The radiologically isolated syndrome: take action when the unexpected is uncovered?
The increasing diagnostic application of magnetic resonance imaging (MRI) in neurology has resulted in an increase in accidental disclosure of asymptomatic brain pathologies with potential clinical significance. Here, we discuss the incidental detection of multiple sclerosis (MS) typical central nervous system (CNS) lesions fulfilling MRI criteria for dissemination in space (radiologically isolated syndrome, RIS) and its diagnostic, prognostic and therapeutic implications. Three recent studies, including a total of 136 RIS cases which were followed for up to 10 years, indicate that a subgroup of such patients will develop MS. MRI-based dissemination in time (DIT) was determined in more than two-thirds and clinically isolated syndrome (CIS) occurred in almost one-third of the patients. Presence of Gadolinium (Gd)-enhancing lesions was identified as potential predictor for MRI-based DIT in one study, and pathological visual evoked potential (VEP) examinations at baseline and Gd-enhancement at the second MRI scan for CIS (clinical DIT) in another study. In the lack of established management guidelines, we propose a pragmatic diagnostic and therapeutic approach for patients with RIS. Individual concepts are required and both "wait" as well as "follow" strategies are justifiable. Further prospective studies are required to elucidate potential biomarkers for narrowing down the high-risk cohort and exploring further characteristics of this disease stage.


Brief International Cognitive Assessment for MS (BICAMS): international standards for validation.
An international expert consensus committee recently recommended a brief battery of tests for cognitive evaluation in multiple sclerosis. The Brief International Cognitive Assessment for MS (BICAMS) battery includes tests of mental processing speed and memory. Recognizing that resources for validation will vary internationally, the committee identified validation priorities, to facilitate international acceptance of BICAMS. Practical matters pertaining to implementation across different languages and countries were discussed. Five steps to achieve optimal psychometric validation were proposed. In Step 1, test stimuli should be standardized for the target culture or language under consideration. In Step 2, examiner instructions must be standardized and translated, including all information from manuals necessary for administration and interpretation. In Step 3, samples of at least 65 healthy persons should be studied for normalization, matched to patients on demographics such as age, gender and education. The objective of Step 4 is test-retest reliability, which can be investigated in a small sample of MS and/or healthy volunteers over 1-3 weeks. Finally, in Step 5, criterion validity should be established by comparing MS and healthy controls. At this time, preliminary studies are underway in a number of countries as we move forward with this international assessment tool for cognition in MS.


The mutual relationship between shift work and depressive complaints--a prospective cohort study.
The aim of this study was to examine longitudinally the mutual relationship between shift work and depressive complaints. Data from the ongoing Maastricht cohort study (1998-2008) were used. Firstly, the impact of shift work on the development of depressive complaints, defined as depressed mood, was studied. Both prospective and retrospective approaches were used, conducting, respectively, survival and logistic regression analyses, correcting for possible confounding factors. Secondly, the impact of depressed mood on changes in shift work at one-year follow-up was studied. All analyses were stratified for men and women and, where possible, for age (<45 versus ≥45 years). Overall, the impact of shift work on the development of depressed mood over a ten-year period was rather small, although, male shift workers ≥45 years did contribute to a higher risk of developing depressed mood [hazard risk (HR) 1.37, 95% confidence interval (95% CI) 1.01-1.86]. Retrospective analyses found higher odds of depressed mood and depressive disorder among former or current male shift workers than "never shift workers" [odds ratio (OR) 1.39, 95% CI 1.09-1.79 and OR 1.79, 95% CI 1.32-2.42, respectively]. Results lacked significance when correcting for demographic and work-related factors. Analyses studying the impact of depressed mood on changes in work schedules showed that the risk to change from shift to day work or from shift work to sick leave was higher when depressed mood was reported at baseline [relative risk (RR) shift to day work 1.98, 95% CI 1.13-3.47; RR shift work to sick leave 2.96, 95% CI 2.00-4.29]. Although shift work did not have a large impact on the development of depressed mood, results might be underestimated due to selection processes and possibly overcorrection.


Substitution reactivity and structural variability induced by tryptamine on the biomimetic rhenium tricarbonyl complex.
A series of seven fac-[Re(CO)3(5Me-Sal-Trypt)(L)] complexes containing tryptamine on the N,O 5-methyl-salicylidene bidentate ligand backbone and where L is MeOH, Py, Imi, DMAP, PPh3 coordinated to the 6th position have been studied, including the formation of a dinuclear Re2 cluster. The crystallographic solid state structures show marked similarity in structural tendency, in particular the rigidity of the Re core and the hydrogen bond interactions similar to those found in protein structures. The rates of formation and stability of the complexes were evaluated by rapid time-resolved stopped-flow techniques and the methanol substitution reaction indicates the significant activation induced by the use of the N,O salicylidene bidentate ligand as manifested by the second-order rate constants for the entering nucleophiles. Both linear and limiting kinetics were observed and a systematic evaluation of the kinetics is reported clearly indicating an interchange type of intimate mechanism for the methanol substitution. The anticancer activity of compounds 1-7 was tested on HeLa cells and it was found that all compounds showed similar cytotoxicity where solubility allowed. IC50-values between ca. 11 and 22 μM indicate that some cytotoxicity resides most likely on the salicylidene-tryptamine ligand. The photoluminescence of the seven complexes is similar in maximum emission wavelength with little variation despite the broad range of ligands coordinated to the 6th position on the metal centre.


Adaptation of the 5-choice serial reaction time task to measure engagement and motivation for alcohol in mice.
Alcohol use disorder (AUD) is related to excessive binge alcohol consumption, and there is considerable interest in associated factors that promote intake. AUD has many behavioral facets that enhance inflexibility toward alcohol consumption, including impulsivity, motivation, and attention. Thus, it is important to understand how these factors might promote responding for alcohol and can change after protracted alcohol intake. Previous studies have explored such behavioral factors using responding for sugar in the 5-Choice Serial Reaction Time Task (5-CSRTT), which allows careful separation of impulsivity, attention, and motivation. Importantly, our studies uniquely focus on using alcohol as the reward throughout training and testing sessions, which is critical for beginning to answer central questions relating to behavioral engagement for alcohol. Alcohol preference and consumption in male C57BL/6 mice were determined from the first 9 sessions of 2-h alcohol drinking which were interspersed among 5-CSRTT training. Interestingly, alcohol preference but not consumption level significantly predicted 5-CSRTT responding for alcohol. In contrast, responding for strawberry milk was not related to alcohol preference. Moreover, high-preference (HP) mice made more correct alcohol-directed responses than low-preference (LP) during the first half of each session and had more longer reward latencies in the second half, with no differences when performing for strawberry milk, suggesting that HP motivation for alcohol may reflect "front-loading." Mice were then exposed to an Intermittent Access to alcohol paradigm and retested in 5-CSRTT. While both HP and LP mice increased 5-CSRTT responding for alcohol, but not strawberry milk, LP performance rose to HP levels, with a greater change in correct and premature responding in LP versus HP. Overall, this study provides three significant findings: (1) alcohol was a suitable reward in the 5-CSRTT, allowing dissection of impulsivity, attention, and motivation in relation to alcohol drinking, (2) alcohol preference was a more sensitive indicator of mouse 5-CSRTT performance than consumption, and (3) intermittent alcohol drinking promoted behavioral engagement with alcohol, especially for individuals with less initial engagement.


Nitrogen handling in the elasmobranch gut: a role for microbial urease.
Ureotelic elasmobranchs require nitrogen for both protein growth and urea-based osmoregulation, and therefore are probably nitrogen-limited in nature. Mechanisms exist for retaining and/or scavenging nitrogen in the gills, kidney, rectal gland and gut, but as yet, the latter are not well characterized. Intestinal sac preparations of the Pacific spiny dogfish shark (Squalus acanthias suckleyi) incubated in vitro strongly reabsorbed urea from the lumen after feeding, but mucosal fluid ammonia concentrations increased with incubation time. Phloretin (0.25 mmol l-1, which blocked urea reabsorption) greatly increased the rate of ammonia accumulation in the lumen. A sensitive [14C]urea-based assay was developed to examine the potential role of microbial urease in this ammonia production. Urease activity was detected in chyme/intestinal fluid and intestinal epithelial tissue of both fed and fasted sharks. Urease was not present in gall-bladder bile. Urease activities were highly variable among animals, but generally greater in chyme than in epithelia, and greater in fed than in fasted sharks. Comparable urease activities were found in chyme and epithelia of the Pacific spotted ratfish (Hydrolagus colliei), a ureotelic holocephalan, but were much lower in ammonotelic teleosts. Urease activity in dogfish chyme was inhibited by acetohydroxamic acid (1 mmol l-1) and by boiling. Treatment of dogfish gut sac preparations with acetohydroxamic acid blocked ammonia production, changing net ammonia accumulation into net ammonia absorption. We propose that microbial urease plays an important role in nitrogen handling in the elasmobranch intestine, allowing some urea-N to be converted to ammonia, which is then reabsorbed for amino acid synthesis or reconversion to urea.


Milestones in the systemic treatment of lung cancer.
Several milestones in the systemic treatment of lung cancer have been reached. Combination chemotherapy of small cell lung cancer was the first of these milestones. The establishment of palliative chemotherapy in patients with advanced non-small cell lung cancer and of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer was another important milestone. Targeted therapies with angiogenesis inhibitors, EGFR inhibitors, and ALK inhibitors also advanced treatment. The clinical introduction of immune checkpoint inhibitors was the latest milestone.


