for children to maintain good oral hygiene. Our analysis revealed that bleeding disorders were more prevalent among this gene pool compared to the nation at large; however, asthma was less common. There are oral and general health disparities among Amish children. There is a lack of awareness among Amish parents with regard to their children's oral health. Key words:Amish, child, dental caries, mobile health units.


LigerCat: using "MeSH Clouds" from journal, article, or gene citations to facilitate the identification of relevant biomedical literature.
The identification of relevant literature from within large collections is often a challenging endeavor. In the context of indexed resources, such as MEDLINE, it has been shown that keywords from a controlled vocabulary (e.g., MeSH) can be used in combination to retrieve relevant search results. One effective strategy for identifying potential search terms is to examine a collection of documents for frequently occurring terms. In this way, "Tag clouds" are a popular mechanism for ascertaining terms associated with a collection of documents. Here, we present the Literature and Genomic Electronic Resource Catalogue (LigerCat) system for exploring biomedical literature through the selection of terms within a "MeSH cloud" that is generated based on an initial query using journal, article, or gene data. The resultant interface is encapsulated within a Web interface: http://ligercat.ubio.org. The system is also available for installation under an MIT license.


Sequence and transcriptional analysis of the barley ctDNA region upstream of psbD-psbC encoding trnK(UUU), rps16, trnQ(UUG), psbK, psbI, and trnS(GCU).
A 6.25 kbp barley plastid DNA region located between psbA and psbD-psbC were sequenced and RNAs produced from this DNA were analyzed. TrnK(UUU), rps16 and trnQ(UUG) were located upstream of psbA. These genes were transcribed from the same DNA strand as psbA and multiple RNAs hybridized to them. TrnK and rsp16 contained introns; a 504 amino acid open reading frame (ORF504) was located within the trnK intron. Between trnQ and psbD-psbC was a 2.24 kbp region encoding psbK, psbI and trnS(GCU). PsbK and psbI are encoded on the same DNA strand as psbD-psbC whereas trnS(GCU) is transcribed from the opposite strand. Two large RNAs accumulate in barley etioplasts which contain psbK, psbI, anti-sense trnS(GCU) and psbD-psbC sequences. Other RNAs encode psbK and psbI only, or psbK only. The divergent trnS(GCU) located upstream of psbD-psbC and a second divergent trnS(UGA) located downstream of psbD-psbC were both expressed. Furthermore, RNA complementary to psbK and psbI mRNA was detected, suggesting that transcription from divergent overlapping transcription units may modulate expression from this DNA region.


Paraneoplastic pemphigus associated with Castleman tumor: a commonly reported subtype of paraneoplastic pemphigus in China.
Castleman tumor, a rare lymphoproliferative disorder, is one of the associated tumors in paraneoplastic pemphigus. We analyzed the characteristics of a group of patients with Castleman tumor to clearly understand and to improve the prognosis of the disease. Ten cases of paraneoplastic pemphigus associated with Castleman tumor treated in the Department of Dermatology, Peking University First Hospital, Beijing, China, from May 1, 1999, to March 31, 2004, were analyzed for clinical aspects, characteristics and histologic features of the tumors, and computed tomographic findings. Literature was reviewed and data were compared with our cases. Castleman tumor was a frequently reported neoplasm in association with paraneoplastic pemphigus in China. The disease was found to be caused by an autoimmune reaction originating from the B lymphocytes in the Castleman tumor. Castleman tumor in association with paraneoplastic pemphigus is a commonly reported subtype of paraneoplastic pemphigus in China. Early detection and removal of the Castleman tumor are crucial for the treatment of this tumor-associated autoimmune disease.


