Network regularised Cox regression and multiplex network models to predict disease comorbidities and survival of cancer.
In cancer genomics, gene expression levels provide important molecular signatures for all types of cancer, and this could be very useful for predicting the survival of cancer patients. However, the main challenge of gene expression data analysis is high dimensionality, and microarray is characterised by few number of samples with large number of genes. To overcome this problem, a variety of penalised Cox proportional hazard models have been proposed. We introduce a novel network regularised Cox proportional hazard model and a novel multiplex network model to measure the disease comorbidities and to predict survival of the cancer patient. Our methods are applied to analyse seven microarray cancer gene expression datasets: breast cancer, ovarian cancer, lung cancer, liver cancer, renal cancer and osteosarcoma. Firstly, we applied a principal component analysis to reduce the dimensionality of original gene expression data. Secondly, we applied a network regularised Cox regression model on the reduced gene expression datasets. By using normalised mutual information method and multiplex network model, we predict the comorbidities for the liver cancer based on the integration of diverse set of omics and clinical data, and we find the diseasome associations (disease-gene association) among different cancers based on the identified common significant genes. Finally, we evaluated the precision of the approach with respect to the accuracy of survival prediction using ROC curves. We report that colon cancer, liver cancer and renal cancer share the CXCL5 gene, and breast cancer, ovarian cancer and renal cancer share the CCND2 gene. Our methods are useful to predict survival of the patient and disease comorbidities more accurately and helpful for improvement of the care of patients with comorbidity. Software in Matlab and R is available on our GitHub page: https://github.com/ssnhcom/NetworkRegularisedCox.git.


Bilingual Language Control in Perception versus Action: MEG Reveals Comprehension Control Mechanisms in Anterior Cingulate Cortex and Domain-General Control of Production in Dorsolateral Prefrontal Cortex.
For multilingual individuals, adaptive goal-directed behavior as enabled by cognitive control includes the management of two or more languages. This work used magnetoencephalography (MEG) to investigate the degree of neural overlap between language control and domain-general cognitive control both in action and perception. Highly proficient Arabic-English bilingual individuals participated in maximally parallel language-switching tasks in production and comprehension as well as in analogous tasks in which, instead of the used language, the semantic category of the comprehended/produced word changed. Our results indicated a clear dissociation of language control mechanisms in production versus comprehension. Language-switching in production recruited dorsolateral prefrontal regions bilaterally and, importantly, these regions were similarly recruited by category-switching. Conversely, effects of language-switching in comprehension were observed in the anterior cingulate cortex and were not shared by category-switching. These results suggest that bilingual individuals rely on adaptive language control strategies and that the neural involvement during language-switching could be extensively influenced by whether the switch is active (e.g., in production) or passive (e.g., in comprehension). In addition, these results support that humans require high-level cognitive control to switch languages in production, but the comprehension of language switches recruits a distinct neural circuitry. The use of MEG enabled us to obtain the first characterization of the spatiotemporal profile of these effects, establishing that switching processes begin ∼ 400 ms after stimulus presentation. This research addresses the neural mechanisms underlying multilingual individuals' ability to successfully manage two or more languages, critically targeting whether language control is uniform across linguistic domains (production and comprehension) and whether it is a subdomain of general cognitive control. The results showed that language production and comprehension rely on different networks: whereas language control in production recruited domain-general networks, the brain bases of switching during comprehension seemed language specific. Therefore, the crucial assumption of the bilingual advantage hypothesis, that there is a close relationship between language control and general cognitive control, seems to only hold during production.


Natural killer cells in HIV-1 infection and therapy.
: Natural killer (NK) cells are important effectors of innate immunity playing a key role in the eradication and clearance of viral infections. Over the recent years, several studies have shown that HIV-1 pathologically changes NK cell homeostasis and hampers their antiviral effector functions. Moreover, high levels of chronic HIV-1 viremia markedly impair those NK cell regulatory features that normally regulate the cross talks between innate and adaptive immune responses. These pathogenic events take place early in the infection and are associated with a pathologic redistribution of NK cell subsets that includes the expansion of anergic CD56/CD16 NK cells with an aberrant repertoire of activating and inhibitory receptors. Nevertheless, the presence of specific haplotypes for NK cell receptors and the engagement of NK cell antibody-dependent cell cytotocity have been reported to control HIV-1 infection. This dichotomy can be extremely useful to both predict the clinical outcome of the infection and to develop alternative antiviral pharmacological approaches. Indeed, the administration of antiretroviral therapy in HIV-1-infected patients restores NK cell phenotype and functions to normal levels. Thus, antiretroviral therapy can help to develop NK cell-directed therapeutic strategies that include the use of broadly neutralizing antibodies and toll-like receptor agonists. The present review discusses how our current knowledge of NK cell pathophysiology in HIV-1 infection is being translated both in experimental and clinical trials aimed at controlling the infection and disease.


Co-dependence of HTLV-1 p12 and p8 functions in virus persistence.
HTLV-1 orf-I is linked to immune evasion, viral replication and persistence. Examining the orf-I sequence of 160 HTLV-1-infected individuals; we found polymorphism of orf-I that alters the relative amounts of p12 and its cleavage product p8. Three groups were identified on the basis of p12 and p8 expression: predominantly p12, predominantly p8 and balanced expression of p12 and p8. We found a significant association between balanced expression of p12 and p8 with high viral DNA loads, a correlate of disease development. To determine the individual roles of p12 and p8 in viral persistence, we constructed infectious molecular clones expressing p12 and p8 (D26), predominantly p12 (G29S) or predominantly p8 (N26). As we previously showed, cells expressing N26 had a higher level of virus transmission in vitro. However, when inoculated into Rhesus macaques, cells producing N26 virus caused only a partial seroconversion in 3 of 4 animals and only 1 of those animals was HTLV-1 DNA positive by PCR. None of the animals exposed to G29S virus seroconverted or had detectable viral DNA. In contrast, 3 of 4 animals exposed to D26 virus seroconverted and were HTLV-1 positive by PCR. In vitro studies in THP-1 cells suggested that expression of p8 was sufficient for productive infection of monocytes. Since orf-I plays a role in T-cell activation and recognition; we compared the CTL response elicited by CD4+ T-cells infected with the different HTLV-1 clones. Although supernatant p19 levels and viral DNA loads for all four infected lines were similar, a significant difference in Tax-specific HLA.A2-restricted killing was observed. Cells infected with Orf-I-knockout virus (12KO), G29S or N26 were killed by CTLs, whereas cells infected with D26 virus were resistant to CTL killing. These results indicate that efficient viral persistence and spread require the combined functions of p12 and p8.


Enhanced recovery pathways in thoracic surgery from Italian VATS Group: perioperative analgesia protocols.
Video-assisted thoracoscopic surgery (VATS) is a minimally invasive technique that allows a faster recovery after thoracic surgery. Although enhanced recovery after surgery (ERAS) principles seem reasonably applicable to thoracic surgery, there is little literature on the application of such a strategy in this context. In regard to pain management, ERAS pathways promote the adoption of a multimodal strategy, tailored to the patients. This approach is based on combining systemic and loco-regional analgesia to favour opioid-sparing strategies. Thoracic paravertebral block is considered the first-line loco-regional technique for VATS. Other techniques include intercostal nerve block and serratus anterior plane block. Nonsteroidal anti-inflammatory drugs and paracetamol are essential part of the multimodal treatment of pain. Also, adjuvant drugs can be useful as opioid-sparing agents. Nevertheless, the treatment of postoperative pain must take into account opioid agents too, if necessary. All above is useful for careful planning and execution of a multimodal analgesic treatment to enhance the recovery of patients. This article summarizes the most recent evidences from literature and authors' experiences on perioperative multimodal analgesia principles for implementing an ERAS program after VATS lobectomy.


Photorealistic large-scale urban city model reconstruction.
The rapid and efficient creation of virtual environments has become a crucial part of virtual reality applications. In particular, civil and defense applications often require and employ detailed models of operations areas for training, simulations of different scenarios, planning for natural or man-made events, monitoring, surveillance, games, and films. A realistic representation of the large-scale environments is therefore imperative for the success of such applications since it increases the immersive experience of its users and helps reduce the difference between physical and virtual reality. However, the task of creating such large-scale virtual environments still remains a time-consuming and manual work. In this work, we propose a novel method for the rapid reconstruction of photorealistic large-scale virtual environments. First, a novel, extendible, parameterized geometric primitive is presented for the automatic building identification and reconstruction of building structures. In addition, buildings with complex roofs containing complex linear and nonlinear surfaces are reconstructed interactively using a linear polygonal and a nonlinear primitive, respectively. Second, we present a rendering pipeline for the composition of photorealistic textures, which unlike existing techniques, can recover missing or occluded texture information by integrating multiple information captured from different optical sensors (ground, aerial, and satellite).


Gastroprotective mechanisms of Citrus lemon (Rutaceae) essential oil and its majority compounds limonene and β-pinene: involvement of heat-shock protein-70, vasoactive intestinal peptide, glutathione, sulfhydryl compounds, nitric oxide and prostaglandin E₂.
Citrus lemon (CL) belongs to Rutaceae family and is popularly known in Brazil as limão siciliano. The phytochemical analysis of CL fruit bark essential oil showed two majority components, limonene (LIM) and β-pinene (PIN). This study aimed to evaluate the gastroprotective mechanism of action from CL, LIM and PIN in ethanol- and indomethacin-induced gastric ulcers and its in vitro anti-Helicobacter pylori activity. After ethanol-induced gastric ulcer, the ulcer area was measured and the stomachs were destined to histology (HE and PAS), immunohistochemistry for HSP-70 and VIP and glutathione (GSH) measurement. The involvement of nitric oxide (NO) and sulfhydryl (SH) compounds was determined. The ulcer area for indomethacin-induced gastric ulcers was measured. PGE₂ concentration was biochemically measured. The minimum inhibitory concentration (MIC) against H. pylori was determined in vitro. In ethanol model, CL and LIM demonstrated 100% of gastroprotection, while PIN did not exert effective gastroprotection (53.26%). In the indomethacin model, CL and LIM offered effective gastroprotection but PIN did not show gastroprotective effect. The gastric ulcer area of rats pretreated with NO-synthase inhibitor or SH-blocker was decreased in comparison to the control group. The MIC obtained for CL was 125 μg/mL, for LIM was 75 μg/mL and for PIN was 500 μg/mL. The gastroprotective effect of CL and LIM was involved with increasing in mucus secretion, HSP-70 and VIP, but not with GSH, NO or SH compounds. CL gastroprotective mechanism is involved with PGE₂. PIN did not present gastroprotective activity.