Effects of a Brief Team Training Program on Surgical Teams' Nontechnical Skills: An Interrupted Time-Series Study.
Up to 60% of adverse events in surgery are the result of poor communication and teamwork. Nontechnical skills in surgery (NOTSS) are critical to the success of surgery and patient safety. The study aim was to evaluate the effect of a brief team training intervention on teams' observed NOTSS. Pretest-posttest interrupted time-series design with statistical process control analysis was used to detect longitudinal changes in teams' NOTSS. We evaluated NOTSS using the revised NOTECHS weekly for 20 to 25 weeks before and after implementation of a team training program. We observed 179 surgical procedures with cardiac, vascular, upper gastrointestinal, and hepatobiliary teams. Mean posttest NOTECHS scores increased across teams, showing special cause variation. There were also significant before and after improvements in NOTECHS scores in respect to professional role and in the use of the Surgical Safety Checklist. Our results suggest associated improvements in teams' NOTSS after implementation of the team training program.


A novel technique for temporally regulated cell type-specific Cre expression and recombination in the pituitary gonadotroph.
Inducing tissue-specific genetic alterations under temporal control allows for the analysis of gene function in particular cell types at specified points in time. We have generated a system for tetracycline-controlled expression of Cre recombinase in mice using the unique CreTeR vector. The gonadotroph-specific bovine alpha-subunit (Balpha) promoter fragment was subcloned into the CreTeR vector, creating a technique for highly regulated expression of Cre recombinase exclusively in pituitary gonadotrophs. Control of Cre recombinase in the CreTeR vector was demonstrated in LbetaT2 pituitary cell lines, where Cre protein was detected in cells treated with doxycycline, but not in untreated cells. In transgenic mice, Cre was expressed in pituitary gonadotrophs of mice treated with doxycycline, but not in non-pituitary tissues or in transgenic mice not treated with doxycycline. We demonstrated Cre expression in the gonadotroph by immunostaining showing co-localization of Cre recombinase with the beta-subunit of LH (LH-beta). Furthermore, by crossing Balpha/CreTeR with R26R mice, we were able to demonstrate functional recombination within pituitary gonadotrophs, detected by lacZ expression. The Balpha/CreTeR mice described here can be used to study the function of virtually any gene in the gonadotroph; in particular, this will be useful in studying genes, which may have distinct roles in development and in the adult.


Assembly and comparative analysis of the complete mitochondrial genome of Trigonella foenum-graecum L.
Trigonella foenum-graecum L. is a Leguminosae plant, and the stems, leaves, and seeds of this plant are rich in chemical components that are of high research value. The chloroplast (cp) genome of T. foenum-graecum has been reported, but the mitochondrial (mt) genome remains unexplored. In this study, we used second- and third-generation sequencing methods, which have the dual advantage of combining high accuracy and longer read length. The results showed that the mt genome of T. foenum-graecum was 345,604 bp in length and 45.28% in GC content. There were 59 genes, including: 33 protein-coding genes (PCGs), 21 tRNA genes, 4 rRNA genes and 1 pseudo gene. Among them, 11 genes contained introns. The mt genome codons of T. foenum-graecum had a significant A/T preference. A total of 202 dispersed repetitive sequences, 96 simple repetitive sequences (SSRs) and 19 tandem repetitive sequences were detected. Nucleotide diversity (Pi) analysis counted the variation in each gene, with atp6 being the most notable. Both synteny and phylogenetic analyses showed close genetic relationship among Trifolium pratense, Trifolium meduseum, Trifolium grandiflorum, Trifolium aureum, Medicago truncatula and T. foenum-graecum. Notably, in the phylogenetic tree, Medicago truncatula demonstrated the highest level of genetic relatedness to T. foenum-graecum, with a strong support value of 100%. The interspecies non-synonymous substitutions (Ka)/synonymous substitutions (Ks) results showed that 23 PCGs had Ka/Ks < 1, indicating that these genes would continue to evolve under purifying selection pressure. In addition, setting the similarity at 70%, 23 homologous sequences were found in the mt genome of T. foenum-graecum. This study explores the mt genome sequence information of T. foenum-graecum and complements our knowledge of the phylogenetic diversity of Leguminosae plants.


An echovirus 18-associated outbreak of aseptic meningitis in Taiwan: epidemiology and diagnostic and genetic aspects.
In 2006, an outbreak of aseptic meningitis was noted in Taiwan. From January to October 2006, a total of 3283 specimens collected from patients with viral infection, including 173 cerebrospinal fluid (CSF) samples, were examined for virus isolation and identification. Overall, 339 enterovirus (EV)-positive cases were identified by virus culture: echovirus 18 (E18) formed the majority (27.4 %, 93 cases), followed by coxsackievirus B2 (13.8 %, 47 cases) and coxsackievirus A2 (10.8 %, 37 cases). The manifestations of the 93 E18 cases were aseptic meningitis (44.1 %), viral exanthema (23.6 %), acute tonsillitis (15.1 %), acute pharyngitis (14.0 %), acute gastritis (11.8 %), herpangina (7.5 %) and bronchopneumonia (5.3 %). Of 107 E18 isolates identified, 100, 62.5 and 19 % were obtained following culture in RD, MRC-5 and A549 cells, respectively. E18 was identified most frequently from throat swabs (67.2 %) and less frequently from stool samples (15.9 %) and CSF (16.8 %). The detection rate of E18 was 78.2 % from CSF, 50 % from stool samples and 22.9 % from throat swabs. Phylogenetic relationships among the E18 strains were examined. Analysis of the partial VP1 gene showed 3.7-23.8 % variation in sequence compared with sequences from GenBank and, notably, the amino acid change V152S was detected in a protruding loop within the VP1 protein. These results indicate that a genetic variant of E18 was circulating and caused an outbreak of aseptic meningitis in Taiwan in 2006.


Coupled Genomic Evolutionary Histories as Signatures of Organismal Innovations in Cephalopods: Co-evolutionary Signatures Across Levels of Genome Organization May Shed Light on Functional Linkage and Origin of Cephalopod Novelties.
How genomic innovation translates into organismal organization remains largely unanswered. Possessing the largest invertebrate nervous system, in conjunction with many species-specific organs, coleoid cephalopods (octopuses, squids, cuttlefishes) provide exciting model systems to investigate how organismal novelties evolve. However, dissecting these processes requires novel approaches that enable deeper interrogation of genome evolution. Here, the existence of specific sets of genomic co-evolutionary signatures between expanded gene families, genome reorganization, and novel genes is posited. It is reasoned that their co-evolution has contributed to the complex organization of cephalopod nervous systems and the emergence of ecologically unique organs. In the course of reviewing this field, how the first cephalopod genomic studies have begun to shed light on the molecular underpinnings of morphological novelty is illustrated and their impact on directing future research is described. It is argued that the application and evolutionary profiling of evolutionary signatures from these studies will help identify and dissect the organismal principles of cephalopod innovations. By providing specific examples, the implications of this approach both within and beyond cephalopod biology are discussed.


Pediatric Trauma: Management and Lessons Learned.
The aim is to prospectively study 125 trauma patients admitted in the pediatric surgery ward in our institute. Pediatric patients admitted in the ward after initial resuscitation in the triage room were included. Isolated neurosurgical and orthopedic injuries were excluded. X-ray cervical spine, hip, and chest and a focused assessment with sonography in trauma ultrasound were done for all patients. Computed tomography of the abdomen or chest was done where relevant. Injury profile and surgical intervention when needed were analyzed. Road traffic accidents and fall from height caused 73.6% of the injuries. School-going children were most commonly affected (60.8%). Distinctive injuries were noted such as abdominal wall hernias and delayed bladder perforation. All solid organ injury irrespective of grade treated conservatively. Forty percent of the children required surgical intervention. Five patients after laparotomy were found to have surgical conditions unrelated to trauma, whereas another 14 required delayed surgery. Five patients had injuries secondary to sexual abuse. All except two patients were discharged in a satisfactory condition and are doing well in the follow-up. In spite of extensive injuries and the need for multiple surgeries, children with trauma have a good prognosis. Close observation during admission and also in follow-up are essential, as many patients may require delayed surgery ≥1 week from injury.


Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway.
Hepatocarcinogenesis commonly involves the gradual progression from hepatitis to fibrosis and cirrhosis, and ultimately to hepatocellular carcinoma (HCC). Endothelin 1 (Edn1) has been identified as a gene that is significantly up-regulated in HBx-induced HCC in mice. In this study, we further investigated the role of edn1 in hepatocarcinogenesis using a transgenic zebrafish model and a cell culture system. Liver-specific edn1 expression caused steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCC in zebrafish. Overexpression of EDN1 in 293T cells enhanced cell proliferation and cell migration in in vitro and xenotransplantation assays and was accompanied with up-regulation of several cell cycle/proliferation- and migration-specific genes. Furthermore, expression of the unfolded protein response (UPR) pathway-related mediators, such as spliced XBP1, ATF6, IRE1, and PERK, was also up-regulated at both the RNA and protein levels. In the presence of an EDN1 inhibitor or an AKT inhibitor, these increases were diminished and the EDN1-induced migration ability also was disappeared, suggesting that the EDN1 effects act through activation of the AKT pathway to enhance the UPR and subsequently activate the expression of downstream genes. Additionally, p-AKT is enhanced in the edn1 transgenic fish compared to the GFP-mCherry control. The micro RNA miR-1 was found to inhibit the expression of EDN1. We also observed an inverse correlation between EDN1 and miR-1 expression in HCC patients. In conclusion, our data suggest that EDN1 plays an important role in HCC progression by activating the PI3K/AKT pathway and is regulated by miR-1.