BOLD coherence reveals segregated functional neural interactions when adapting to distinct torque perturbations.
In the natural world, we experience and adapt to multiple extrinsic perturbations. This poses a challenge to neural circuits in discriminating between different context-appropriate responses. Using event-related fMRI, we characterized the neural dynamics involved in this process by randomly delivering a position- or velocity-dependent torque perturbation to subjects' arms during a target-capture task. Each perturbation was color-cued during movement preparation to provide contextual information. Although trajectories differed between perturbations, subjects significantly reduced error under both conditions. This was paralleled by reduced BOLD signal in the right dentate nucleus, the left sensorimotor cortex, and the left intraparietal sulcus. Trials included "NoGo" conditions to dissociate activity related to preparation from execution and adaptation. Subsequent analysis identified perturbation-specific neural processes underlying preparation ("NoGo") and adaptation ("Go") early and late into learning. Between-perturbation comparisons of BOLD magnitude revealed negligible differences for both preparation and adaptation trials. However, a network-level analysis of BOLD coherence revealed that by late learning, response preparation ("NoGo") was attributed to a relative focusing of coherence within cortical and basal ganglia networks in both perturbation conditions, demonstrating a common network interaction for establishing arbitrary visuomotor associations. Conversely, late-learning adaptation ("Go") was attributed to a focusing of BOLD coherence between a cortical-basal ganglia network in the viscous condition and between a cortical-cerebellar network in the positional condition. Our findings demonstrate that trial-to-trial acquisition of two distinct adaptive responses is attributed not to anatomically segregated regions, but to differential functional interactions within common sensorimotor circuits.


Perceptions of Emergency Care by Sexual and Gender Minorities in Colorado: Barriers, Quality, and Factors Affecting Identity Disclosure.
Expanding on data concerning emergency department (ED) use and avoidance by the sexual minority (those who identify as lesbian, gay, bisexual, queer, other [LGTBQ+]) and gender minority (those who identify as transgender, gender nonconforming, other) community may inform future ED LGTBQ+ training and clinical practice. Investigation objectives included characterizing rates of emergency care avoidance, identifying barriers to emergency care, and assessing emergency care quality and cultural competency for sexual and gender minorities. In this population-based, cross-sectional needs assessment, sexual minority, gender minority, and/or cisgender heterosexual-identified participants were selected based on participants' subscription to newsletters or social media accounts for One Colorado, an LGBTQ+ advocacy organization. Each participant completed a single digital survey that collected qualitative and quantitative data about ED perception, use, and demographics. A total of 477 LGBTQ+ or heterosexual-identified individuals (mean age = 44.3 (standard deviation [SD] = 16.7)) participated in the study. Lifetime emergency care avoidance rates for gender minorities were markedly increased (odds ratio [OR] 3.8, 95% confidence interval [CI], 2.2 - 6.6; P <.001), while avoidance rates for sexual minorities were similar to those of cisgender heterosexual respondents (17% vs 14%; P <.001). Gender minorities were more likely than sexual minorities to both avoid emergency care due to fear of discrimination (43% vs 15%; P =.002) and to have experienced discrimination during their last ED visit (OR 11, [95% CI, 5-24]; P <.001). No significant differences were observed between participants in care avoidance due to financial reasons or prior negative experiences. No cited ED factors that influenced identity disclosure decisions were distinctly predictive. Gender minorities are more likely than sexual minorities and heterosexual cisgender individuals to report ED avoidance and discrimination at last ED visit. Future work characterizing deficits in LGBTQ+ ED care might reduce these avoidance and discrimination rates, enhancing the level of patient care provided to this population.


Benchmarking of the CAP-88 and GENII computer codes using 1990 and 1991 monitored atmospheric releases from the Idaho National Engineering Laboratory.
The CAP-88 environmental radiological assessment computer code was benchmark tested to establish confidence in its results. The results from CAP-88 were compared to the results from the GENII computer code, which has undergone rigorous testing. The codes were benchmarked using 1990 and 1991 monitored atmospheric releases from Idaho National Engineering Laboratory facilities and the results (the effective dose equivalent to the maximally exposed offsite individual) were quantitatively compared using a metric based on the uncertainty in the Gaussian plume model and terrestrial transport models. The results of the benchmark tests were within the 95% acceptance region specified in the test protocol. CAP-88 was found to overpredict effective dose equivalent relative to GENII for elevated releases, largely because CAP-88 calculates a larger atmospheric dispersion factor (chi/Q) than does GENII using the same meteorological data. However, CAP-88 consistently underpredicted effective dose equivalent relative to GENII for ground-level releases. This was because CAP-88 accounts for the processes of plume depletion by dry and wet deposition while GENII does not account for these processes. The effect of depletion was tested and found to be most important for a ground-level release of a highly depositing species such as radioiodine which implies that acceptable benchmark results would be difficult to obtain for a highly dopositing species.