Volatile organic compounds concentrations during the construction process in newly-built timber-frame houses: source identification and emission kinetics.
Building and furniture materials are known to be major sources of volatile organic compounds (VOCs) indoors. During the construction process, an introduced material can have a more or less long-term impact on the indoor air quality according to the building characteristics. In this study, field measurements were carried out at six construction stages in three energy-efficient timber-frame houses. Data analysis focused on the ten most abundant compounds found among an initial list of fifteen target VOCs, namely formaldehyde, acetaldehyde, hexanal, toluene, m/p-xylenes, ethylbenzene, styrene, α-pinene, 3-carene and d-limonene. The chemical compositions and concentration variation patterns were recorded. The results showed a high pollution count, with m/p-xylenes and ethylbenzene concentrations ranging from 1900 to 5100 μg m-3 occurring at the time of the structural work (representing more than 88% of the sum of the target VOCs). Emission tests done on a large number of materials used in the construction revealed that this pollution is due to the emissions from the polyurethane adhesive mastic used as a sealing material. The emission kinetics of polyurethane adhesive mastic was assessed alone and also within a material assembly reconstituting a room wall. The results showed that the superposition of materials led to a slowing down of the VOC emission process from polyurethane adhesive mastic, which explains the concentration decays recorded in houses during the construction process. At the final construction stage, the concentration levels were low for all compounds (the sums of the target VOCs were between 18 and 32 μg m-3), with the aldehydes (formaldehyde, acetaldehyde and hexanal) now becoming the major fraction in the chemical composition in the last stages of construction (representing 50-70% of the sum of the target VOCs). This is in agreement with the fact that the sources of aldehydes are the most numerous among the materials and have rather slow emission kinetics.


The late chlamydial inclusion membrane is not derived from the endocytic pathway and is relatively deficient in host proteins.
Chlamydiae are obligate intracellular parasites which multiply within infected cells in a membrane-bound structure termed an inclusion. Newly internalized bacteria are surrounded by host plasma membrane; however, the source of membrane for the expansion of the inclusion is unknown. To determine if the membrane for the mature inclusion was derived by fusion with cellular organelles, we stained infected cells with fluorescent or electron-dense markers specific for organelles and examined inclusions for those markers. We observed no evidence for the presence of endoplasmic reticulum, Golgi, late endosomal, or lysosomal proteins in the inclusion. These data suggest that the expansion of the inclusion membrane, beginning 24 h postinoculation, does not occur by the addition of host proteins resulting from either de novo host synthesis or by fusion with preexisting membranes. To determine the source of the expanding inclusion membrane, antibodies were produced against isolated membranes from Chlamydia-infected mouse cells. The antibodies were demonstrated to be solely against Chlamydia-specified proteins by both immunoprecipitation of [35S]methionine-labeled extracts and Western blotting (immunoblotting). Techniques were used to semipermeabilize Chlamydia-infected cells without disrupting the permeability of the inclusion, allowing antibodies access to the outer surface of the inclusion membrane. Immunofluorescent staining demonstrated a ring-like fluorescence around inclusions in semipermeabilized cells, whereas Triton X-100-permeabilized cells showed staining throughout the inclusion. These studies demonstrate that the inclusion membrane is made up, in part, of Chlamydia-specified proteins and not of existing host membrane proteins.


2019 Seoul Consensus on Esophageal Achalasia Guidelines.
Esophageal achalasia is a primary motility disorder characterized by insufficient lower esophageal sphincter relaxation and loss of esophageal peristalsis. Achalasia is a chronic disease that causes progressive irreversible loss of esophageal motor function. The recent development of high-resolution manometry has facilitated the diagnosis of achalasia, and determining the achalasia subtypes based on high-resolution manometry can be important when deciding on treatment methods. Peroral endoscopic myotomy is less invasive than surgery with comparable efficacy. The present guidelines (the "2019 Seoul Consensus on Esophageal Achalasia Guidelines") were developed based on evidence-based medicine; the Asian Neurogastroenterology and Motility Association and Korean Society of Neurogastroenterology and Motility served as the operating and development committees, respectively. The development of the guidelines began in June 2018, and a draft consensus based on the Delphi process was achieved in April 2019. The guidelines consist of 18 recommendations: 2 pertaining to the definition and epidemiology of achalasia, 6 pertaining to diagnoses, and 10 pertaining to treatments. The endoscopic treatment section is based on the latest evidence from meta-analyses. Clinicians (including gastroenterologists, upper gastrointestinal tract surgeons, general physicians, nurses, and other hospital workers) and patients could use these guidelines to make an informed decision on the management of achalasia.


Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967.
Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.


Influence of Application Time on Dentin Bond Performance in Different Etching Modes of Universal Adhesives.
We attempted to determine the effect of universal adhesive application time on dentin bond performance in different etching modes based on shear bond strength (SBS) tests and surface free energy (SFE) measurements. The five universal adhesives used were Adhese Universal (AU), Clearfil Universal Bond Quick (CQ), G-Premio Bond (GP), Scotchbond Universal (SU), and Tokuyama Universal Bond (TU). Bovine dentin specimens were divided into four groups of 10 for each adhesive. SBS and SFE were determined after applying the following surface treatments: 1) self-etch (SE) mode with immediate air blowing after adhesive application (IA treatment), 2) SE mode with prolonged application time (PA treatment), 3) etch-and-rinse (ER) mode with IA treatment, and 4) ER mode with PA treatment. Bonded specimens were subjected to SBS testing. The SFE of adhesive-treated dentin surfaces was measured after rinsing with acetone and water. Three-way analysis of variance revealed that dentin SBS values (p<0.001) were significantly influenced by the factors of adhesive type and application duration, but the factor of pre-etching was not significant (p=0.985). The manufacturer's instructions require longer application times for AU and SU, which showed significantly lower SBS values in IA than in PA treatment in both etching modes. However, the difference in the other adhesives was not significant between the IA and PA treatments in either etching mode. The total SFE (γS) was dependent on the adhesive and etching mode. The γS value of the initial group (SiC paper ground group) at baseline was 69.5 (mN·m-1) and that of the pre-etching group at baseline was 30.6 (mN·m-1). For all the adhesives, γS in SE mode showed significantly higher values than in ER mode, regardless of the application time. In SE mode, almost all universal adhesives tested showed lower γS values in PA treatment than in IA treatment. For ER mode, all the adhesives showed significantly higher γS values than those of the pre-etching baseline, regardless of the application time. Most adhesives did not show any significant differences in γS values between IA and PA treatments, regardless of etching mode.


Clinical practice patterns among native and immigrant doctors doing out-of-hours work in Norway: a registry-based observational study.
To evaluate whether immigrant and native Norwegian doctors differ in their practice patterns. Observational study. Out-of-hours (OOH) emergency primary healthcare in Norway, 2008. All primary care physicians doing OOH work, altogether 4165 physicians. Number of patient contacts per doctor. Use of laboratory tests, minor surgery, sickness certification and length of consultations. Use of diagnoses related to psychiatric and sexual health. Choice of management strategy with psychiatric patients (psychotherapy or hospitalisation). 21.4% of the physicians were immigrants, and they had 30.6% of the patient contacts. Immigrant doctors from Asia, Africa and Latin America had most patient contacts, 633 (95% CI 549 to 716), while native Norwegian doctors had 306 (95% CI 288 to 325). In multivariate analyses, immigrant physicians did not differ significantly from native Norwegians regarding use of laboratory tests, minor surgery or length of consultations, but immigrant doctors wrote more sickness certificates, OR 1.75 (95% CI 1.24 to 2.47) for immigrant doctors from Europe, North America and Oceania versus native Norwegian doctors and OR 1.56 (95% CI 1.15 to 2.11) for immigrant doctors from Asia, Africa and Latin America versus native Norwegians. Immigrant physicians from Europe, North America and Oceania used more diagnoses related to pregnancy, family planning and female genitals, OR 1.55 (95% CI 1.11 to 2.16), versus native Norwegian physicians. Immigrant doctors from Asia, Africa and Latin America used less psychiatric diagnoses, OR 0.71 (95% CI 0.53 to 0.95), versus native Norwegian doctors but did not differ significantly in their management of recognised psychiatric illness. Immigrant doctors make an important contribution to OOH emergency primary healthcare in Norway. The authors found only modest evidence that their clinical practice patterns are different from that of native Norwegian doctors.


Intake of fruits, vegetables, and soy foods in relation to breast cancer risk in Korean women: a case-control study.
We conducted a case-control study to examine the relationship between fruit, vegetable, and soy food intake and breast cancer risk in Korean women. Incident cases (n=359) were identified through cancer biopsies between March 1999 and August 2003 at two university hospitals in Seoul, Korea. Hospital-based controls (n=708) were selected from patients in the same hospitals during the same period. Subjects were asked by personal interview to indicate their average fruit, vegetable, and soy food intake for a 12-mo period 3 yr prior to the baseline phase. A food intake-frequency questionnaire (98 items) was given by a trained dietitian. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjustment for confounding factors and total energy intake. There was no association between the intake of total fruits, vegetables, or soy food and breast cancer risk. Increasing consumption of grapes was linked to a significant protective effect against risk of breast cancer (OR=0.66; 95% CI=0.41-0.86; P<0.01). Among the vegetables, reduced risk was observed with high tomato intake (OR=0.62; 95% CI=0.38-0.81; P<0.01). Among soy foods, high consumption of cooked soybeans, including yellow and black soybeans, had an association with reduced breast cancer (OR=0.67; 95% CI=0.45-0.91; P<0.02). Our data suggest that increased intake of some fruits, vegetables, and soy foods may be associated with breast cancer risk reduction in Korean women.