Recruitment of Tup1-Ssn6 by yeast hypoxic genes and chromatin-independent exclusion of TATA binding protein.
The Tup1-Ssn6 general repression complex in Saccharomyces cerevisiae represses a wide variety of regulons. Regulon-specific DNA binding proteins recruit the repression complex, and their synthesis, activity, or localization controls the conditions for repression. Rox1 is the hypoxic regulon-specific protein, and a second DNA binding protein, Mot3, augments repression at tightly controlled genes. We addressed the requirements for Tup1-Ssn6 recruitment to two hypoxic genes, ANB1 and HEM13, by using chromatin immunoprecipitation assays. Either Rox1 or Mot3 could recruit Ssn6, but Tup1 recruitment required Ssn6 and Rox1. We also monitored events during derepression. Rox1 and Mot3 dissociated from DNA quickly, accounting for the rapid accumulation of ANB1 and HEM13 RNAs, suggesting a simple explanation for induction. However, Tup1 remained associated with these genes, suggesting that the localization of Tup1-Ssn6 is not the sole determinant of repression. We could not reproduce the observation that deletion of the Tup1-Ssn6-interacting protein Cti6 was required for induction. Finally, Tup1 is capable of repression through a chromatin-dependent mechanism, the positioning of a nucleosome over the TATA box, or a chromatin-independent mechanism. We found that the rate of derepression was independent of the positioned nucleosome and that the TATA binding protein was excluded from ANB1 even in the absence of the positioned nucleosome. The mediator factor Srb7 has been shown to interact with Tup1 and to play a role in repression at several regulons, but we found that significant levels of repression remained in srb7 mutants even when the chromatin-dependent repression mechanism was eliminated. These findings suggest that the repression of different regulons or genes may invoke different mechanisms.


A National Spinal Muscular Atrophy Registry for Real-World Evidence.
Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.


Spectrum of pulmonary neuroendocrine proliferations and neoplasms.
Neuroendocrine neoplasms are ubiquitous tumors found throughout the body, most commonly in the gastrointestinal tract followed by the thorax. Neuroendocrine cells occur normally in the bronchial and bronchiolar epithelium and may be solitary or may occur in clusters. Although neuroendocrine cell proliferations may be found in association with chronic lung disease, a broad range of neuroendocrine proliferations and neoplasms may occur and exhibit variable biologic behavior. Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) is a diffuse idiopathic form of neuroendocrine cell hyperplasia and is considered a preinvasive lesion that may give rise to carcinoid tumors. Patients with DIPNECH are typically older women who may be asymptomatic or may present with chronic respiratory symptoms. DIPNECH manifests as multifocal bilateral pulmonary micronodules on expiratory high-resolution computed tomographic (CT) images; the air trapping is secondary to constrictive bronchiolitis. Carcinoid tumors are low-grade malignant neoplasms that typically affect symptomatic children and young adults. Carcinoids manifest as well-defined pulmonary nodules or masses that are often closely related to central bronchi. They may exhibit intrinsic calcification and contrast material enhancement at CT, and patients with carcinoids may have postobstructive atelectasis and pneumonia. Although typical carcinoids are indolent neoplasms and patients have a good prognosis, atypical carcinoids are aggressive malignancies with a propensity for metastasis. Both are optimally treated with complete surgical excision. Large cell neuroendocrine carcinoma and small cell lung cancer are highly aggressive neuroendocrine malignancies that usually affect elderly smokers. These tumors manifest with large peripheral or central pulmonary masses. Local invasion, intrathoracic lymphadenopathy, and distant metastases are frequent at presentation. As a result, affected patients may not be candidates for surgical resection, are often treated with chemotherapy with or without radiation, and have a poor prognosis.


Monoclonal and polyclonal gammopathy measured by serum free light chain and immunofixation subdivide the clinical outcomes of diffuse large B-cell lymphoma according to molecular classification.
Elevated serum free light chain (FLC) is known to be an adverse prognostic factor for diffuse large B-cell lymphoma (DLBCL). We hypothesized that monoclonal gammopathy (MG; elevated kappa [κ] or lambda [λ] FLC with an abnormal κ/λ ratio or a positive IF [immunofixation]) and polyclonal gammopathy (PG; elevated κ and/or λ FLC with a normal κ/λ ratio and a negative IF) would have different clinical outcome according to the molecular classification of DLBCL. In addition, MG would be a poor prognostic factor in patients with activated B-cell like type of DLBCL. Molecular classification of DLBCL, such as germinal center B-cell (GCB) type and non-GCB type, was performed according to the Hans algorithm. Among 175 newly diagnosed DLBCL patients, 96 (54.9 %) patients had an elevated FLC. MG and PG were observed in 34 and 68 patients, respectively. The 2-year overall survival (OS) and event-free survival (EFS) rates were 79.0 % and 71.6 %, respectively. In multivariate analysis, high-intermediate/high International Prognostic Index score and elevated FLC were significant for the OS (P = 0.002, P = 0.005, respectively) and EFS (P < 0.002, P = 0.010, respectively). MG and PG were also associated with inferior OS (P = 0.002, P = 0.011, respectively) and EFS (P = 0.002, P = 0.013, respectively). Ninety-six patients from a total 133 evaluable patients were classified to the non-GCB type. Patients with PG showed inferior clinical outcome for OS and EFS in patients with the GCB type (P = 0.006, P = 0.035, respectively). MG was a significant poor prognostic factor for OS and EFS in patients with the non-GCB type (P = 0.017, P = 0.004, respectively). MG was a poor prognostic maker in patients with the non-GCB type and PG was a poor prognostic indicator for the GCB type of DLBCL who were treated with R-CHOP.


[Small retinoblastoma: early diagnosis and combined eye-preserving treatment].
The presented review devoted to early diagnosis and combined eye-preserving treatment of small retinoblastoma emphasizes significance of using optical coherence tomography and transpupillary thermotherapy in malignant retinal tumors along with other options.


Appropriately spaced nuclear localizing signals are necessary for efficient nuclear import of nonnuclear proteins.
To deliver nonnuclear proteins into the nucleus, we have examined the locations and number of nuclear localizing signals by use of simian virus 40 large T-antigen (SV40Ta) and yeast enhanced green fluorescent protein (yEGFP) in Saccharomyces cerevisiae as a model system. When only one SV40Ta was added to either the N- or C-terminus of yEGFP, the fluorescence of yEGFP was detected in both the nucleus and the cytoplasm. When two SV40Ta signals were added, one to the N-terminus and one to the C-terminus of yEGFP (SV40Ta-yEGFP-SV40Ta), the fluorescence of yEGFP was localized in only the nucleus. When the presequence of cytochrome oxidase subunit IV (pCOXIV) was inserted between the SV40Ta and the N-terminus of yEGFP (SV40Ta-pCOXIV-yEGFP-SV40Ta) in this construct, the fluorescence was located in both the nucleus and the cytoplasm, suggesting that the increased distance between the two SV40Ta signals decreased the efficiency of transport into the nucleus. When an additional SV40Ta signal was inserted between pCOXIV and yEGFP (SV40Ta-pCOXIV-SV40Ta-yEGFP), the fluorescence was localized only in the nucleus, indicating that two SV40Ta signals spaced by pCOXIV of 28 amino acid residues forming an alpha-helix are potent in transporting yEGFP into the nucleus. These results indicate that two SV40Ta signals spaced appropriately are essential for the efficient transport of the nonnuclear protein into the nucleus.


[Idiopathic thrombocytopenic purpura and pregnancy].
ITP is the most common autoimmune disease during pregnancy. Whereas the maternal risk due to the extreme thrombocytopenia can be calculated, the risk to the foetus is difficult to predict. As there is no correlation between maternal and foetal platelet count, no generalisations can be made as to the preferable method of delivery. The methods of treatment with special reference to pregnancy and the various procedures necessary during delivery are discussed.


[Organization of preventive and antiepidemic measures in conditions of massive outbreak of Legionnaires' disease in population of town Verkhnyaya Pyshma. Epidemiologist's work experience in ensuring biosafety].
Data on organization and carrying out of preventive and antiepidemic measures in hospital during mass hospitalization (> 190 cases) of patients with community-acquired pneumonia caused by Legionella pneumophila are presented. Experience of physicians-epidemiologists in determination of directions of work in hospital, procedures of interaction, extent and description of biosafety measures in order to prevent nosocomial spread of infection to patients and staff are described.


Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo.
This brief resume summarizes the evidence which shows that melatonin is a significant free radical scavenger and antioxidant at both physiological and pharmacological concentrations in vivo. Surgical removal of the pineal gland, a procedure which lowers endogenous melatonin levels in the blood, exaggerates molecular damage due to free radicals during an oxidative challenge. Likewise, providing supplemental melatonin during periods of massive free radical production greatly lowers the resulting tissue damage and dysfunction. In the current review, these findings are considered in terms of neurodegenerative diseases, cancer, ischemia/reperfusion injury and aging. Besides being a highly effective direct free radical scavenger and indirect antioxidant, melatonin has several features that make it of clinical interest. Thus, melatonin is readily absorbed when it is administered via any route, it crosses all morphophysiological barriers, e.g., blood-brain barrier and placenta, with ease, it seems to enter all parts of every cell where it prevents oxidative damage, it preserves mitochondrial function, and it has low toxicity. While blood melatonin levels are normally low, tissue levels of the indoleamine can be considerably higher and at some sites, e.g., in bone marrow cells and bile, melatonin concentrations exceed those in the blood by several orders of magnitude. What constitutes a physiological level of melatonin must be redefined in terms of the bodily fluid, tissue and subcellular compartment being examined.


Identification and characterization of an animal delta(12) fatty acid desaturase gene by heterologous expression in Saccharomyces cerevisiae.
We have cloned a Caenorhabditis elegans cDNA encoding a Delta12 fatty acid desaturase and demonstrated its activity by heterologous expression in Saccharomyces cerevisiae. The predicted protein is highly homologous both to the cloned plant genes with similar function and to the published sequence of the C. elegans omega-3 fatty acid desaturase. In addition, it conforms to the structural constraints expected of a membrane-bound fatty acid desaturase including the canonical histidine-rich regions. This is the first report of a cloned animal Delta(12) desaturase gene. Expression of this cDNA in yeast resulted in the accumulation of 16:2 and 18:2 (linoleic) acids. The increase of membrane fluidity brought about by this change in unsaturation was measured. The production of polyunsaturated fatty acids in yeast cells and the concomitant increase in membrane fluidity was correlated with a modest increase in growth rate at low temperature and with increased resistance to ethanol and oxidative stress.