Do disabled elderly Medicare beneficiaries with major depression make less use of a consumer-directed home care voucher benefit?
Older adults with major depression may underutilize consumer-directed long-term care. Systematic underutilization would create disparities in outcomes, undermining program effectiveness. The Medicare Primary and Consumer-Directed Care Demonstration included a consumer-directed indemnity benefit that paid for goods and services not financed by traditional Medicare. Overall and for most categories of goods and services there was little difference in use and expenditures between those with and without major depression. However, among those using the benefit to hire in-home workers, arguably the most important consumer-directed purchase, average spending for workers was about 30% lower for depressed persons. While our findings are generally reassuring for public policy, future research is needed to verify that major depression is associated with less spending on in-home workers.


Microstructural white matter changes underlying cognitive and behavioural impairment in ALS--an in vivo study using DTI.
A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients. We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures. Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts. In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients.


Establishment of functional acinar-like cultures from human salivary glands.
Disorders of human salivary glands resulting from therapeutic radiation treatment for head and neck cancers or from the autoimmune disease Sjögren syndrome (SS) frequently result in the reduction or complete loss of saliva secretion. Such irreversible dysfunction of the salivary glands is due to the impairment of acinar cells, the major glandular cells of protein, salt secretion, and fluid movement. Availability of primary epithelial cells from human salivary gland tissue is critical for studying the underlying mechanisms of these irreversible disorders. We applied 2 culture system techniques on human minor salivary gland epithelial cells (phmSG) and optimized the growth conditions to achieve the maintenance of phmSG in an acinar-like phenotype. These phmSG cells exhibited progenitor cell markers (keratin 5 and nanog) as well as acinar-specific markers-namely, α-amylase, cystatin C, TMEM16A, and NKCC1. Importantly, with an increase of the calcium concentration in the growth medium, these phmSG cells were further promoted to acinar-like cells in vitro, as indicated by an increase in AQP5 expression. In addition, these phmSG cells also demonstrated functional calcium mobilization, formation of epithelial monolayer with high transepithelial electrical resistance (TER), and polarized secretion of α-amylase secretion after β-adrenergic receptor stimulation. Taken together, suitable growth conditions have been established to isolate and support culture of acinar-like cells from the human salivary gland. These primary epithelial cells can be useful for study of molecular mechanisms involved in regulating the function of acinar cells and in the loss of salivary gland function in patients.


Direct and indirect economic and health consequences of COPD in Denmark: a national register-based study: 1998-2010.
Chronic obstructive pulmonary disease (COPD) is among the leading causes of morbidity and mortality worldwide, but longitudinal studies of the economic consequences of COPD are scarce. This Danish study evaluated for the first time ever the economic consequences of COPD of an entire nation before and after the diagnosis. Records from the Danish National Patient Registry (1998-2010), direct and indirect costs, including frequency of primary and secondary sector contacts and procedures, medication, unemployment benefits and social transfer payments were extracted from national databases. 131 811 patients with COPD were identified and compared with 131 811 randomly selected controls matched for age, gender, educational level, residence and marital status. Direct and indirect economic and health consequences of COPD in Denmark in the time period 1998-2010. Patients with COPD had a poor survival. The average (95% CI) 12-year survival rate was 0.364 (0.364 to 0.368) compared with 0.686 among controls (0.682 to 0.690). COPD was associated with significantly higher rates of health-related contacts, medication use and higher socioeconomic costs. The employment and the income rates of employed patients with COPD were significantly lower compared with controls. The annual net costs, including social transfers were €8572 for patients with COPD. These consequences were present up to 11 years before first-time diagnosis in the secondary healthcare sector and became more pronounced with disease advancement. This study provides unique national data on direct and indirect costs before and after initial diagnosis with COPD in Denmark as well as mortality, health and economic consequences for the individual and for society. It could be speculated that early identification and intervention might contribute to the solution.