Regulation of exopolysaccharide production in Rhizobium leguminosarum biovar viciae WSM710 involves exoR.
A mildly acid-sensitive mutant of Rhizobium leguminosarum bv. viciae WSM710 (WR6-35) produced colonies which were more mucoid in phenotype than the wild-type. Strain WR6-35 contained a single copy of Tn5 and the observed mucoid phenotype, acid sensitivity and Tn5-induced kanamycin resistance were 100% co-transducible using phage RL38. WR6-35 produced threefold more exopolysaccharide (EPS) than the wild-type in minimal medium devoid of a nitrogen source. EPS produced by the mutant and the wild-type was identical as determined by proton NMR spectra. An EcoRI rhizobial fragment containing Tn5 and flanking rhizobial sequences was cloned from the mutant, restriction mapped and sequenced. There was extensive similarity between the ORF disrupted by Tn5 in R. leguminosarum bv. viciae WR6-35 and the exoR gene of Rhizobium (Sinorhizobium) meliloti Rm1021 (71.3% identity over 892 bp). At the protein level there was 70% identity and 93.3% similarity over 267 amino acids with the ExoR protein of R. meliloti Rm1021. Hydrophilicity profiles of the two proteins from these two rhizobia are superimposable. This gene in R. leguminosarum bv. viciae was thus designated exoR. The data suggest that Tn5 has disrupted a regulatory gene encoding a protein that negatively modulates EPS biosynthesis in R. leguminosarum bv. viciae WSM710. Despite earlier suggestions that EPS production and acid tolerance might be positively correlated, disruption of exoR in either R. leguminosarum bv. viciae or R. meliloti and its associated overproduction of EPS does not result in a more acid-tolerant phenotype than the wild-type when cultures are screened on conventional laboratory agar.


Toxicity Management: Development of a Novel and Immune-Mediated Adverse Events Algorithm .
Novel immunotherapy and biologic agents are being developed with the potential to improve outcomes and reduce long-term toxicities among individuals with hematologic malignancies. These emerging drugs affect neoplastic cells and the surrounding microenvironment, causing unique immune-mediated toxicities. . The aim was to develop an algorithm for clinical staff to manage unique toxicities associated with next-generation immunotherapies indicated in the hematologic population, using a system-focused approach. . Data were collected using specific toxicities based on the four major novel biologic classes. Immune-mediated adverse events were reported across studies. Based on published literature, institutional experience, and group consensus, a novel algorithm for managing immune-mediated toxicities was created. . The development of this treatment algorithm provides a more streamlined approach for managing common but unique toxicities and improves safety, compliance, patient outcome, and quality of life with novel immuno-oncologic agents.


Data clustering methods for the determination of cerebral autoregulation functionality.
Cerebral blood flow is regulated over a range of systemic blood pressures through the cerebral autoregulation (CA) control mechanism. The COx measure based on near infrared spectroscopy (NIRS) has been proposed as a suitable technique for the analysis of CA as it is non-invasive and provides a simpler acquisition methodology than other methods. The COx method relies on data binning and thresholding to determine the change between intact and impaired autoregulation zones. In the work reported here we have developed a novel method of differentiating the intact and impaired CA blood pressure regimes using clustering methods on unbinned data. K-means and Gaussian mixture model algorithms were used to analyse a porcine data set. The determination of the lower limit of autoregulation (LLA) was compared to a traditional binned data approach. Good agreement was found between the methods. The work highlights the potential application of using data clustering tools in the monitoring of CA function.


Interfacing human induced pluripotent stem cell-derived neurons with designed nanowire arrays as a future platform for medical applications.
Nanostructured substrates such as nanowire arrays form a powerful tool for building next-generation medical devices. So far, human pluripotent stem cell-derived neurons-a revolutionary tool for studying physiological function and modeling neurodegenerative diseases-have not been applied to such innovative substrates, due to the highly demanding nature of stem cell quality control and directed differentiation procedures to generate specialized cell types. Our study closes this gap, by presenting electrophysiologically mature human pluripotent stem cell-derived neurons on a set of nanowires in different patterns and growth densities after only four weeks of maturation-thereof 14 to 16 days on the nanowire arrays. While cell viability is maintained on all nanowire substrates, the settling regime of the cells can be controlled and tuned by the nanowire density from a fakir-like state to a complete nanowire wrapping state. Especially, full electrophysiological integrity of the neurons independent of the settling regime has been revealed by patch clamp experiments showing characteristic action potentials. Based on these results, our protocol has the potential to open new pathways in stem cell research and regenerative medicine utilizing human stem cell-derived neurons on tailor-made nanostructured substrates.


Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells.
At the initial stage of carcinogenesis, transformation occurs in a single cell within an epithelial sheet. However, it remains unknown what happens at the boundary between normal and transformed cells. Using Madin-Darby canine kidney (MDCK) cells transformed with temperature-sensitive v-Src, we have examined the interface between normal and Src-transformed epithelial cells. We show that Src-transformed cells are apically extruded when surrounded by normal cells, but not when Src cells alone are cultured, suggesting that apical extrusion occurs in a cell-context-dependent manner. We also observe apical extrusion of Src-transformed cells in the enveloping layer of zebrafish gastrula embryos. When Src-transformed MDCK cells are surrounded by normal MDCK cells, myosin-II and focal adhesion kinase (FAK) are activated in Src cells, which further activate downstream mitogen-activated protein kinase (MAPK). Importantly, activation of these signalling pathways depends on the presence of surrounding normal cells and plays a crucial role in apical extrusion of Src cells. Collectively, these results indicate that interaction with surrounding normal epithelial cells influences the signalling pathways and behaviour of Src-transformed cells.


Direct determination of chemical oxygen demand by anodic decomposition of organic compounds at a diamond electrode.
Chemical oxygen demand (COD) was measured directly with a simple electrochemical method using a boron-doped diamond (BDD) electrode. By applying a highly positive potential (+2.5 V vs Ag/AgCl) to an aqueous electrolyte containing potassium hydrogen phthalate, glucose, and lactic acid or sodium dodecylbenzenesulfonate using a BDD electrode, an anodic current corresponding to the electrolytic decomposition of these organic compounds was observed. No such current was seen on glassy carbon or platinum electrodes due to a significant background current caused by the oxygen evolution reaction. The electric charge for the anodic current observed at the BDD electrode was found to be consistent with the theoretical charge required for the electrolytic decomposition of the organic compounds to CO2 and was used to calculate COD. This analysis was performed by a simple I-t measurement at constant potential using a BDD electrode, and no calibration was needed. This new simple indicator, "ECOD" (electrochemical oxygen demand), will be useful for continuous monitoring of industrial wastewater with low protein concentrations and on-site instant analysis of natural water with a BDD electrode-based portable ECOD meter.


Physical activity levels in patients on hemodialysis and healthy sedentary controls.
Patients on dialysis have reduced exercise tolerance compared with age-matched sedentary controls. The reasons for this debility have not been fully elucidated, but physical inactivity could be a contributing factor. The purpose of the current study was to determine whether patients on hemodialysis are less active than healthy sedentary controls and to explore clinical correlates of physical activity level in a group of hemodialysis patients. Thirty-four hemodialysis patients and 80 healthy sedentary individuals participated in the study. Physical activity was measured for seven days with a three-dimensional accelerometer and with an activity questionnaire. Vector magnitude values from the accelerometer for the dialysis and control subjects were 104,718 +/- 9631 and 161,255 +/- 6792 arbitrary units per day, respectively (P < 0.0001, mean +/- SEM). The estimated energy expenditure values derived from the questionnaire were 33.6 +/- 0.5 kcal/kg/day and 36.2 +/- 0.5 kcal/kg/day (P = 0.002). The difference between patients on dialysis and controls increased with advancing age. Among the dialysis subjects, some measures of nutritional status correlated with physical activity level, including serum albumin concentration (r = 0.58, P = 0.003), serum creatinine concentration (r = 0.37, P = 0. 03), and phase angle derived from bioelectrical impedance analysis (r = 0.40, P = 0.02). Patients on hemodialysis are less active than healthy sedentary controls, and this difference is more pronounced among older individuals. There is an association between the level of physical activity and nutritional status among patients on dialysis. These findings are of great concern, given the trend toward increasing age in incident dialysis patients and the well-known association between inactivity and increased mortality in the general population.


Reversible assembly and disassembly of receptor-decorated gold nanoparticles controlled by ion recognition.
The controlled assembly of randomly dispersed colloidal particles can provide access to materials with advanced optical and electronic properties while providing fundamental insights into self-assembly processes in nature and nanotechnology. Typically, self-assembled nanoparticles are prepared by exploiting electrostatic interactions, lithographic techniques, and covalently linked molecular scaffolds. This results in static morphologies that cannot be disassembled easily. On the other hand, having access to systems that can be assembled or disassembled in a controlled manner could allow for in-depth understanding of the nanoparticles as well as rational control over the morphology and fundamental properties of the resulting constructs. If the changes in aggregation are induced by a specific external chemical stimulus, it could also permit the development of new chemosensors. Here we demonstrate the reversible assembly and disassembly of gold nanoparticles achieved by modulating the noncovalent interactions between surface-bound calix[4]pyrroles and added bis-imidazolium cations. We also demonstrate the use of these nanoparticles in the selective sensing of anions.