Incidence and risk factors of urinary tract infection in very low birth weight infants.
To describe the incidence and associated risk factors of urinary tract infection (UTI) in very low birth weight (VLBW) infants and to determine the value of diagnostic imaging studies after the first UTI episode before discharge from the neonatal intensive care unit (NICU). VLBW infants born during 2003-2012 were reviewed for UTI. In a nested case-control study, potential risk factors of UTI were compared between infants with UTI (cases) versus birth weight and gestational age matched controls. Renal ultrasonography (USG) and voiding cystourethrography (VCUG) results were reviewed in cases. During the study period, 54.7% of urine culture specimens were collected by sterile methods. 3% (45/1,495) of VLBW infants met the study definition for UTI. UTI was diagnosed at mean postnatal age of 33.1±22.9 days. There was no significant difference in gender, ethnicity, antenatal steroid exposure, blood culture positive sepsis, ionotropic support, respiratory support and enteral feeding practices between cases and controls. Cases had a significantly higher cholestasis compared to controls (22% vs. 9% ; p = 0.03). However, cholestasis was not a significant predictor of UTI in the adjusted analysis [adjusted OR 2.38 (95% CI 0.84 to 6.80), p = 0.11]. Cases had higher central line days, parenteral nutrition days, total mechanical ventilation days, chronic lung disease, and length of stay compared to controls. Renal USG was abnormal in 37% and VCUG was abnormal in 17% of cases. The incidence of UTI in contemporary VLBW infants is relatively low compared to previous decades. Since no significant UTI predictors could be identified, urine culture by sterile methods is the only reliable way to exclude UTI. The majority of infants with UTI have normal renal anatomy. UTI in VLBW infants is associated with increased morbidity and length of stay.


The relevance of growth rates in urine to the pathogenesis of urinary-tract infections due to Micrococcus subgroup 3 (Staphylococcus saprophyticus biotype 3).
A novobiocin-resistant "biotype" of Micrococcus subgroup 3 (Staphylococcus saprophyticus) is known to be a primary pathogen of the female urinary tract and to cause infections as severe as those produced by Escherichia coli. The growth characteristics of this virulent biotype were compared in vitro with those of other Micrococcaceae and of E. coli to determine whether rapid growth explains the virulence of the biotype. Nutrient broth was shown to have growth-supporting qualities that differed from those of urine and it was therefore unsuitable for these studies. In urine, the virulent biotype grew more slowly, had a longer lag period, and reached much lower final viable counts than did Escherichia coli. Surprisingly, the virulent biotype also grew more slowly and reached a lower final viable count than did several other Micrococcaceae isolated from the urinary tract of healthy women. Urine from women who had suffered a recent infection with the virulent biotype had growth-supporting properties similar to those of urine from healthy women. Experiments with filtered forestream urine suggested that urethral secretions do not contain a factor determining growth rates of this organism in urine. The possibility that virulent strains adapt to rapid growth in urine was excluded. No evidence was obtained that the virulent biotype inhibits the growth of other Micrococcaceae in urine. Ability to grow rapidly in urine does not therefore explain the virulence of novobiocin-resistant strains of subgroup-3 micrococci.


Expression of miR-210 in senile COPD complicating primary lung cancer.
To analyze the expression and clinical significance of miR-210 in patients with senile chronic obstructive pulmonary disease (COPD) complicating primary lung cancer. 30 cases of COPD PATIENTS AND METHODS: 30 cases of primary lung cancer and 30 cases of COPD complicating lung cancer were selected. MiR-210 can function as the cancer suppressor gene in progress from COPD to primary lung cancer and may be used as an important auxiliary diagnosis index. Analysis of correlations between MiR-210 expression with clinical features such as age, sex, disease type, COPD disease classification, pathological pattern of neoplasia and TNM staging. The expression of miR-210 of COPD Group was significantly higher than the Lung Cancer Group. The level of COPD Complicating Lung Cancer was the lowest (p < 0.05). There was no remarkable difference among sex, age, smoking status, hypertension, diabetes mellitus and pathological type in each group (p > 0.05). Expression of miR-210 was lower with the aggravation of COPD and an increase of TNM staging (p < 0.05). MiR-210 expression level in the diagnosis of COPD complicating lung cancer had the sensitivity of 76.8%, specificity of 72.3%, accuracy of 0.73, 95% CI of 0.63-0.85 and critical value of 0.1825.


The optimal cut-off point of C-reactive protein as an optional component of metabolic syndrome in Japan.
C-reactive protein (CRP) independently predicts cardiovascular disease (CVD) and is considered to be part of metabolic syndrome (MS). The concentration of CRP are proposed to be <1.0 mg/L as low risk, 1.0 to 3.0 mg/L as intermediate risk, and >3.0 mg/L as high risk for CVD in Western society. Apparently healthy 179 men and 166 women were categorized with modified National Cholesterol Education Program Adult Treatment Panel III criteria (body mass index > or = 25 in place of abdominal obesity) for defining MS. The cut-off points of CRP were evaluated for both MS defined by impaired fasting glucose criteria of > or = 110 mg/dl (MS110) and > or = 100 mg/dl (MS100), separately by sex. The optimal cut-off point of CRP was 0.65 mg/L in all subgroups. The sensitivity and specificity of this CRP value for male MS100, female MS100, male MS110, and female MS110 were 0.650 and 0.626, 1.000 and 0.771, 0.739 and 0.609, and 1.000 and 0.756, respectively. The optimal cut-off point of CRP for MS might be 0.65 mg/L in Japan and this value can be useful in routine clinical practice and studies on MS.


Regulation of soil organic C mineralisation at the pore scale.
Little is known about the factors that regulate C mineralisation at the soil pore scale or how these factors vary throughout the pore network. This study sought to understand how the decomposition of organic carbon varies within the soil pore network and to determine the relative importance of local environmental properties relative to biological properties as controlling factors. This was achieved by sterilising samples of soil and reinoculating them with axenic bacterial suspensions using the matric potential to target different locations in the pore network. Carbon mineralisation curves were described with two-compartment first-order models to distinguish CO2 derived from the labile organic carbon released during sterilisation from CO2 derived from organic C unaffected by sterilisation. The data indicated that the size of the labile pool of organic C, possibly of microbial origin, varied as a function of location in the pore network but that the organic carbon unaffected by sterilisation did not. The mineralisation rate of the labile C varied with the bacterial type inoculated, but the mineralisation rate of the organic C unaffected by sterilisation was insensitive to bacterial type. Taken together, the results suggest that microbial metabolism is a less significant regulator of soil organic carbon decomposition than are microbial habitat properties.


Human immunodeficiency virus infection in diabetic intravenous drug users.
--To evaluate the association between diabetes and human immunodeficiency virus (HIV) seroprevalence in a population of intravenous (IV) drug users. --Cross-sectional survey in a cohort of IV drug users. --Community-based study clinic. --The study included 2921 individuals with a history of IV drug use in the past 10 years; over 90% had injected drugs in the past year and 77% in the past month; only 15% were receiving drug treatment. --The HIV seroprevalence among IV drug users with and without a history of diabetes. --Those IV drug users with a history of diabetes had significantly lower HIV seroprevalence (9.8%) than nondiabetic IV drug users (24.3%; P = .03). Despite similar duration and intensity of drug use and sexual practices, diabetic IV drug users tended not to share injection paraphernalia and were less likely to attend shooting galleries than nondiabetic IV drug users. --Our data suggest that the apparent protective effect of diabetes against HIV infection in IV drug users is most likely due to their safer injection practices afforded by their ready access to sterile injection equipment.


Cytotoxic sesquiterpenes from Nardostachys chinensis.
Five cytostatic sesquiterpenes, desoxo-narchinol-A (1), nardosinone (2), debilon (3), nardosinonediol (4) and kanshone A (5), were isolated from the roots and rhizomes of Nardostachys chinensis (Valerianaceae). The steric structure of 1 was determined by nuclear Overhauser effects (NOEs) and the exciton chirality method. All five showed cytotoxic activity against P-388 cells and the structure-activity relationship of 1 was also discussed.


Broad-spectrum biofilm inhibition by Kingella kingae exopolysaccharide.
Cell-free extracts prepared from Kingella kingae colony biofilms were found to inhibit biofilm formation by Aggregatibacter actinomycetemcomitans, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Candida albicans, and K. kingae. The extracts evidently inhibited biofilm formation by modifying the physicochemical properties of the cell surface, the biofilm matrix, and the substrate. Chemical and biochemical analyses indicated that the biofilm inhibition activity in the K. kingae extract was due to polysaccharide. Structural analyses showed that the extract contained two major polysaccharides. One was a linear polysaccharide with the structure →6)-α-d-GlcNAcp-(1→5)-β-d-OclAp-(2→, which was identical to a capsular polysaccharide produced by Actinobacillus pleuropneumoniae serotype 5. The second was a novel linear polysaccharide, designated PAM galactan, with the structure →3)-β-d-Galf-(1→6)-β-d-Galf-(1→. Purified PAM galactan exhibited broad-spectrum biofilm inhibition activity. A cluster of three K. kingae genes encoding UDP-galactopyranose mutase (ugm) and two putative galactofuranosyl transferases was sufficient for the synthesis of PAM galactan in Escherichia coli. PAM galactan is one of a growing number of bacterial polysaccharides that exhibit antibiofilm activity. The biological roles and potential technological applications of these molecules remain unknown.