S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: updated results from a phase 3 trial.
We report updated progression-free survival (PFS) and overall survival (OS) data from a trial that compared capecitabine plus oxaliplatin (CapeOX) versus S-1 plus oxaliplatin (SOX) for the first-line treatment of metastatic colorectal cancer. This trial was a randomized, two-armed, non-inferiority phase 3 comparison of CapeOX (capecitabine 1000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1) versus SOX (S-1 40 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1). The primary end point was to show non-inferiority of SOX relative to CapeOX in terms of PFS. Thus, a follow-up exploratory analysis of PFS and OS was performed. The intention to treat (ITT) population was comprised of 340 patients (SOX arm: 168 and CapeOX arm: 172). The updated median PFS was 7.1 months (95% CI 6.4-8.0) in the SOX group and 6.3 months (95% CI 4.9-6.7) in the CapeOX group (hazard ratio [HR], 0.83 [0.66-1.04], p = .10). The median OS was 19.0 months (95% CI 15.3-23.0) in the SOX group and 18.4 months (95% CI 14.1-20.7) in the CapeOX group (HR, 0.86 [0.68-1.08], p = .19). Subgroup analyses according to principal demographic factors such as sex, age, ECOG (Eastern Cooperative Oncology Group) performance status, primary tumor location, measurability, previous adjuvant therapy, number of metastatic organs, and liver metastases showed no interaction between any of these characteristics and the treatment. Updated survival analysis shows that SOX is similar to CapeOX, confirming the initial PFS analysis. Therefore, the SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. NCT00677443 and May 12 2008.


[The maturation of the E.E.G. and sleep; genetic and environmental factors (author's transl)].
Whilst studying the post-natal maturation of reflexes, EEG activity, rhythmic activity in Slonaker's wheels and the learning of adult mice, strains showing less pronounced rhythmic activity and more immature EEG and reflexes at birth were discovered. On the other hand some strains having a shorter post-natal period manifest an early maturation of their central nervous system. The results indicate that complex interactions exist between genotype and environment when the different post-natal maturation appearances are considered and that EEG activity may be useful in assessing development.


Distal Tibiofibular Joint Reconstruction Using Autograft in a Rare Case of Lower Limb Sclerosing/Spindle Cell Rhabdomyosarcoma: A Two-Year Follow-Up.
Sclerosing/spindle cell rhabdomyosarcoma (s-scRMS) is a rare variant of striated muscle tumours. It has been recognised as an individual entity, the fourth subtype of rhabdomyosarcoma in the latest WHO classification. In the paediatric population, it occurs more commonly in the paratesticular area, whereas in adults, it occurs more commonly in the head and neck region. It has distinctive characteristics in terms of its histopathological and immunochemistry findings, which help in accurate diagnosis. The mainstay of treatment is a multimodal approach, i.e., surgery, chemotherapy, and radiation therapy. However, no standard care is still being established internationally for adult cases. In adults, this tumour has a poorer prognosis as compared to children. We describe a patient with s-scRMS of the lower limb who has undergone wide local resection of the tumour with surgical reconstruction of the distal tibiofibular joint with autograft and its two-year outcome.