Population-based study of intra-household gender differences in water insecurity: reliability and validity of a survey instrument for use in rural Uganda.
Hundreds of millions of people worldwide lack adequate access to water. Water insecurity, which is defined as having limited or uncertain availability of safe water or the ability to acquire safe water in socially acceptable ways, is typically overlooked by development organizations focusing on water availability. To address the urgent need in the literature for validated measures of water insecurity, we conducted a population-based study in rural Uganda with 327 reproductive-age women and 204 linked men from the same households. We used a novel method of photo identification so that we could accurately elicit study participants' primary household water sources, thereby enabling us to identify water sources for objective water quality testing and distance/elevation measurement. Our psychometric analyses provided strong evidence of the internal structure, reliability, and validity of a new eight-item Household Water Insecurity Access Scale (HWIAS). Important intra-household gender differences in perceptions of water insecurity were observed, with men generally perceiving household water insecurity as being less severe compared to women. In summary, the HWIAS represents a reliable and valid measure of water insecurity, particularly among women, and may be useful for informing and evaluating interventions to improve water access in resource-limited settings.


The polycomb complex protein mes-2/E(z) promotes the transition from developmental plasticity to differentiation in C. elegans embryos.
We have used expression profiling and in vivo imaging to characterize Caenorhabditis elegans embryos as they transit from a developmentally plastic state to the onset of differentiation. Normally, this transition is accompanied by activation of developmental regulators and differentiation genes, downregulation of early-expressed genes, and large-scale reorganization of chromatin. We find that loss of plasticity and differentiation onset depends on the Polycomb complex protein mes-2/E(Z). mes-2 mutants display prolonged developmental plasticity in response to heterologous developmental regulators. Early-expressed genes remain active, differentiation genes fail to reach wild-type levels, and chromatin retains a decompacted morphology in mes-2 mutants. By contrast, loss of the developmental regulators pha-4/FoxA or end-1/GATA does not prolong plasticity. This study establishes a model by which to analyze developmental plasticity within an intact embryo. mes-2 orchestrates large-scale changes in chromatin organization and gene expression to promote the timely loss of developmental plasticity. Our findings indicate that loss of plasticity can be uncoupled from cell fate specification.


Chemical modification reveals involvement of tyrosine in ligand binding to dopamine D1 and D2 receptors.
The effect of tyrosine-alkylating agents on the ligand-binding properties of bovine striatal dopamine D1 and D2 receptors was investigated. The tyrosine-alkylating agents, p-nitrobenzenesulphonylfluoride (pNBSF) and tetranitromethane (TNM) caused a time-and dose-dependent loss of the binding of [3H]SCH-23390 and [3H]spiroperidol, ligands specific for dopamine D1 and D2 receptors, respectively. The two dopamine receptors, however, showed a differential sensitivity to inactivation by these agents. The mechanism of inhibition of the two receptors appears to be complex as treatment of membranes with pNBSF and TNM resulted in a decrease of both the Kd and the Bmax of ligand binding. Spiroperidol almost completely protected the TNM-induced inhibition of [3H]spiroperidol binding to dopamine D2 receptors whereas SCH-23390 afforded only partial protection of the [3H]SCH-23390 binding by TNM suggesting that more than one tyrosine groups may be involved in the D1 receptor binding activity.


Interactions between HOXD and Gli3 genes control the limb apical ectodermal ridge via Fgf10.
The development of the vertebrate limb is dependent upon two signaling centers, the apical ectodermal ridge (AER), which provides the underlying mesenchyme with essential growth factors, and the zone of polarizing activity (ZPA), the source of the Sonic hedgehog (SHH) product. Recent work involving gain and loss of function of Hox genes has emphasized their impact both on AER maintenance and Shh transcriptional activation. Here, we describe antagonistic interactions between posterior Hoxd genes and Gli3, suggesting that the latter product protects the AER from the deleterious effect of the formers, and we present evidence that Fgf10 is the mediator of HOX-dependent AER expansion. Furthermore, the striking similarity between some of the hereby observed Hox/Gli3-dependent morphogenetic defects and those displayed by fetuses with severely altered retinoic acid metabolism suggests a tight connection between these various pathways. The nature of these potential interactions is discussed in the context of proximal-distal growth and patterning.


Comparative proteomics analysis of salt response reveals sex-related photosynthetic inhibition by salinity in Populus cathayana cuttings.
Male and female poplar ( Populus cathayana Rehd.) cuttings respond differently to salinity stress. To understand these differences better, comparative morphological, physiological, and proteomics analyses were performed. Treatments with different concentrations of NaCl applied to male and female poplar cuttings for 4 weeks showed that females reacted more negatively at the morphological and physiological levels than did males, visible as shriveled leaves, decreased growth, lowered photosynthetic capacities, and greater Na(+) accumulation. The proteome analysis identified 73 proteins from 82 sexually related salt-responsive spots. They were involved in photosynthesis, protein folding and assembly, synthesis and degradation, carbon, energy and steroid metabolism, plant stress and defense, redox homeostasis, signal transduction, and so forth. The sex-related changes of these proteins were consistent with the different morphological and physiological responses in males and females. In conclusion, the higher salt resistance of male P. cathayana cuttings is related to higher expression and lower degradation of proteins in the photosynthetic apparatus, more effective metabolic mechanism and protective system, and greater capacity of hydrogen peroxide scavenging. This research allows us to further understand the possible different management strategies of cellular activities in male and female Populus when confronted by salt stress.


Approaches to mid-infrared, super-resolution imaging and spectroscopy.
This perspective highlights recent advances in super-resolution, mid-infrared imaging and spectroscopy. It provides an overview of the different near field microscopy techniques developed to address the problem of chemically imaging specimens in the mid-infrared "fingerprint" region of the spectrum with high spatial resolution. We focus on a recently developed far-field optical technique, called infrared photothermal heterodyne imaging (IR-PHI), and discusses the technique in detail. Its practical implementation in terms of equipment used, optical geometries employed, and underlying contrast mechanism are described. Milestones where IR-PHI has led to notable advances in bioscience and materials science are summarized. The perspective concludes with a future outlook for robust and readily accessible high spatial resolution, mid-infrared imaging and spectroscopy techniques.


Trait evolution, resource specialization and vulnerability to plant extinctions among Antillean hummingbirds.
Species traits are thought to predict feeding specialization and the vulnerability of a species to extinctions of interaction partners, but the context in which a species evolved and currently inhabits may also matter. Notably, the predictive power of traits may require that traits evolved to fit interaction partners. Furthermore, local abiotic and biotic conditions may be important. On islands, for instance, specialized and vulnerable species are predicted to be found mainly in mountains, whereas species in lowlands should be generalized and less vulnerable. We evaluated these predictions for hummingbirds and their nectar-food plants on Antillean islands. Our results suggest that the rates of hummingbird trait divergence were higher among ancestral mainland forms before the colonization of the Antilles. In correspondence with the limited trait evolution that occurred within the Antilles, local abiotic and biotic conditions-not species traits-correlate with hummingbird resource specialization and the vulnerability of hummingbirds to extinctions of their floral resources. Specifically, hummingbirds were more specialized and vulnerable in conditions with high topographical complexity, high rainfall, low temperatures and high floral resource richness, which characterize the Antillean Mountains. These findings show that resource specialization and species vulnerability to extinctions of interaction partners are highly context-dependent.


Partial characterization of abnormal salivary proteins associated with rheumatoid arthritis.
Isoelectric focusing of parotid saliva from 33 patients with rheumatoid arthritis but without clinical evidence of salivary gland involvement revealed multiple abnormal proteins of pI 3.95-4.25 in all cases, whereas only two out of 16 samples from normal healthy individuals exhibited any similar bands. Although rheumatoid factors of abnormally low isoelectric point and restricted heterogeneity were detected in this pI region in five of the diseased samples, these could not account for all of the bands even in these cases. The abnormal proteins did not otherwise cross-react with antisera to immunoglobulin (Ig) G, IgA or albumin. Analysis of rheumatoid arthritis parotid saliva by a method involving adsorption of rheumatoid factors to immobilized rabbit immunoglobulin revealed the presence of salivary rheumatoid factors (in seven patients) of all the major immunoglobulin classes, including secretory-IgA in two patients. Although these abnormal proteins are as yet uncharacterized, their presence could form the basis of a non-invasive procedure in the diagnosis of salivary gland and connective tissue disorders.


An Engineered Allele of afsQ1 Facilitates the Discovery and Investigation of Cryptic Natural Products.
New approaches to antimicrobial discovery are needed to address the growing threat of antibiotic resistance. The Streptomyces genus, a proven source of antibiotics, is recognized as having a large reservoir of untapped secondary metabolic genes, many of which are likely to produce uncharacterized compounds. However, most of these compounds are currently inaccessible, as they are not expressed under standard laboratory conditions. Here, we present a novel methodology for activating these "cryptic" metabolites by heterologously expressing a constitutively active pleiotropic regulator. By screening wild Streptomyces isolates, we identified the antibiotic siamycin-I, a lasso peptide that we show is active against multidrug pathogens. We further revealed that siamycin-I interferes with cell wall integrity via lipid II. This new technology has the potential to be broadly applied for use in the discovery of additional "cryptic" metabolites.


The effects of ethosuximide on amino acids in genetic absence epilepsy rat model.
Genetic absence epilepsy rats from Strasbourg (GAERS), a selectively inbred strain of Wistar rats, has been validated as an experimental model for human absence epilepsy. In this model, systemic administration of ethosuximide (ETX) was shown to reduce the spike and wave discharges (SWD). In this study, gamma-aminobutyric acid (GABA) and L-glutamic acid levels in response to ETX injections (i.p., 100 mg/kg) were measured in the microdialysis samples collected from the ventrolateral thalamus (VLT) and the primary motor cortex (M1) area of Wistar rats and GAERS by using HPLC with fluorescent detection. Throughout the microdialysis procedure, continuous EEG recording was performed where ETX was shown to suppress the SWD activity. We demonstrated increased basal GABA levels in the M1 and VLT of GAERS, and ETX treatment did not produce any effect on higher GABA levels in the VLT, but suppressed the increased GABA levels significantly in the M1 of GAERS. All these findings denote the importance of corticothalamic circuitry and the role of increased GABA tonus in primary motor cortex and thalamus of GAERS. The primary motor cortex also seems to be involved in the SWD activity and ETX exerts, at least partially, its neurotransmitter effects through it.