Emerging School Readiness Profiles: Motor Skills Matter for Cognitive- and Non-cognitive First Grade School Outcomes.
A promising approach for studying school readiness involves a person-centered approach, aimed at exploring how functioning in diverse developmental domains conjointly affects children's school outcomes. Currently, however, a systematic understanding lacks of how motor skills, in conjunction with other school readiness skills, affect a child's school outcomes. Additionally, little is known about longitudinal associations of school readiness with non-academic (e.g., socioemotional) school outcomes. Therefore, we examined the school readiness skills of a sample of Dutch children (N = 91) with a mean age of 3 years and 4 months (46% girls). We used a multi-informant test battery to assess children's school readiness in terms of executive functions (EFs), language and emergent literacy, motor skills, and socioemotional behavior. During the spring term of a child's first grade year, we collected academic and non-academic (i.e., EFs, motor skills, socioemotional- and classroom behavior, and creative thinking) school outcomes. A latent profile analysis revealed four distinct profiles. Children in the "Parent Positive" (29%) profile were rated positively by their parents, and performed variably on motor and language/emergent literacy skills tests. The second profile-"Multiple Strengths" (13%)-consisted of children showing strengths in multiple domains, especially with respect to motor skills. Children from the third profile-"Average Performers" (50%)-did not show any distinct strengths or weaknesses, rather displayed school readiness skill levels close to, or just below the sample mean. Finally, the "Parental Concern" (8%) profile was characterized by high levels of parental concerns, while displaying slightly above average performance on specific motor and language skills. Motor skills clearly distinguished between profiles, next to parent-rated EFs and socioemotional behavior, and to a lesser extent emergent literacy skills. School readiness profiles were found to differ in mean scores on first grade academic achievement, parent- and teacher-rated EFs, motor skills, parent-rated socioemotional functioning, and pre-requisite learning skills. The pattern of mean differences was complex, suggesting that profiles could not be ranked from low to high in terms of school outcomes. Longitudinal studies are needed to disentangle the interaction between emerging school readiness of the child and the surrounding context.


Linear regression for bivariate censored data via multiple imputation.
Bivariate survival data arise, for example, in twin studies and studies of both eyes or ears of the same individual. Often it is of interest to regress the survival times on a set of predictors. In this paper we extend Wei and Tanner's multiple imputation approach for linear regression with univariate censored data to bivariate censored data. We formulate a class of censored bivariate linear regression methods by iterating between the following two steps: 1. the data is augmented by imputing survival times for censored observations; 2. a linear model is fit to the imputed complete data. We consider three different methods to implement these two steps. In particular, the marginal (independence) approach ignores the possible correlation between two survival times when estimating the regression coefficient. To improve the efficiency, we propose two methods that account for the correlation between the survival times. First, we improve the efficiency by using generalized least squares regression in step 2. Second, instead of generating data from an estimate of the marginal distribution we generate data from a bivariate log-spline density estimate in step 1. Through simulation studies we find that the performance of the two methods that take the dependence into account is close and that they are both more efficient than the marginal approach. The methods are applied to a data set from an otitis media clinical trial.


Enhanced real-time monitoring of adeno-associated virus trafficking by virus-quantum dot conjugates.
The unique spectral properties of semiconductor quantum dots (QDs) enable long-term live-cell imaging and ultrasensitive detection of viral particles, which in turn can potentially provide a practical means for detailed analysis of the underlying molecular mechanisms of virus entry. In this study, we report a general method of labeling adeno-associated virus serotype 2 (AAV2) with QDs for enhanced visualization of the intracellular behavior of viruses in living target cells. It was found that the mild conditions required for this QD conjugation reaction allowed for the retention of viral infectivity of AAV2. Furthermore, quantitative analysis of viral motility in living cells suggested that QD-labeling had no significant effect on the intracellular transport properties of AAV2 particles compared to those of conventional organic dye-labeled AAV2. Our imaging study demonstrated that QD-AAV2 was internalized mainly through a clathrin-dependent pathway and then trafficked through various endosomes. It was also observed that QD-AAV2 particles exploit the cytoskeleton network to facilitate their transport within cells, and the labeling study provided evidence that the ubiquitin-proteasome system was likely involved in the intracellular trafficking of AAV2, at least at the level of nuclear transport. Taken together, our findings reveal the potential of this QD-labeling method for monitoring the intracellular dynamics of virus-host cell interactions and interrogating the molecular mechanisms of viral infection in greater detail.


Effect of 1 Year Krill Oil Supplementation on Cognitive Achievement of Dutch Adolescents: A Double-Blind Randomized Controlled Trial.
Long-chain polyunsaturated fatty acids (LCPUFA) are important for brain development and function, maybe especially during adolescence. Observational studies have demonstrated an association between fish consumption (a source of LCPUFA) and cognition in adolescents, but intervention trials are lacking. The goal of the current study was to investigate the effect of one year of krill oil (a source of LCPUFA) supplementation on the cognitive performance of adolescents with a low Omega-3 Index (O3I ≤ 5%). A double-blind, randomized, and placebo-controlled supplementation trial with repeated measurements (baseline (T0), three months (T1), six months (T2), and 12 months (T3)) in adolescents (267 randomized) was executed. Participants were randomized to 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day in Cohort I or placebo and 800 mg EPA + DHA per day in Cohort II or placebo. O3I was monitored by a finger prick at all time points. At T0, T2, and T3, participants executed a neurocognitive test battery. Covariate corrected mixed models were run with either condition (krill or placebo) or O3I as predictors. Krill oil supplementation led to a small but significant increase in mean O3I, but few participants increased to the intended O3I range (8-11%). There was no significant effect of supplementation on the neurocognitive tests, nor a relationship between O3I and neurocognitive test scores. The increase in O3I was small in most participants, probably due to non-compliance. Possibly the increase in O3I was too small to demonstrate an effect. More research on the influence of LCPUFAs on cognition in adolescents is needed.


Relationship between exercise systolic blood pressure and left ventricular geometry in overweight, mildly hypertensive patients.
To examine the association between the graded exercise systolic blood pressure (SBP) response and left ventricular (LV) geometric structure in patients with untreated mild hypertension. The study included 80 sedentary, overweight patients (43 female and 37 male) with unmedicated high normal blood pressure or stage 1-2 hypertension. An echocardiogram was used to determine LV mass and the relative wall thickness (RWT) in relation to the chamber dimension. Participants performed a maximal graded exercise test, and the SBP was recorded at workloads of 2, 4 and 6 metabolic equivalents and at peak exercise. Separate statistical models were used to determine the influence of LV mass indexed for height(2.7) (LVMIh) and RWT on submaximal exercise SBP and peak exercise SBP, controlling for resting SBP, age, gender, ethnicity and body mass index. A greater RWT was associated with a higher submaximal SBP level (P = 0.038). Neither LVMIh (P = 0.989) nor the interaction of RWT and LVMIh (P = 0.787) were related to the submaximal SBP. None of the main or interaction effects of RWT and LVMIh were associated with the peak exercise SBP level. Increases in RWT were associated with higher submaximal exercise SBP responses in a sample of overweight, unmedicated hypertensives. These results suggest that RWT is an important determinant of the association between cardiac mass and exercise SBP response.


Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion.
Tumor cells adapt to nutrient-limited environments by inducing gene expression that ensures adequate nutrients to sustain metabolic demands. For example, during amino acid limitations, ATF4 in the amino acid response induces expression of asparagine synthetase (ASNS), which provides for asparagine biosynthesis. Acute lymphoblastic leukemia (ALL) cells are sensitive to asparagine depletion, and administration of the asparagine depletion enzyme l-asparaginase is an important therapy option. ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress. Therefore, understanding the mechanisms regulating ASNS expression is important to define the adaptive processes underlying tumor progression and treatment. Here we show that DNA hypermethylation at the ASNS promoter prevents its transcriptional expression following asparagine depletion. Insufficient expression of ASNS leads to asparagine deficiency, which facilitates ATF4-independent induction of CCAAT-enhancer-binding protein homologous protein (CHOP), which triggers apoptosis. We conclude that chromatin accessibility is critical for ATF4 activity at the ASNS promoter, which can switch ALL cells from an ATF4-dependent adaptive response to ATF4-independent apoptosis during asparagine depletion. This work may also help explain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers.


Supersymmetric optimization of second-harmonic generation in mid-infrared quantum cascade lasers.
We describe a procedure to optimize mid-infrared quantum cascade lasers with respect to the resonant second-order optical susceptibility, based on supersymmetric quantum mechanics. Realization of the optimized potential can be obtained by composition grading of ternary alloys, such as in InGaAs/AlInAs-based structures. The approach yields designs not only with strongly enhanced predicted nonlinear conversion efficiencies, but also with significantly improved modal gain compared with demonstrated devices.


Plasma dopamine: regulation and significance.
Dopamine (DA) normally circulates in plasma. The plasma concentration of the free form of DA is approximately equivalent to that of epinephrine (E) and 20% that of norepinephrine (NE). The free form constitutes less than 2% of total plasma DA, and the remainder exists predominantly as sulfate or glucuronide conjugates. DA is found in adrenal medulla and cortex, peripheral nerves, sympathetic ganglia, carotid body, and kidney, but quantitatively the origin of circulating DA remains poorly understood. Plasma concentrations of free DA increase in association with events that increase sympathetic tone, although to a much lesser degree than seen for NE or E. Thus, upright posture, bicycle exercise, a variety of emotional and physical stresses, and hypoglycemia may be associated with increases in plasma free DA. Plasma DA decreases during the course of dietary sodium depletion in humans, in contrast to the plasma NE response, and consistent with a physiological role for DA in the regulation of aldosterone secretion. Plasma DA increases after administration of its precursor L-dihydroxyphenylalanine, together with the decarboxylase inhibitor carbidopa. Plasma NE and (in some studies) plasma DA decrease after administration of the DA receptor agonist bromocriptine. In contrast, plasma DA and one of its major metabolites, homovanillic acid, increase after administration of the DA receptor antagonist haloperidol. Administration of the endogenous opioid peptide beta-endorphin into the brain increases central sympathetic outflow, thus increasing plasma DA concentration, although to a lesser extent than for NE or E. Disordered basal concentrations of DA in plasma or disordered responses of plasma DA have been reported in a number of disease states. Clear understanding of physiological roles of DA in plasma and of its pathophysiology awaits definition.