Progressive resistance training in head and neck cancer patients during concomitant chemoradiotherapy -- design of the DAHANCA 31 randomized trial.
Head and neck cancer patients undergoing concomitant chemoradiotherapy (CCRT) frequently experience loss of muscle mass and reduced functional performance. Positive effects of exercise training are reported for many cancer types but biological mechanisms need further elucidation. This randomized study investigates whether progressive resistance training (PRT) may attenuate loss of muscle mass and functional performance. Furthermore, biochemical markers and muscle biopsies will be investigated trying to link biological mechanisms to training effects. At the Departments of Oncology at Herlev and Aarhus University Hospitals, patients with stage III/IV squamous cell carcinoma of the head and neck, scheduled for CCRT are randomized 1:1 to either a 12-week PRT program or control group, both with 1 year follow-up. Planned enrollment is 72 patients, and stratification variables are study site, sex, p16-status, and body mass index. Primary endpoint is difference in change in lean body mass (LBM) after 12 weeks of PRT, assessed by dual-energy X-ray absorptiometry (DXA). The hypothesis is that 12 weeks of PRT can attenuate the loss of LBM by at least 25%. Secondary endpoints include training adherence, changes in body composition, muscle strength, functional performance, weight, adverse events, dietary intake, self-reported physical activity, quality of life, labor market affiliation, blood biochemistry, plasma cytokine concentrations, NK-cell frequency in blood, sarcomeric protein content in muscles, as well as muscle fiber type and fiber size in muscle biopsies. Muscle biopsies are optional. This randomized study investigates the impact of a 12-week progressive resistance training program on lean body mass and several other physiological endpoints, as well as impact on adverse events and quality of life. Furthermore, a translational approach is integrated with extensive biological sampling and exploration into cytokines and mechanisms involved. The current paper discusses decisions and methods behind exercise in head and neck cancer patients undergoing concomitant chemoradiotherapy. Approved by the Regional Ethics Committee for the Capital Region of Denmark (protocol id: H-15003725) and registered retrospectively at ClinicalTrials.gov ( NCT02557529 ) September 11th 2015.


Effects of delayed excision of oviducts/ovaries on mouse oocytes and embryos.
To achieve the best and reproducible results of experiments, effects of delayed excision of oviducts/ovaries on mouse ovarian/ovulated oocytes and embryos have been studied. Oviducts/ovaries were excised at different times after death of mice and effects of the postmortem interval on ovarian/ovulated oocytes and embryos were analyzed. When oviduct excision was delayed 10 min, many ovulated oocytes lysed or underwent in vitro spontaneous activation, and this postmortem effect aggravated with the extension of postmortem interval and oocyte aging. Oocytes from different mouse strains responded differently to delayed oviduct removal. Delayed oviduct excision did not cause lysis of zygotes or embryos but compromised their developmental potential. When ovaries were excised at 30 min after death, percentages of atretic follicles increased while blastocyst cell number declined significantly after oocyte maturation in vitro. Preservation of oviducts in vitro, in intact or opened abdomen at different temperatures and histological analysis of oviducts from different treatments suggested that toxic substance(s) were secreted from the dying oviducts which induced oocyte lysis and spontaneous activation and both this effect itself and the sensitivity of oocytes to this effect was temperature dependent. It is concluded that a short delay of oviduct/ovary removal had marked detrimental effects on oocytes and embryos. This must be taken into account in experiments using oocytes or embryos from slaughtered animals. The data may also be important for estimation of the time of death in forensic medicine and for rescue of oocytes from deceased valuable or endangered mammals.


Staying true to our values.
With the JCR published last summer, the IF of the EJPD reached 0.683! This is the highest value that the journal has ever reached and it shows a clear progression compared to the 2015 value of 0.421. This event, occurred shortly after the death of professor Giuliano Falcolini, led me to reflect and read again his editorial published in the issue N.3, 2011 of the EJPD. In that editorial professor Falcolini communicated with joy and enthusiasm ( ... we were honoured and thrilled to see our European Journal of Paediatric Dentistry included in the list ...) to the whole dental scientific world that the journal had been awarded the IF (the editorial can be read in full at http://www.ejpd.eu/bibliografia_detail. asp? id=399). I believe that reading again what he wrote at the time is the best way to remember him and to be aware of the solid foundations that professor Falcolini has laid in order to succeed both as journal and scientific society. The enthusiasm, joy, and desire to do well, together with the rigorous scientific competence with which professor Falcolini led the EJPD in those years are the same values that the whole SIOI group will continue to follow in order to reach new and higher goals.