Coregistration of fNIRS Data on to the Realistic Head Model.
In this paper, we propose a method to visualize fNIRS(Functional Near Infrared Spectroscopy) data on a realistic head model. In order to illustrate the success of this study, we used fNIRS data obtained during the Stroop task. For the realistic head model, high resolution T1 weighted MR images are used. Preliminary results show that proposed method will be usefull for visualization of fNIRS data and also these results are correlated with EEG (Electroencephalogram) topograpghic mapping for the same Stroop Task.


Myelitis associated with atopic disorders in Japan: a retrospective clinical study of the past 20 years.
To clarify the clinical features of myelitis associated with atopic disorders in Japanese patients. We retrospectively studied the clinical, immunological and electrophysiological features of 68 consecutive patients with myelitis of acute or subacute onset diagnosed at Kyushu University Hospital during the past 20 years. While only 2 of 28 (7%) patients with myelitis diagnosed between 1979 and 1993 had either atopic dermatitis (AD) or bronchial asthma (BA), 19 of 40 (48%) patients with myelitis diagnosed between 1994 and 1998 did. Among the 40 patients with myelitis diagnosed between 1994 and 1998, 19 patients with either AD or BA as well as 21 patients without either disease showed a significantly higher level of serum total IgE, higher frequency of hyperIgEaemia and higher frequency of mite antigen-specific IgE than 82 healthy controls. Myelitis patients with AD presenting as persistent paresthesia/dysesthesia in all four limbs showed cervical cord lesions on MRI and abnormalities in upper limb motor evoked potentials but no abnormalities in the cerebrospinal fluid (CSF), while myelitis patients with BA showed preferential involvement of the lower motor neurons clinically and electromyographically. In addition, 12 patients with myelitis who had hyperIgEaemia and mite antigen-specific IgE but neither AD nor BA showed incomplete transverse myelitis with mild motor disability and few CSF abnormalities. The clinical features of myelitis associated with atopic disorders were in part distinguished by the type of preceding atopic disorder, and also were different from those of hyperIgEaemic myelitis with no preceding atopic disorders.


IMPROVING (SOFTWARE) PATENT QUALITY THROUGH THE ADMINISTRATIVE PROCESS.
The available evidence indicates that patent quality, particularly in the area of software, needs improvement. This Article argues that even an agency as institutionally constrained as the U.S. Patent and Trademark Office ("PTO") could implement a portfolio of pragmatic, cost-effective quality improvement strategies. The argument in favor of these strategies draws upon not only legal theory and doctrine but also new data from a PTO software examination unit with relatively strict practices. Strategies that resolve around Section 112 of the patent statute could usefully be deployed at the initial examination stage. Other strategies could be deployed within the new post-issuance procedures available to the agency under the America Invents Act. Notably, although the strategies the Article discusses have the virtue of being neutral as to technology, they are likely to have a very significant practical impact in the area of software.


Cholesterol levels and statin use in patients with coronary heart disease treated in primary care settings.
Therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, has proven to be effective in the treatment of lipid disorders. However, statin therapy continues to be underused, even though statins are a relatively safe and well-tolerated class of agents. In this study, we assessed trends in lipid control in patients with heart disease who receive most of their health care in primary care clinics. The objective was to determine whether systems of care implemented within a large medical group are associated with improved treatment and control of dyslipidemia in a high-risk group of coronary heart disease patients. All adults with heart disease in a Minnesota medical group (N = 2947) were identified using diagnosis and procedure codes related to coronary heart disease (sensitivity = 0.85; positive predictive value = 0.89) in 1996. Study subjects were observed from 1995 to 1998. Subjects had a baseline and follow-up test for low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Changes between baseline and follow-up measurements and trends in the use of statins and other lipid-active agents among the study subjects were analyzed. Among 1388 subjects with two or more eligible lipid measurements, mean low-density lipoprotein cholesterol improved from 137.6 mg/dL to 111.0 mg/dL (P < .001), and mean high-density lipoprotein cholesterol improved from 42.3 mg/dL to 46.3 mg/dL (P < .001). The percentage of patients with low-density lipoprotein cholesterol < or = 100 mg/dL rose from 12.5% to 39.8% (P < .001), and the percentage with high-density lipoprotein cholesterol > or = 40 mg/dL rose from 52.5% to 67.6% (P < .001). In multivariate models, statin use was identified as the main factor that contributed to the improvement in low-density lipoprotein cholesterol (P < .001). Men had greater decreases in low-density lipoprotein cholesterol than women after adjusting for other variables (P < .001). Statin use rose from 24.3% at baseline to 69.6% at follow-up. The statin discontinuation rate was 8.3% for baseline statin users and 12.2% for subjects who used statins at any time during the study period. Investment in better heart disease care for patients in primary care clinics led to major improvement in lipid control over 30 months, primarily due to increased statin use. Improvements in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were sufficient to substantially reduce risk of subsequent major cardiovascular events.


Relationship between radiological characteristics and combined 1p and 19q deletion in World Health Organization grade III oligodendroglial tumours.
The radiological characteristics of World Health Organization grade III oligodendroglial tumours in relation to chromosome 1p and 19q deletions were analysed. 56 patients recently diagnosed with anaplastic oligodendroglioma (AO, n=49) or anaplastic oligoastrocytoma (AOA, n=7) were studied. Their preoperative magnetic resonance images were examined. Deletions of chromosome 1p and 19q were determined using the fluorescence in situ hybridisation method. Both 1p and 19q chromosomes had deletions (1p19q codeletion) in 39 patients (36 AO and 3 AOA). Tumors associated with the 1p19q codeletion were predominantly located in the frontal lobe (p=0.044). The magnetic resonance image characteristics of indistinct tumour borders (p=0.005 on T1, p=0.036 on T2) and a heterogeneous intratumoural signal intensity (p=0.033 on T1, p=0.041 on T2) were significantly correlated with the 1p19q codeletion. Analysis of patient survival showed those with the 1p19q-co-deleted tumours survived significantly longer than those lacking the 1p19q codeletion (p=0.042). The presence of a heterogeneous signal intensity in T2-weighted images, a characteristic significantly related to the 1p19q codeletion, indicated a favourable prognosis for patients' survival (HR; 0.125, 95% CI, 0.016 to 0.963, p=0.046) based on multivariate analysis. A relationship between radiological characteristics and molecular signatures in AO/AOAs was shown. It is believed that radiological characteristics have prognostic value as a surrogate marker for molecular characteristics.


The perioperative dialogue reduces postoperative stress in children undergoing day surgery as confirmed by salivary cortisol.
To evaluate the efficacy of 'the perioperative dialogue (PD)' by analyzing salivary cortisol, in 5- to 11-year-old children undergoing day surgery. To deal with anxiety prior to investigations and/or procedures, children need to be confident and informed about what is going to happen. Therefore, intervention strategies should be initiated before admission to hospital. Children (n = 93), 79 boys and 14 girls, scheduled for elective day surgery requiring general anesthesia were randomly recruited into three groups: (i) standard perioperative care (n = 31), (ii) standard perioperative care including preoperative information (n = 31), and (iii) the PD (n = 31). Saliva was sampled for cortisol analysis at specific time points during the pre- and perioperative procedures. The children who received the PD had significantly lower (P = 0.003) salivary cortisol concentrations postoperatively. Moreover, it continuously decreased during the day of surgery compared with the other two groups (P < 0.01). Among the children who received analgesics, the PD group received significantly less morphine (P = 0.014) related to bodyweight: the mean dose was 0.1 mg·kg(-1) (n = 9) in the control group vs 0.04 mg·kg(-1) (n = 6) in the PD group. Irrespective of group, there was a positive correlation between the children's morphine consumption and salivary cortisol concentration (r = 0.56; P = 0.038). The W-B scale score was higher in the group that received morphine (median = 3 vs median=1; P = 0.001). The PD's caring, continuity, and on-going dialogues were associated with low concentrations of salivary cortisol postoperatively and reduced morphine consumption and thus appears to be a valuable complement to standard perioperative care in children undergoing day surgery.


SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.
Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis.


A second T-region of the soybean-supervirulent chrysopine-type Ti plasmid pTiChry5, and construction of a fully disarmed vir helper plasmid.
Agrobacterium tumefaciens Chry5, which is particularly virulent on soybeans, induces tumors that produce a family of Amadori-type opines that includes deoxyfructosyl glutamine (Dfg) and its lactone, chrysopine (Chy). Cosmid clones mapping to the right of the known oncogenic T-region of pTiChry5 conferred Amadori opine production on tumors induced by the nopaline strain C58. Sequence analysis of DNA held in common among these cosmids identified two 25-bp, direct repeats flanking an 8.5-kb segment of pTiChry5. These probable border sequences are closely related to those of other known T-regions and define a second T-region of pTiChry5, called T-right (TR), that confers production of the Amadoriopines. The oncogenic T-left region (TL) was located precisely by identifying and sequencing the likely border repeats defining this segment. The two T-regions are separated by approximately 15 kb of plasmid DNA. Based on these results, we predicted that pKYRT1, a vir helper plasmid derived from pTiChry5, still contains all of TR and the leftmost 9 kb of TL. Consistent with this hypothesis, transgenic Arabidopsis thaliana plants selected for with a marker encoded by a binary plasmid following transformation with KYRT1 co-inherited production of the Amadori opines at high frequency. All opine-positive transgenic plants also contained TR-DNA, while those plants that lacked TR-DNA failed to produce the opines. Moreover, A. thaliana infected with KYRT1 in which an nptII gene driven by the 35S promoter of Cauliflower mosaic virus was inserted directly into the vir helper plasmid yielded kanamycin-resistant transformants at a low but detectable frequency. These results demonstrate that pKYRT1 is not disarmed, and can transfer Ti plasmid DNA to plants. A new vir helper plasmid was constructed from pTiChry5 by two rounds of sacB-mediated selection for deletion events. This plasmid, called pKPSF2, lacks both of the known T-regions and their borders. pKPSF2 failed to transfer Ti plasmid DNA to plants, but mobilized the T-region of a binary plasmid at an efficiency indistinguishable from those of pKYRT1 and the nopaline-type vir helper plasmid pMP90.