Injuries, envenomations and stings from exotic pets.
A variety of exotic vertebrate and invertebrate species are kept as 'pets' including fishes, amphibians (for example, frogs and toads), reptiles (turtles, crocodiles, lizards and snakes), birds, mammals (for example, primates, civets, and lions), and invertebrates (for example spiders, scorpions, and centipedes), and ownership of some of these animals is rising. Data for 2009-2011 suggest that the number of homes with reptiles rose by approximately 12.5%. Recent surveys, including only some of these animals, indicated that they might be present in around 18.6% of homes (equal to approximately 42 million animals of which around 40 million are indoor or outdoor fish). Many exotic 'pets' are capable of causing injury or poisoning to their keepers and some contacts prove fatal. We examined NHS Health Episode Statistics for England using selected formal categories for hospital admissions and bed days for 2004-2010 using the following categories of injury, envenomation or sting; bitten or struck by crocodile or alligator; bitten or crushed by other reptiles: contact with venomous snakes and lizards; contact with scorpions. Between 2004 and 2010 these data conservatively show a total of 760 full consultation episodes, 709 admissions and 2,121 hospital bed days were associated with injuries probably from exotic pets. Injuries, envenomations and stings from exotic pets constitute a small but important component of emerging medical problems. Greater awareness of relevant injuries and medical sequelae from exotic pet keeping may help medics formulate their clinical assessment and advice to patients.


Proteomic Analysis of Phytophthora infestans Reveals the Importance of Cell Wall Proteins in Pathogenicity.
The oomycete Phytophthora infestans is the most harmful pathogen of potato. It causes the disease late blight, which generates increased yearly costs of up to one billion euro in the EU alone and is difficult to control. We have performed a large-scale quantitative proteomics study of six P. infestans life stages with the aim to identify proteins that change in abundance during development, with a focus on preinfectious life stages. Over 10 000 peptides from 2061 proteins were analyzed. We identified several abundance profiles of proteins that were up- or downregulated in different combinations of life stages. One of these profiles contained 59 proteins that were more abundant in germinated cysts and appressoria. A large majority of these proteins were not previously recognized as being appressorial proteins or involved in the infection process. Among those are proteins with putative roles in transport, amino acid metabolism, pathogenicity (including one RXLR effector) and cell wall structure modification. We analyzed the expression of the genes encoding nine of these proteins using RT-qPCR and found an increase in transcript levels during disease progression, in agreement with the hypothesis that these proteins are important in early infection. Among the nine proteins was a group involved in cell wall structure modification and adhesion, including three closely related, uncharacterized proteins encoded by PITG_01131, PITG_01132, and PITG_16135, here denoted Piacwp1-3 Transient silencing of these genes resulted in reduced severity of infection, indicating that these proteins are important for pathogenicity. Our results contribute to further insight into P. infestans biology, and indicate processes that might be relevant for the pathogen while preparing for host cell penetration and during infection. The mass spectrometry data have been deposited to ProteomeXchange via the PRIDE partner repository with the data set identifier PXD002446.


Community attitudes and mammography use: does it really matter what other people think?
This study examined whether community characteristics, particularly community attitudes regarding mammography use, are associated with women's use of mammography in rural communities. Forty communities in predominantly rural areas of Washington State were selected for inclusion in this study based on their size and distance from an urban center. Characteristics of the communities were assessed as were characteristics of women living in the communities. From each community, random samples of 352 women between 50 and 80 years old participated by completing a telephone survey that included questions on a variety of topics, including their use of mammography. Logistic regression analyses revealed community of residence to be a significant predictor of individual women's mammography use after adjusting for individual level predictors of mammography use including age, education, employment, marital status, financial situation, and ease of access to medical services. An examination of the influence of community characteristics revealed women living in communities with supportive community attitudes towards mammography use report higher levels of mammography use than do women living in communities with less supportive attitudes. The presence or absence of male or female physicians or of mammography facilities in a local community was not associated with statistically significant effects on women's mammography use. Community attitudes are associated with mammography use in rural communities. Public health interventions that change community attitudes may have effects that extend beyond the people directly contacted by these interventions.


Rescue of Infectious Salmon Anemia Virus (ISAV) from Cloned cDNA.
The piscine orthomyxovirus called infectious salmon anemia virus (ISAV) is one of the most important emerging pathogens affecting the salmon industry worldwide. The first reverse genetics system for ISAV, which allows the generation of recombinant ISA virus (rISAV), is an important tool for the characterization and study of this virus. The plasmid-based reverse genetics system for ISAV includes the use of a novel fish promoter, the Atlantic salmon internal transcribed spacer region 1 (ITS-1). The salmon, viral, and mammalian genetic elements included in the pSS-URG vectors allow the expression of the eight viral RNA segments. In addition to four cytomegalovirus (CMV)-based vectors that express the four proteins of the ISAV ribonucleoprotein complex, the eight pSS-URG vectors allowed the generation of infectious rISAV in salmon cells.


Identification of four key prognostic genes and three potential drugs in human papillomavirus negative head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed. Three microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein-protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). The top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines. Finally, the therapeutic value of NVP-AUY922 was tested in vivo based on three HPV-negative HNSCC models, and statistical analysis was performed. In total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three-NVP-AUY922, fostamatinib and PP-2-greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo. In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.


Role of primary sensorimotor cortices in generating inhibitory motor response in humans.
To clarify the mechanism by which inhibitory motor responses such as cortical negative myoclonus are generated in humans, three patients with medically intractable partial epilepsy (two with frontal lobe epilepsy and one with parietal lobe epilepsy) were studied by means of direct cortical stimulation with a single electric pulse through subdural electrodes. All underwent chronic long-term video/EEG monitoring, cortical mapping by 50 Hz electric cortical stimulation and recording of cortical somatosensory evoked potentials with chronically implanted subdural grid electrodes (3 mm in diameter and centre-to-centre distance of 1 cm) to map both epileptogenic and functional zones. After these clinical evaluations, cortical stimulation by single electric pulse (0.3 ms duration, 1 Hz) was carried out through pairs of subdural electrodes located at the primary sensorimotor area (MI-SI), pre-supplementary motor area (pre-SMA) and lateral negative motor area (lateral NMA), while surface EMG was recorded from the muscles of the contralateral hand. The results showed that (i) in all subjects, single pulse stimulation of MI-SI elicited a motor evoked potential (MEP) followed by a silent period (SP) in the contralateral distal hand muscles, the latter lasting 300 ms after the stimulus. The duration of SP was proportional to the size of the preceding MEP. In one subject, SP without any preceding MEP was elicited, and, in another subject, there was a short SP immediately before MEP in the contralateral thenar muscle. (ii) Following the stimulation of either pre-SMA or lateral NMA, no SP was observed. It is concluded that the inhibitory mechanism within the MI-SI, but probably not in the non-primary motor areas, either closely linked to or completely independent of excitation, most likely plays an important role in eliciting brief negative motor phenomena such as cortical negative myoclonus or SP.


Spider-Web-Inspired Stretchable Graphene Woven Fabric for Highly Sensitive, Transparent, Wearable Strain Sensors.
Advanced wearable strain sensors with high sensitivity and stretchability are an essential component of flexible and soft electronic devices. Conventional metal- and semiconductor-based strain sensors are rigid, fragile, and opaque, restricting their applications in wearable electronics. Graphene-based percolative structures possess high flexibility and transparency but lack high sensitivity and stretchability. Inspired by the highly flexible spider web architecture, we propose semitransparent, ultrasensitive, and wearable strain sensors made from an elastomer-filled graphene woven fabric (E-GWF) for monitoring human physiological signals. The highly flexible elastomer microskeleton and the hierarchical structure of a graphene tube offer the strain sensor with both excellent sensing and switching capabilities. Two different types of E-GWF sensors, including freestanding E-GWF and E-GWF/polydimethylsiloxane (PDMS) composites, are developed. When their structure is controlled and optimized, the E-GWF strain sensors simultaneously exhibit extraordinary characteristics, such as a high gauge factor (70 at 10% strain, which ascends to 282 at 20%) in respect to other semitransparent or transparent strain sensors, a broad sensing range up to 30%, and excellent linearity. The E-GWF/PDMS composite sensor shows a unique reversible switching behavior at a high strain level of 30-50%, making it a suitable material for fast and reversible strain switching required in many early warning systems. With a view to real-world applications of these sensors and switches, we demonstrate human motion detection and switch controls of light-emitting-diode lamps and liquid-crystal-display circuits. Their unique structure and capabilities can find a wide range of practical applications, such as health monitoring, medical diagnosis, early warning systems for structural failure, and wearable displays.


Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by Ras.
Phosphoinositide-specific phospholipase C (PI-PLC) plays a pivotal role in regulation of intracellular signal transduction from various receptor molecules. More than 10 members of human PI-PLC isoforms have been identified and classified into three classes beta, gamma, and delta, which are regulated by distinct mechanisms. Here we report identification of a novel class of human PI-PLC, named PLCepsilon, which is characterized by the presence of a Ras-associating domain at its C terminus and a CDC25-like domain at its N terminus. The Ras-associating domain of PLCepsilon specifically binds to the GTP-bound forms of Ha-Ras and Rap1A. The dissociation constant for Ha-Ras is estimated to be approximately 40 nm, comparable with those of other Ras effectors. Co-expression of an activated Ha-Ras mutant with PLCepsilon induces its translocation from the cytosol to the plasma membrane. Upon stimulation with epidermal growth factor, similar translocation of ectopically expressed PLCepsilon is observed, which is inhibited by co-expression of dominant-negative Ha-Ras. Furthermore, using a liposome-based reconstitution assay, it is shown that the phosphatidylinositol 4,5-bisphosphate-hydrolyzing activity of PLCepsilon is stimulated in vitro by Ha-Ras in a GTP-dependent manner. These results indicate that Ras directly regulates phosphoinositide breakdown through membrane targeting of PLCepsilon.