Saccharomyces cerevisiae Rab-GDI displacement factor ortholog Yip3p forms distinct complexes with the Ypt1 Rab GTPase and the reticulon Rtn1p.
Rab GTPases are crucial regulators of organelle biogenesis, maintenance, and transport. Multiple Rabs are expressed in all cells, and each is localized to a distinct set of organelles, but little is known regarding the mechanisms by which Rabs are targeted to their resident organelles. Integral membrane proteins have been postulated to serve as receptors that recruit Rabs from the cytosol in a complex with the Rab chaperone, GDI, to facilitate the dissociation of Rab and GDI, hence facilitating loading of Rabs on membranes. We show here that the yeast (Saccharomyces cerevisiae) Golgi Rab GTPase Ypt1p can be copurified with the integral membrane protein Yip3p from detergent cell extracts. In addition, a member of the highly conserved reticulon protein family, Rtn1p, is also associated with Yip3p in vivo. However, Ypt1p did not copurify with Rtn1p, indicating that Yip3p is a component of at least two different protein complexes. Yip3p and Rtn1p are only partially colocalized in cells, with Yip3p localized predominantly to the Golgi and secondarily to the endoplasmic reticulum, whereas Rtn1p is localized predominantly to the endoplasmic reticulum and secondarily to the Golgi. Surprisingly, the intracellular localization of Rabs was not perturbed in yip3Delta or rtn1Delta mutants, suggesting that these proteins do not play a role in targeting Rabs to intracellular membranes. These data indicate that Yip3p may have multiple functions and that its interaction with Rabs is not critical for their recruitment to organelle membranes.


Evaluation of Resistance Screening Methods for Sclerotinia Stem Rot of Soybean and Dry Bean.
Three methods to identify levels of resistance to Sclerotinia sclerotiorum in soybean (Glycine max) and dry bean (Phaseolus vulgaris) were compared using multiple data analyses. The three methods were mycelial plug inoculations of cotyledons, cut stems, and detached leaves. Six S. sclerotiorum isolates of known relative aggressiveness were inoculated on each of three soybean and dry bean cultivars with varied response to S. sclerotiorum. For soybean, all three inoculation methods accurately identified isolate aggressiveness irrespective of cultivar, but identification of susceptible and partially resistant soybean cultivars was influenced by isolate. For dry bean, the cotyledon and cut stem methods accurately identified isolate aggressiveness, but identification of susceptible and partially resistant dry bean cultivars was influenced by isolate and inoculation method. The cut stem method had the smallest coefficient of variation and was more precise for detecting interactions. When considering root mean square residual error combined over species and experiments, coefficient of variation based on residual error, significance of isolate-by-cultivar interaction from ANOVA, rank correlation between pairs of methods, and sensitivity ratio for the three resistance screening methods under controlled environmental conditions, the cut stem method was statistically better than the cotyledon and detached leaf methods for evaluating resistance in soybean and dry bean cultivars.


Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S.
Whole-body irradiation at the minimal lethal dose causes bone marrow failure and death within 12-18 days. To identify the principal components of the hematopoietic system that are radioprotective, we transplanted lethally irradiated mice with purified progenitors: common myeloid progenitors (CMPs), megakaryocyte/erythrocyte-restricted progenitors (MEPs), or granulocyte/monocyte-restricted progenitors (GMPs). Transplanted CMPs gave rise to cells both of the granulocyte/monocyte (GM) series and the megakaryocyte/erythrocyte series, whereas GMPs or MEPs showed reconstitution of only GM or ME cells, respectively. CMPs and MEPs but not GMPs protected mice in a dose-dependent manner, suggesting that erythrocytes, platelets, or both are the critical effectors of radioprotection. Accordingly, CMPs and MEPs formed robust colonies in recipient bone marrow and spleen, whereas GMPs formed small colonies that rapidly disappeared. Direct comparisons of spleen CFU (CFU-S) potentials among each progenitor subset showed that MEPs contain the vast majority of day 8 CFU-S activity, suggesting that day 8 CFU-S are the precursors of radioprotective cell subsets. All animals radioprotected for 30 days subsequently survived for at least 6 months post-transplant, and showed only host-derived hematopoiesis after 30 days. These findings suggest that rare hematopoietic stem cells survive myeloablation that can eventually repopulate irradiated hosts if myeloerythroid-restricted progenitors transiently rescue ablated animals through the critical window of bone marrow failure.


Who has housing affordability problems? Disparities in Housing Cost burden by Race, Nativity and Legal Status in Los Angeles.
Housing costs are a substantial component of U.S. household expenditures. Those who allocate a large proportion of their income to housing often have to make difficult financial decisions with significant short-term and long-term implications for adults and children. This study employs cross-sectional data from the first wave of the Los Angeles Family and Neighborhood Survey (L.A.FANS) collected between 2000 and 2002 to examine the most common U.S. standard of housing affordability, the likelihood of spending thirty percent or more of income on shelter costs. Multivariate analyses of a low-income sample of U.S. born Latinos, Whites, African Americans, authorized Latino immigrants and unauthorized Latino immigrants focus on baseline and persistent differences in the likelihood of being cost burdened by race, nativity and legal status. Nearly half or more of each group of low-income respondents experience housing affordability problems. The results suggest that immigrants' legal status is the primary source of disparities among those examined, with the multivariate analyses revealing large and persistent disparities for unauthorized Latino immigrants relative to most other groups. Moreover, the higher odds of housing cost burden observed for unauthorized immigrants compared with their authorized immigrant counterparts remains substantial, accounting for traditional indicators of immigrant assimilation. These results are consistent with emerging scholarship regarding the role of legal status in shaping immigrant outcomes in the United States.


[Occurrence of hospital infection among interned elderly in a university hospital].
Hospital infection is an important cause of morbidity and mortality in the elderly population. The objective of this study was to evaluate the occurrence of hospital infection and risk factors associated with it. This is a prospective study of a sample of 332 elderly people, 60 years and older, interned in a university hospital, between September 1999 and February 2000. Sample size was calculated according to the Fisher and Belle formula, with a confidence interval of 0.95%, from a total of 760 elderly patients interned, in proportion to the number of patients present in each in-patient unit, in the 1997. Criteria for defining hospital infection were those established by the Center for Diseases and Prevention Control. Odds ratio and logistic regression were utilized for statistical analysis of the data. The rate of hospital infection was 23.6%. The prevalent topographies of infection were respiratory infections (27.6%), urinary tract infections (26.4%) and surgical wound infections (23.6%). The period of hospitalization of patients who did have hospital infections was 6.9 days, while those who had hospital infections were hospitalized for 15.9 days (p<0.05). Mortality rate among hospitalized patients was 9.6% and the rate of lethality among patients with hospital infection was 22.9% (p<0.05). Risk factors found for hospital infection were cholangiography (odds ratio (OR) =46.4, confidence interval 95% (CI95%) =4.4-485); diabetes mellitus (OR=9.9, CI 95% =4.4-22.3); chronic obstructive pulmonary disease (OR=8.3, CI 95% =2.9-23.7); urinary catheters (OR=5, CI 95% =2.7-11.8); hospitalization with community infection (OR=3.9, CI 95% =1.7-8.9) and mechanic ventilation (OR=3.8, CI 95% =1.9-6.3). Hospital infection presented elevated incidence and lethality and it increased the period of hospitalization among the elderly studied.


The effectiveness of interventions in the management of patients with primary frozen shoulder.
There are many types of treatment used to manage the frozen shoulder, but there is no consensus on how best to manage patients with this painful and debilitating condition. We conducted a review of the evidence of the effectiveness of interventions used to manage primary frozen shoulder using the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Physiotherapy Evidence Database, MEDLINE and EMBASE without language or date restrictions up to April 2009. Two authors independently applied selection criteria and assessed the quality of systematic reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Data were synthesised narratively, with emphasis placed on assessing the quality of evidence. In total, 758 titles and abstracts were identified and screened, which resulted in the inclusion of 11 systematic reviews. Although these met most of the AMSTAR quality criteria, there was insufficient evidence to draw firm conclusions about the effectiveness of treatments commonly used to manage a frozen shoulder. This was mostly due to poor methodological quality and small sample size in primary studies included in the reviews. We found no reviews evaluating surgical interventions. More rigorous randomised trials are needed to evaluate the treatments used for frozen shoulder.


Vitamin D and Autism Spectrum Disorder: A Literature Review.
Low vitamin D status in early development has been hypothesised as an environmental risk factor for Autism Spectrum Disorder (ASD), given the concurrent increase in the prevalence of these two conditions, and the association of vitamin D with many ASD-associated medical conditions. Identification of vitamin D-ASD factors may provide indications for primary and secondary prevention interventions. We systematically reviewed the literature for studies on vitamin D-ASD relationship, including potential mechanistic pathways. We identified seven specific areas, including: latitude, season of conception/birth, maternal migration/ethnicity, vitamin D status of mothers and ASD patients, and vitamin D intervention to prevent and treat ASD. Due to differences in the methodological procedures and inconsistent results, drawing conclusions from the first three areas is difficult. Using a more direct measure of vitamin D status--that is, serum 25(OH)D level during pregnancy or childhood--we found growing evidence for a relationship between vitamin D and ASD. These findings are supported by convincing evidence from experimental studies investigating the mechanistic pathways. However, with few primary and secondary prevention intervention trials, this relationship cannot be determined, unless randomised placebo-controlled trials of vitamin D as a preventive or disease-modifying measure in ASD patients are available.


Concentrated assemblies of magnetic nanoparticles in ionic liquids.
Maghemite (γ-Fe2O3) nanoparticles (NPs) can be successfully dispersed in a protic ionic liquid, ethylammonium nitrate (EAN), by transfer from aqueous dispersions into EAN. As the aqueous systems are well controlled, several parameters can be tuned. Their crucial role towards the interparticle potential and the structure of the dispersions is evidenced: (i) the size of the NPs tunes the interparticle attraction monitoring dispersions to be either monophasic or gas-liquid-like phase separated; (ii) the nature of the initial counterion in water (here sodium, lithium or ethylammonium) and the amount of added water (<20 vol%) modulate the interparticle repulsion. Very concentrated dispersions with a volume fraction of around 25% are obtained thanks to the gas-liquid-like phase separations. Such conclusions are derived from a fine structural and dynamical study of the dispersions on a large range of spatial scales by coupling several techniques: chemical analyses, optical microscopy, dynamic light scattering, magneto-optic birefringence and small angle scattering.


Aryl hydrocarbon receptor-dependent retention of nuclear HuR suppresses cigarette smoke-induced cyclooxygenase-2 expression independent of DNA-binding.
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to man-made environmental toxicants, has emerged as an endogenous regulator of cyclooxygenase-2 (Cox-2) by a mechanism that is poorly understood. In this study, we first used AhR-deficient (AhR(-/-) ) primary pulmonary cells, together with pharmacological tools to inhibit new RNA synthesis, to show that the AhR is a prominent factor in the destabilization of Cox-2 mRNA. The destabilization of Cox-2 mRNA and subsequent suppression of cigarette smoke-induced COX-2 protein expression by the AhR was independent of its ability to bind the dioxin response element (DRE), thereby differentiating the DRE-driven toxicological AhR pathway from its anti-inflammatory abilities. We further describe that the AhR destabilizes Cox-2 mRNA by sequestering HuR within the nucleus. The role of HuR in AhR stabilization of Cox-2 mRNA was confirmed by knockdown of HuR, which resulted in rapid Cox-2 mRNA degradation. Finally, in the lungs of AhR(-/-) mice exposed to cigarette smoke, there was little Cox-2 mRNA despite robust COX-2 protein expression, a finding that correlates with almost exclusive cytoplasmic HuR within the lungs of AhR(-/-) mice. Therefore, we propose that the AhR plays an important role in suppressing the expression of inflammatory proteins, a function that extends beyond the ability of the AhR to respond to man-made toxicants. These findings open the possibility that a DRE-independent AhR pathway may be exploited therapeutically as an anti-inflammatory target.


Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study.
A study was undertaken to evaluate exacerbations and their impact on the health related quality of life (HRQL) of patients with chronic obstructive pulmonary disease (COPD). A 2 year follow up study was performed in 336 patients with COPD of mean (SD) age 66 (8.2) years and mean (SD) forced expiratory volume in 1 second (FEV(1)) 33 (8)% predicted. Spirometric tests, questions regarding exacerbations of COPD, and HRQL measurements (St George's Respiratory Questionnaire (SGRQ) and SF-12 Health Survey) were conducted at 6 month intervals. A total of 1015 exacerbations were recorded, and 103 (30.7%) patients required at least one hospital admission during the study. After adjustment for baseline characteristics and season of assessment, frequent exacerbations had a negative effect on HRQL in patients with moderate COPD (FEV(1) 35-50% predicted); the change in SGRQ total score of moderate patients with > or =3 exacerbations was almost two points per year greater (worse) than those with <3 exacerbations during the follow up (p = 0.042). For patients with severe COPD (FEV(1) <35% predicted) exacerbations had no effect on HRQL. The change in SGRQ total score of patients admitted to hospital was almost 2 points per year greater (worse) than patients not admitted, but this effect failed to show statistical significance in any severity group. There was a significant and independent seasonal effect on HRQL since SGRQ total scores were, on average, 3 points better in measurements performed in spring/summer than in those measured in the winter (p<0.001). Frequent exacerbations significantly impair HRQL of patients with moderate COPD. A significant and independent effect of seasonality was also observed.


Pre-pubertal children born post-term have reduced insulin sensitivity and other markers of the metabolic syndrome.
There are no data on the metabolic consequences of post-term birth (≥42 weeks gestation). We hypothesized that post-term birth would adversely affect insulin sensitivity, as well as other metabolic parameters and body composition in childhood. 77 healthy pre-pubertal children, born appropriate-for-gestational-age were studied in Auckland, New Zealand: 36 born post-term (18 boys) and 41 (27 boys) born at term (38-40 weeks gestation). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman's minimal model. Other assessments included fasting hormone concentrations and lipid profiles, body composition from whole-body dual-energy X-ray absorptiometry, 24-hour ambulatory blood pressure monitoring, and inflammatory markers. Insulin sensitivity was 34% lower in post-term than in term children (7.7 vs. 11.6 x10⁻⁴·min⁻¹·(mU/l); p<0.0001). There was a compensatory increase in acute insulin response among post-term children (418 vs 304 mU/l; p=0.037), who also displayed lower glucose effectiveness than those born at term (2.25 vs 3.11 x10⁻²·min⁻¹; p=0.047). Post-term children not only had more body fat (p=0.014) and less fat-free mass (p=0.014), but also had increased central adiposity with more truncal fat (p=0.017) and greater android to gynoid fat ratio (p=0.007) compared to term controls. Further, post-term children displayed other markers of the metabolic syndrome: lower normal nocturnal systolic blood pressure dipping (p=0.027), lower adiponectin concentrations (p=0.005), as well as higher leptin (p=0.008) and uric acid (p=0.033) concentrations. Post-term boys (but not girls) also displayed a less favourable lipid profile, with higher total cholesterol (p=0.018) and LDL-C (p=0.006) concentrations, and total cholesterol to HDL-C ratio (p=0.048). Post-term children have reduced insulin sensitivity and display a number of early markers of the metabolic syndrome. These findings could have important implications for the management of prolonged pregnancies. Future studies need to examine potential impacts later in life, as well as possible underlying mechanisms.


Central alterations of neuromuscular function and feedback from group III-IV muscle afferents following exhaustive high-intensity one-leg dynamic exercise.
The aims of this investigation were to describe the central alterations of neuromuscular function induced by exhaustive high-intensity one-leg dynamic exercise (OLDE, study 1) and to indirectly quantify feedback from group III-IV muscle afferents via muscle occlusion (MO, study 2) in healthy adult male humans. We hypothesized that these central alterations and their recovery are associated with changes in afferent feedback. Both studies consisted of two time-to-exhaustion tests at 85% peak power output. In study 1, voluntary activation level (VAL), M-wave, cervicomedullary motor evoked potential (CMEP), motor evoked potential (MEP), and MEP cortical silent period (CSP) of the knee extensor muscles were measured. In study 2, mean arterial pressure (MAP) and leg muscle pain were measured during MO. Measurements were performed preexercise, at exhaustion, and after 3 min recovery. Compared with preexercise values, VAL was lower at exhaustion (-13 ± 13%, P < 0.05) and after 3 min of recovery (-6 ± 6%, P = 0.05). CMEP area/M area was lower at exhaustion (-38 ± 13%, P < 0.01) and recovered after 3 min. MEP area/M area was higher at exhaustion (+25 ± 27%, P < 0.01) and after 3 min of recovery (+17 ± 20%, P < 0.01). CSP was higher (+19 ± 9%, P < 0.01) only at exhaustion and recovered after 3 min. Markers of afferent feedback (MAP and leg muscle pain during MO) were significantly higher only at exhaustion. These findings suggest that the alterations in spinal excitability and CSP induced by high-intensity OLDE are associated with an increase in afferent feedback at exhaustion, whereas central fatigue does not fully recover even when significant afferent feedback is no longer present.


Risk factors of falls in inpatients and their practical use in identifying high-risk persons at admission: Fukushima Medical University Hospital cohort study.
To clarify the risk factors for falls in hospital settings and to propose the use of such factors to identify high-risk persons at admission. Prospective cohort study. Fukushima Medical University Hospital, Japan, from August 2008 and September 2009. 9957 adult consecutive inpatients admitted to our hospital. Information was collected at admission from clinical records obtained from a structured questionnaire conducted in face-to-face interviews with subjects by nurses and doctors and fall events were collected from clinical records. The proportion of patients who fell during follow-up was 2.5% and the incidence of falls was 3.28 per 100 person-days. There were significant differences in age, history of falling, cognitive dysfunction, planned surgery, wheelchair use, need for help to move, use of a remote caring system, rehabilitation, use of laxative, hypnotic or psychotropic medications and need for help with activities of daily living (ADL) between patients who did and did not fall. Multivariable adjusted ORs for falls showed that age, history of falls and need for help with ADL were common risk factors in both men and women. Using psychotropic medication also increased the risk of falling in men while cognitive dysfunction and use of hypnotic medication increased the risk of falling in women. Planned surgery was associated with a low risk of falls in women. To prevent falls in inpatients it is important to identify high-risk persons. Age, history of falling and the need for help with ADL are the most important pieces of information to be obtained at admission. Care plans for patients including fall prevention should be clear and considered.


Biomonitoring of Toxic Effects of Pesticides in Occupationally Exposed Individuals.
Workers in pesticide manufacturing industries are constantly exposed to pesticides. Genetic biomonitoring provides an early identification of potential cancer and genetic diseases in exposed populations. The objectives of this biomonitoring study were to assess DNA damage through comet assay in blood samples collected from industry workers and compare these results with those of classical analytical techniques used for complete blood count analysis. Samples from controls (n = 20) and exposed workers (n = 38) from an industrial area in Multan, Pakistan, were subjected to various tests. Malathion residues in blood samples were measured by gas chromatography. The exposed workers who were employed in the pesticide manufacturing industry for a longer period (i.e., 13-25 years) had significantly higher DNA tail length (7.04 μm) than the controls (0.94 μm). Workers in the exposed group also had higher white blood cell and red blood cell counts, and lower levels of mean corpuscular hemoglobin (MCH), MCH concentration, and mean corpuscular volume in comparison with normal levels for these parameters. Malathion was not detected in the control group. However, in the exposed group, 72% of whole blood samples had malathion with a mean value of 0.14 mg/L (range 0.01-0.31 mg/L). We found a strong correlation (R (2) = 0.91) between DNA damage in terms of tail length and malathion concentration in blood. Intensive efforts and trainings are thus required to build awareness about safety practices and to change industrial workers' attitude to prevent harmful environmental and anthropogenic effects.