Genetic correlations of polygenic disease traits: from theory to practice.
The genetic correlation describes the genetic relationship between two traits and can contribute to a better understanding of the shared biological pathways and/or the causality relationships between them. The rarity of large family cohorts with recorded instances of two traits, particularly disease traits, has made it difficult to estimate genetic correlations using traditional epidemiological approaches. However, advances in genomic methodologies, such as genome-wide association studies, and widespread sharing of data now allow genetic correlations to be estimated for virtually any trait pair. Here, we review the definition, estimation, interpretation and uses of genetic correlations, with a focus on applications to human disease.


[Role of transesophageal echocardiography in the assessment and therapeutic management of patients with acute ischemic cerebral events before the age of 65].
Ischemic stroke is the leading cause of mortality in Portugal, with around 30 to 50 % of cases being of cardioembolic etiology. Transesophageal echocardiography (TEE) has assumed growing importance in the detection of cardiac sources of embolism. However, there is controversy regarding the implications of TEE findings for the therapeutic approach to patients with ischemic stroke. To analyze TEE findings in the diagnostic work-up of patients with ischemic cerebral events and to determine their influence on therapeutic strategy. We retrospectively studied patients with stroke or transient ischemic attack (TIA) before the age of 65, of no apparent cause after carotid ultrasound, electrocardiogram and transthoracic echocardiography, who underwent TEE between 1992 and 2009. The following diagnoses on TEE were considered as potential embolic sources: atrial septal defect; patent foramen ovale (PFO); atrial septal aneurysm (ASA); vegetations; tumors; intracavitary thrombi; and aortic plaques >2mm (ascending aorta and arch). We analyzed 294 patients, mean age 45 years, 56.8 % men. TEE revealed a potential cardioembolic source in 36.7 % of the patients, PFO and ASA being the most frequent. Throughout the period considered, there was an increase in the number of exams performed, as well as in diagnoses, mainly PFO and ASA. Comparison of patients with and without a diagnosis on TEE showed that the former were older and were more often prescribed oral anticoagulation. By multivariate analysis, the presence of a positive TEE finding was shown to be an independent predictor of treatment with oral anticoagulation (OR=2.48; CI 95%: 1.42-4.34; p=0.001). In the population under analysis, TEE was useful in identifying potential cardioembolic sources and influenced the therapeutic strategy.


Anti-TNF-alpha therapy with infliximab in spondyloarthritides.
For patients with active ankylosing spondylitis (AS), medical therapy with TNF-blockers such as infliximab is increasingly considered the standard of care. This is especially true for patients who continue to have symptoms of active inflammation despite medication with nonsteroidal antiinflammatory drugs at the maximum possible dose. Insufficient control of disease activity as indicated by pain, stiffness and decrease of function is the most common clinical reason for starting anti-TNF therapy. The most recent follow-up data show that anti-TNF therapy with infliximab is clinically efficacious and safe, not only on a short- but also on a long-term basis in AS. Furthermore, there is evidence that infliximab also works in other spondyloarthritides (SpA) such as SpA associated with psoriasis, undifferentiated (early axial) SpA and in SpA associated with chronic inflammatory bowel diseases. Its benefit has even been reported in cases of reactive SpA. Withdrawal of long-term therapy in AS patients usually leads to flares and relapses after several weeks to months, but single cases of lasting remission have been reported. Only limited data are available regarding the optimal dosage of infliximab in SpA. In clinical practice, selected patients might not need doses of infliximab higher than 3 mg/kg but most patients will need doses of 5 mg/kg. A definite influence on radiographic progression after long-term continuous treatment with infliximab compared with conventional therapy has not been proven so far. This is in contrast to function and mobility, which even slightly improve over time in the patients who are still on therapy after 5 or more years (slightly over 50% of the initially treated patients in clinical trials). Antibody formation may lead to loss of efficacy (secondary nonresponse). Serious adverse events on anti-TNF therapy have remained rare as these can be largely prevented by appropriate screening. The large benefits of anti-TNF therapy in AS seem to outweigh the few shortcomings of this treatment.


Effects of antiepileptic drugs on sexual function and reproductive hormones of male epileptic patients.
Diminished libido and sexual dysfunction are unusually common among male epileptic patients. The most important etiologic factor may be antiepileptic drugs (AEDs)-induced androgen deficiency. We compared reproductive hormone levels among men with epilepsy taking various AEDs and normal controls. Subjects were 59 male epileptic patients who aged 24 ± 5 years. They had been receiving lamotrigine (LTG) (n = 17), carbamazepine (CBZ) (n = 18), and sodium valproate (VPA) (n = 15) for at least 6 months. We also recruited 23 healthy controls. Testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), androstenedione (AND), luteinizing hormone (LH), and follicle stimulatin hormone (FSH) levels and gonadal efficiency (testosterone/LH) were compared between the four groups. The patients and the control group were examined and evaluated for male reproduction by urology and endocrinology services. Subjects receiving CBZ, VPA, and LTG had significantly lower mean testosterone levels than the control group (P < 0.01). In addition, patients receiving LTG had significantly higher mean testosterone levels than CBZ and VPA groups (P < 0.01) and controls (P < 0.05). There were not any significant differences between the groups in mean estradiol levels. The mean AND level in VPA was higher than CBZ, LTG, and control groups (P < 0.01). Men receiving CBZ had significantly lower DHEAS levels than the other groups (P < 0.01). Testosterone/LH ratio in the control group was more than other groups (P < 0.01). On the other hand, this value in LTG group was higher than CBZ and VPA groups (P < 0.01). However, CBZ and VPA groups were not significantly different in terms of testosterone/LH ratio. Although the mean levels of reproductive hormones were lower in the LTG group compared to the controls, among traditional antiepileptic drugs, LTG had fewer side effects on reproductive hormones. Therefore, it is a good adjuvant and substitute drug for epilepsy control instead of CBZ and VPA.


C3 Glomerulopathy and post-infectious glomerulonephritis define a disease spectrum.
Post-infectious glomerulonephritis (PIGN) usually follows a benign course, but few children have an atypical, severe presentation, and these exceptional cases have been linked to the dysregulation of the complement alternative pathway (CAP). There is a considerable overlap in the histopathological features of PIGN and C3 glomerulopathy (C3G), which is also associated with CAP dysregulation but has a poorer outcome. We hypothesized that PIGN and C3G define a disease spectrum, and that in the past there may be some children with C3G who were misclassified with PIGN before C3G was described as a separate disease entity. Children with PIGN (n = 33) diagnosed between 1985 and 2010 who underwent a renal biopsy due to their unusual course were reviewed and of them, 8 were reclassified into C3G based on the current classification criteria. Outcome was based on the degree of proteinuria, C3 level, and renal function at follow-up. Sixteen (72.7%) children with typical PIGN recovered completely as compared to only 2 (25%) with C3G. Of note, children with "typical" PIGN had a more severe disease course at onset; however, the outcome at last follow up was favorable. Our results support the hypothesis that PIGN and C3G form a disease spectrum and have different long-term clinical implications and management strategies.


Amiloride-sensitive sodium channels in confluent M-1 mouse cortical collecting duct cells.
Confluent M-1 cells show electrogenic Na+ absorption and possess an amiloride-sensitive Na(+)-conductance (Korbmacher et al., J. Gen. Physiol. 102:761-793, 1993). In the present study, we further characterized this conductance and identified the underlying single channels using conventional patch clamp technique. Moreover, we isolated poly(A)+ RNA from M-1 cells to express the channels in Xenopus laevis oocytes, and to check for the presence of transcripts related to the epithelial Na+ channel recently cloned from rat colon (Canessa et al., Nature 361:467-470, 1993). Patch clamp experiments were performed in 6-13-day-old confluent M-1 cells at 37 degrees C. In whole-cell experiments application of 10(-5) M amiloride caused a hyperpolarization of 24.9, SEM +/- 2.2 mV (n = 35) and a reduction of the inward current by 107 +/- 10 pA (n = 51) at a holding potential of -60 mV. Complete removal of bath Na+ had similar effects, indicating that the amiloride-sensitive component of the inward current is a Na+ current. The effect of amiloride was concentration-dependent with half-inhibition at 0.22 microM. The Na+ current saturated with increasing extracellular Na+ concentrations with an apparent Km of 24 mM. Na+ replacement for Li+ demonstrated a higher apical membrane conductance for Li+ than for Na+. In excised inside-out (i/o) or outside-out (o/o) patches from the apical membrane, we observed single-channels which showed slow kinetics and were reversibly inhibited by amiloride. Their average conductance for Na+ was 6.8 +/- 0.5 pS (n = 15) and for Li+ 11.2 +/- 1.0 pS (n = 14). They had no measurable conductance for K+. In o/o patches, channel activity was slightly voltage dependent with an open probability (NPo) of 0.46 +/- 0.14 and 0.16 +/- 0.05 at a holding potential of -100 and 0 mV, respectively (n = 8, P < 0.05). Using the two-microelectrode voltage-clamp technique, we assayed defolliculated stage V-VI Xenopus oocytes for an amiloride-sensitive inward current 1-6 days after injection with H2O or with 20-50 ng of M-1 poly(A)+ RNA. In poly(A)+ RNA-injected oocytes held at -60 or -100 mV application of amiloride (2 microM) reduced the Na-inward current by 25.5 +/- 4.6 nA (n = 25) while it had no effect in H2O-injected oocytes (n = 19). Northern blot analysis of M-1 poly(A+) RNA revealed the presence of transcripts related to the three known subunits of the rat colon Na+ channel (Canessa et al., Nature 367:463-467, 1994). We conclude that the channel in M-1 cells is closely related to the amiloride-sensitive epithelial Na+ channel in the rat colon and that the M-1 cell line provides a useful tool to investigate the biophysical and molecular properties of the corresponding channel in the cortical collecting duct.