Ultrasonographic measurements of adrenal glands in cats with hyperthyroidism.
Feline hyperthyroidism is potentially associated with exaggerated responsiveness of the adrenal gland cortex. The adrenal glands of 23 hyperthyroid cats were examined ultrasonographically and compared to the adrenal glands of 30 control cats. Ten hyperthyroid cats had received antithyroid drugs until 2 weeks before sonography, the other 13 were untreated. There was no difference in adrenal gland shape between healthy and hyperthyroid cats: bean-shaped, well-defined, hypoechoic structures surrounded by a hyperechoic halo in 43/60 (71.6%) healthy cats and 34/46 (73.9%) hyperthyroid cats; more ovoid in 13/60 (21.6%) healthy cats and 9/46 (19.6%) hyperthyroid cats while more elongated in 4/60 (6.7%) healthy cats, 3/46 (6.5%) hyperthyroid cats. Hyperechoic foci were present in 9/23 (39.1%) hyperthyroid cats and 2/30 (6.7%) healthy cats. The adrenal glands were significantly larger in hyperthyroid cats, although there was overlap in size range. The mean difference between hyperthyroid cats and healthy cats was 1.6 and 1.7 mm in left and right adrenal gland length, 0.8 and 0.9 mm in left and right cranial adrenal gland height, and 0.4 and 0.9 mm in left and right caudal adrenal gland height. There was no significant difference between the adrenal gland measurements in treated and untreated hyperthyroid cats. The adrenomegaly was most likely associated with the hypersecretion of the adrenal cortex documented in hyperthyroid cats. Hyperthyroidism should be an alternative to hyperadrenocorticism, hyperaldosteronism, and acromegaly in cats with bilateral moderate adrenomegaly.


Ultrasound cardioscopy: embarking on a new journey.
To present the results of investigation of a new application of invasive ultrasonography-ultrasound cardioscopy, a procedure in which a self-contained ultrasound device is capable not only of producing an under-blood field of view but also of delivering diagnostic and therapeutic tools. Twenty adult mongrel dogs were studied with the ultrasound cardioscopy device during experimental catheter ablation procedures. A rigid prototype probe, 34 cm long and 8 mm in diameter with a 7-MHz side-viewing transducer at the tip and an 8-F diameter tool delivery port, was introduced through the right external jugular vein into the right heart chambers. Remote and device-directed ablation procedures were monitored. Subsequently, the canine hearts were excised and examined. The self-contained cardioscopy device with a contained ablation catheter could both direct and visualize a specified ablation injury. Under-blood observation of the details of the ablation procedure was possible. Although a learning curve existed for appropriate manipulation of the device, inspection of the excised hearts showed that the size of the injury was accurately predicted with use of ultrasound cardioscopy. Ultrasound cardioscopy is a promising means of performing precise under-blood diagnostic and therapeutic maneuvers.


DBC1 is a suppressor of B cell activation by negatively regulating alternative NF-κB transcriptional activity.
CD40 and BAFFR signaling play important roles in B cell proliferation and Ig production. In this study, we found that B cells from mice with deletion of Dbc1 gene (Dbc1(-/-)) show elevated proliferation, and IgG1 and IgA production upon in vitro CD40 and BAFF, but not BCR and LPS stimulation, indicating that DBC1 inhibits CD40/BAFF-mediated B cell activation in a cell-intrinsic manner. Microarray analysis and chromatin immunoprecipitation experiments reveal that DBC1 inhibits B cell function by selectively suppressing the transcriptional activity of alternative NF-κB members RelB and p52 upon CD40 stimulation. As a result, when immunized with nitrophenylated-keyhole limpet hemocyanin, Dbc1(-/-) mice produce significantly increased levels of germinal center B cells, plasma cells, and Ag-specific Ig. Finally, loss of DBC1 in mice leads to higher susceptibility to experimental autoimmune myasthenia gravis. Our study identifies DBC1 as a novel regulator of B cell activation by suppressing the alternative NF-κB pathway.


Benign-appearing Intraspinal Malignant Peripheral Nerve Sheath Tumors: Treatments and Outcomes of 14 Consecutive Patients.
To investigate the clinical characteristics and prognostic factors that may influence outcomes of patients undergoing benignappearing intraspinal malignant peripheral nerve sheath tumors (MPNSTs). This study included a total of 14 consecutive patients who were diagnosed with benign intraspinal tumors firstly and confirmed as intraspinal MPNSTs by pathology. The univariate analyses of various clinical factors were performed to identify variables that could predict prognosis. Endpoints were mortality and local recurrence. The survival rate was estimated using the Kaplan?Meier method, and differences were analyzed by carrying out the log-rank test. In addition, factors with p values of ?0.05 were considered statistically significant. Benign-appearing intraspinal MPNSTs showed some different clinical features compared with spinal MPNSTs and intraspinal benign tumors. The present study found that age at diagnosis, Neurofibromatosis type 1 (NF-1) history, tumor sites, malignant grade, Ki-67 and tumor resection method might be factors closely associated with recurrence and survival of intraspinal MPNSTs patients. Benign-appearing intraspinal MPNSTs are relatively rare tumors with a better overall prognosis compared with common spinal MPNSTs. A lot of factors can affect patients" survival and local recurrence. These prognostic factors still require further confirmation with further studies including more patients.


Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.
In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.


Littrow-mounted diffraction grating cavity.
Grating resonators are not characterized by a single cavity length, and thus the cavity-mode spacing cannot simply be obtained from the standing-wave pattern. This problem is studied in a Littrow grating cavity with geometric ray tracing and a result of the scalar diffraction theory for the phase of a plane wave diffracted at a grating. The round-trip phase in the cavity is considered, and it is shown that a grating cavity may be modeled by a tilted-mirror Fabry-Perot cavity. The tilt magnitude depends linearly on the wavelength deviation from the resonant Littrow wavelength, and the mirror separation, L(C), is equal to the grating-cavity length at the center of the aperture. The model shows that the cavity axial mode separation may be determined from the standard expression, c/2L(C). An effect of finesse decrease and mode broadening, which are linearly dependent on wavelength deviation from the central Littrow wavelength, are predicted. A passive grating cavity was experimentally studied with an interferometric method and a tunable laser to demonstrate the discussed hypotheses.


Differences in gene transcriptomic pattern of Plasmodium falciparum in children with cerebral malaria and asymptomatic carriers.
The mechanisms underlying the heterogeneity of clinical malaria remain largely unknown. We hypothesized that differential gene expression contributes to phenotypic variation of parasites which results in a specific interaction with the host, leading to different clinical features of malaria. In this study, we analyzed the transcriptomes of isolates obtained from asymptomatic carriers and patients with uncomplicated or cerebral malaria. We also investigated the transcriptomes of 3D7 clone and 3D7-Lib that expresses severe malaria associated-variant surface antigen. Our findings revealed a specific up-regulation of genes involved in pathogenesis, adhesion to host cell, and erythrocyte aggregation in parasites from patients with cerebral malaria and 3D7-Lib, compared to parasites from asymptomatic carriers and 3D7, respectively. However, we did not find any significant difference between the transcriptomes of parasites from cerebral malaria and uncomplicated malaria, suggesting similar transcriptomic pattern in these two parasite populations. The difference between isolates from asymptomatic children and cerebral malaria concerned genes coding for exported proteins, Maurer's cleft proteins, transcriptional factor proteins, proteins implicated in protein transport, as well as Plasmodium conserved and hypothetical proteins. Interestingly, UPs A1, A2, A3 and UPs B1 of var genes were predominantly found in cerebral malaria-associated isolates and those containing architectural domains of DC4, DC5, DC13 and their neighboring rif genes in 3D7-lib. Therefore, more investigations are needed to analyze the effective role of these genes during malaria infection to provide with new knowledge on malaria pathology. In addition, concomitant regulation of genes within the chromosomal neighborhood suggests a common mechanism of gene regulation in P. falciparum.


Anaemia predictors in patients with chronic hepatitis C treated with ribavirin and direct-acting antiviral agents.
Anaemia is the most common side effect associated with ribavirin (RBV). This study intended to assess its incidence and determine its predictive factors in patients with hepatitis C virus on RBV plus direct-acting antiviral agents (DAAs). A retrospective study of patients receiving RBV+DAA was conducted. Serum haemoglobin (Hb) was determined at baseline and monitored 4 weekly. Anaemia was defined as a single occurrence of Hb <10 g/dL. Bivariate and multivariate logistic regression analyses were conducted to assess the relationship between the occurrence of anaemia and the following factors: age, gender, FibroScan score, viral load, cirrhotic status (yes/no), RBV dose, glomerular filtration rate (GFR), alanine amino transferase, albumin, treatment duration (12 vs ≥12 weeks), baseline Hb, and Hb% drop (weeks 0-2). 152 patients were included, of which 15.1% experienced anaemia. The analysis revealed that estimated GFR (eGFR), baseline Hb, 12-week treatment duration and Hb% drop (weeks 0-2) were significantly associated with the likelihood of developing anaemia (p<0.05). Two mathematical models were subsequently developed to predict patients at risk of anaemia: a pretreatment model (positive predictive value 86.6%) which included eGFR, baseline Hb and 12-week treatment duration and an intratreatment model (positive predictive value of 90.48%) which in addition included the Hb% drop (weeks 0-2). Anaemia was found to be less significant in this cohort compared with studies on RBV plus pegylated interferon, telaprevir or boceprevir combinations, but higher than those on newer DAAs. Baseline Hb, eGFR, 12-week treatment duration and Hb% drop (weeks 0-2) significantly predicted the risk of anaemia and were used to construct two predictive models.