Quinine conjugates and quinine analogues as potential antimalarial agents.
Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds.


Effects of dietary fiber on the rat intestinal mucosa exposed to low doses of a carcinogen.
Changes in morphological and immunohistochemical parameters were studied in the rat intestinal mucosa exposed to low doses of a carcinogen and administered with dietary fibers. Tumors were induced by five subcutaneous injections of 1,2-dimethylhydrazine, 10 mg/kg rat, once a week. Rats were fed a semi-synthetic fiber-free diet (control) or a high-fiber diets (15%) derived from cellulose, tomato peels or white grape. The rats were sacrificed 24 weeks after the first carcinogen's injection. The ileum, colon and tumors were removed for the study. Areas of the mucosal stroma and of lymph infiltrations, and mitotic index were studied along with morphological parameters. Immunohistochemical parameters included determination of Ki-67 proliferating protein and apoptotic index. Areas of the stroma in colon tumors increased in rats fed tomato peels. Changes in areas of lymphoid infiltrates were related to the type of diet and tumor presence. Lymphoid infiltrations were found to be highly developed in the colon area close to tumors, especially in rats fed the white-grape diet. Mitotic index and Ki-67 protein increased significantly in the colon area close to a tumor and in tumors themselves without any relation to the fiber varieties consumed. Changes in the rate of apoptosis were not related to the preventive effect of diets: apoptotic index was high in tumors obtained from rats fed the high-cellulose diet with high tumor-preventive effects and also from rats fed the high-tomato-peel diet with low tumor-preventive effects. No morphological changes were found in the ileum of rats exposed to a carcinogen and fed different dietary fibers. In the colon, a carcinogen even in low concentrations inhibited the lymphoid system in the mucosa located far from the tumor or close to the tumor. An increase in the proliferation rate in the colon close to the tumor may reflect the development of precanceromatous processes or may be related to the effect of growth factors expressed by tumor cells. Finding adenoma-like dysplasia near tumors may be possible in early stages of the development of new tumors. In addition, activation of the lymphoid system of the colon following consumption to specific dietary fiber may be a mechanism by which fiber protect against cancer.


Caring for doctors.
M.G., an orthopaedic surgeon, is stopped in the hallway of his hospital by one of his medical colleagues. The physician begins to ask several questions regarding a recent onset of shoulder pain. M.G. suggests that the colleague be seen in the office so that a complete evaluation of the shoulder can be performed. The colleague asks if he can try some home exercises and anti-inflammatory medications first. M.G. shows him some basic shoulder exercises. Several weeks later, the colleague meets M.G. again and is furious at him, stating that the problem was not his shoulder at all but rather a cervical disc herniation.


Inception and deprescribing of statins in people aged over 80 years: cohort study.
statin use over the age of 80 years is weakly evidence-based. This study aimed to estimate rates of statin inception and deprescribing by frailty level in people aged 80 years or older. a cohort of 212,566 participants aged ≥80 years was sampled from the UK Clinical Practice Research Datalink. Statin inception was defined as a first-ever prescription in a non-statin user; deprescribing was defined as a last ever statin prescription more than 6 months before the end of participant records. Rates were estimated in a time-to-event framework allowing for mortality as a competing risk. Co-variates were age, gender, frailty category and prevention type. prevalent statin use increased from 2001-5 (9.9%) to 2011-15 (49.3%). Inception of statins in never-users was low overall at 2.4% per year (95% confidence interval (CI) 2.2-2.6%) and declined with age. Deprescribing of statins in current users occurred at a rate of 5.6% (95% CI 5.4-5.9%) per year overall and increased with age, reaching 17.8% per year (95% CI 6.7-28.9%) among centenarians. Deprescribing was slightly higher for primary prevention (6.5% per year) than secondary prevention (5.2% per year) indications (P < 0.001). Deprescribing increased with frailty level being 5.0% per year in 'fit' participants and 7.1% in 'severe' frailty (P < 0.001). statin use has increased in the over 80s but deprescribing is common and increases with age and frailty level. These paradoxical findings highlight a need for better evidence to inform statin use and discontinuation for people aged ≥80 years.


The expanded family of ammonium transporters in the perennial poplar plant.
* Ammonium and nitrate are the prevalent nitrogen sources for growth and development of higher plants. Here, we report on the characterization of the ammonium transporter (AMT) family in the perennial species Populus trichocarpa. * In silico analysis and expression analysis of AMT genes from poplar was performed. In addition, AMT1;2 and AMT1;6 function was studied in detail by heterologous expression in yeast. * The P. trichocarpa genome contains 14 putative AMTs, which is more than twice the number of AMTs in Arabidopsis. In roots, the high-affinity AMT1;2 strongly increased upon mycorrhiza formation and might be partly responsible for the high-affinity ammonium uptake component measured in poplar. Transcript level for the high-affinity AMT1;6 was strongly affected by the diurnal cycle. AMT3;1 was exclusively expressed in senescing poplar leaves. Remarkably AMT2;1 was highly expressed in leaves while AMT2;2 was mostly expressed in petioles. Specific expression of AMT1;5 in stamen and of AMT1;6 in female flower indicate that they have key functions in reproductive organ development in poplar. * The present study provides basic genomic and transcriptomic information for the poplar AMT family and will pave the way for deciphering the precise role of AMTs in poplar physiology.


Isolation and partial characterization of the extracellular polysaccharides and lipopolysaccharides from fast-growing Rhizobium japonicum USDA 205 and its Nod- mutant, HC205, which lacks the symbiotic plasmid.
The extracellular polysaccharides and lipopolysaccharides (LPSs) from two fast-growing Rhizobium japonicum strains, USDA 205 and HC205, were isolated and partially characterized. Strain HC205 is a Nod- mutant of USDA 205 which lacks the symbiotic plasmid. The extracellular polysaccharides from both strains are very similar in composition, having galactose, glucose, glucuronic acid, and acyl groups. The extracellular polysaccharides do not contain detectable levels of pyruvate. Methylation analysis shows that the extracellular polysaccharides from both strains have the same glycosyl linkages. The LPSs were purified by a modified phenol-water extraction procedure and gel filtration chromatography. The LPSs from USDA 205 and HC205 elute as broad peaks from the gel filtration column and contain 2-keto-3-deoxyoctonic acid as one of the major sugar components. Each broad 2-keto-3-deoxyoctonic acid-containing peak has a distinct shoulder on its leading edge. The shoulder and the remainder of the broad peak are separated and labeled LPSI and LPSII, respectively. Glucose (and 2-keto-3-deoxyoctonic acid) is a major sugar in the LPSI fractions. Both the LPSII fractions contain 2-keto-3-deoxyoctonic acid as the major sugar (about 20% of the mass). There are a number of quantitative differences in these LPS fractions between strain USDA 205 and HC205. Polyacrylamide gel electrophoresis shows that the LPSs are heterogeneous molecules but less heterogeneous than the LPSs from Salmonella minnesota or Rhizobium leguminosarum. The LPSI fractions from both USDA 205 and HC205 show a single lower-molecular-weight band and a higher-molecular-weight banding region which contains several bands. No bands are observed for the LPSII fractions from either USDA 205 or HC205.


Imaging diagnosis of colorectal liver metastases.
Rapid advances in imaging technology have improved the detection, characterization and staging of colorectal liver metastases. Multi-modality imaging approach is usually the more useful in diagnosis colorectal liver metastases. It is well established that hepatic resection improves the long-term prognosis of many patients with liver metastases. However, incomplete resection does not prolong survival, so knowledge of the exact extent of intra-hepatic disease is crucially important in determining patient management and outcome. The diagnosis of liver metastases relies first and totally on imaging to decide which patients may be surgical candidates. This review will discuss the imaging options and their appropriate indications. Imaging and evaluating of colorectal liver metastases (CRLM) have been performed with contrast-enhanced ultrasound, multi-detector computed tomography, magnetic resonance imaging (MRI) with extra-cellular contrast media and liver-specific contrast media MRI, and positron emission tomography/computed tomography. This review will concentrate on the imaging approach of CRLM, and also discuss certain characteristics of some liver lesions. We aim to highlight the advantages of each imaging technique, as well as underscoring potential pitfalls and limitations.


Principles of docking: An overview of search algorithms and a guide to scoring functions.
The docking field has come of age. The time is ripe to present the principles of docking, reviewing the current state of the field. Two reasons are largely responsible for the maturity of the computational docking area. First, the early optimism that the very presence of the "correct" native conformation within the list of predicted docked conformations signals a near solution to the docking problem, has been replaced by the stark realization of the extreme difficulty of the next scoring/ranking step. Second, in the last couple of years more realistic approaches to handling molecular flexibility in docking schemes have emerged. As in folding, these derive from concepts abstracted from statistical mechanics, namely, populations. Docking and folding are interrelated. From the purely physical standpoint, binding and folding are analogous processes, with similar underlying principles. Computationally, the tools developed for docking will be tremendously useful for folding. For large, multidomain proteins, domain docking is probably the only rational way, mimicking the hierarchical nature of protein folding. The complexity of the problem is huge. Here we divide the computational docking problem into its two separate components. As in folding, solving the docking problem involves efficient search (and matching) algorithms, which cover the relevant conformational space, and selective scoring functions, which are both efficient and effectively discriminate between native and non-native solutions. It is universally recognized that docking of drugs is immensely important. However, protein-protein docking is equally so, relating to recognition, cellular pathways, and macromolecular assemblies. Proteins function when they are bound to other molecules. Consequently, we present the review from both the computational and the biological points of view. Although large, it covers only partially the extensive body of literature, relating to small (drug) and to large protein-protein molecule docking, to rigid and to flexible. Unfortunately, when reviewing these, a major difficulty in assessing the results is the non-uniformity in the formats in which they are presented in the literature. Consequently, we further propose a way to rectify it here.