Utility of patient-specific silicone renal models for planning and rehearsal of complex tumour resections prior to robot-assisted laparoscopic partial nephrectomy.
To describe our experience using patient-specific tissue-like kidney models created with advanced three-dimensional (3D)-printing technology for preoperative planning and surgical rehearsal prior to robot-assisted laparoscopic partial nephrectomy (RALPN). A feasibility study of 10 patients with solid renal masses who underwent RALPN after preoperative rehearsal using 3D-print kidney models. A single surgeon performed all surgical rehearsals and procedures. Using standard preoperative imaging and 3D reconstruction, we generated pre-surgical models using a silicone-based material. All surgical rehearsals were performed using the da Vinci® robotic system (Intuitive Surgical Inc., Sunnyvale, CA, USA) before the actual procedure. To determine construct validity, we compared resection times between the model and actual tumour in a patient-specific manner. Using 3D laser scanning in the operating room, we quantified and compared the shape and tumour volume resected for each model and patient tumour. We generated patient-specific models for 10 patients with complex tumour anatomy. R.E.N.A.L. nephrometry scores were between 7 and 11, with a mean maximal tumour diameter of 40.6 mm. The mean resection times between model and patient (6:58 vs 8:22 min, P = 0.162) and tumour volumes between the computer model, excised model, and excised tumour (38.88 vs 38.50 vs 41.79 mm3 , P = 0.98) were not significantly different. We have developed a patient-specific pre-surgical simulation protocol for RALPN. We demonstrated construct validity and provided accurate representation of enucleation time and resected tissue volume. This simulation platform can assist in surgical decision-making, provide preoperative rehearsals, and improve surgical training.


Molecular classification and genetic pathways in hyperplastic polyposis syndrome.
Hyperplastic Polyposis (HPPS) is a poorly characterized syndrome that increases colorectal cancer (CRC) risk. We aimed to provide a molecular classification of HPPS. We obtained 282 tumours from 32 putative HPPS patients with >or= 10 hyperplastic polyps (HPs); some patients also had adenomas and CRCs. We found no good evidence of microsatellite instability (MSI) in our samples. The epithelium of HPs was monoclonal. Somatic BRAF mutations occurred in two-thirds of our patients' HPs, and KRAS2 mutations in 10%; both mutations were more common in younger cases. The respective mutation frequencies in a set of 'sporadic' HPs were 18% and 10%. Importantly, the putative HPPS patients generally fell into two readily defined groups, one set whose polyps had BRAF mutations, and another set whose polyps had KRAS2 mutations. The most plausible explanation for this observation is that there exist different forms of inherited predisposition to HPPS, and that these determine whether polyps follow a BRAF or KRAS2 pathway. Most adenomas and CRCs from our putative HPPS patients had 'classical' morphology and few of these lesions had BRAF or KRAS2 mutations. These findings suggest that tumourigenesis in HPPS does not necessarily follow the 'serrated' pathway. Although current definitions of HPPS are sub-optimal, we suggest that diagnosis could benefit from molecular analysis. Specifically, testing BRAF and KRAS2 mutations, and perhaps MSI, in multiple polyps could help to distinguish HPPS from sporadic HPs. We propose a specific model which would have diagnosed five more of our cases as HPPS compared with the WHO clinical criteria.


Effect of delirium motoric subtypes on administrative documentation of delirium in the surgical intensive care unit.
This study compares the proportions of surgical intensive care unit (ICU) patients with delirium detected using the Confusion Assessment Method for the ICU (CAM-ICU) who received administrative documentation for delirium using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, stratified by delirium motoric subtypes. This retrospective cohort study was conducted at a surgical ICU from 06/2012 to 05/2013. Delirium was assessed twice daily and was defined as having ≥1 positive CAM-ICU rating. Delirious patients were categorized into hyperactive/mixed and hypoactive subtypes using corresponding Richmond Agitation Sedation Scales. Administrative documentation of delirium was defined as having ≥1 of 32 unique ICD-9-CM codes. Proportions were compared using Pearson's Chi-square test. Of included patients, 40 % (423/1055) were diagnosed with delirium, and 17 % (183/1055) had an ICD-9-CM code for delirium. The sensitivity and specificity of ICD-9-CM codes for delirium were 36 and 95 %. ICD-9-CM codes for delirium were available for 42 % (95 % CI 35-48 %; 105/253) of patients with hyperactive/mixed delirium and 27 % (95 % CI 20-34 %; 46/170) of patients with hypoactive delirium (relative risk = 1.5; 95 % CI 1.2-2.0; p = 0.002). ICD-9-CM codes yielded a low sensitivity for identifying patients with CAM-ICU positive delirium and were more likely to identify hyperactive/mixed delirium compared with hypoactive delirium.


Degenerate Optical Cavities. II: Effect of Misalignments.
A simple expression is given for the response of degenerate cavities suffering from arbitrary misalignments, and numerical results are presented. The method of resonance excitation is carried out analytically with the help of a complex ray representation of gaussian beams. It is first shown that the modulus and phase of such complex rays can be identified with, respectively, the beam radius and the phase of the on-axis field. This identification simplifies the calculation of the coupling factor between two gaussian beams, which is needed in deriving the expression for the response. For the case of conventional cavities, the results are in exact agreement with results derived from the Laguerre-Gauss or Hermite-Gauss mode theory. The case of degenerate cavities with large and possibly nonorthogonal misalignments, of interest in various nonresonant multipath systems, is also discussed.


Effect of switching therapy to pegaptanib in eyes with the persistent cases of exudative age-related macular degeneration.
Purpose of this study was to evaluate the efficacy of switching to pegaptanib monotherapy for persistent cases of exudative age-related macular degeneration (AMD).Out of 296 eyes of 296 patients treated with ranibizumab or ranibizumab combined with photodynamic therapy (PDT), 50 eyes of 50 AMD patients were found to be resistant to these treatments. Over a 12-month period, intravitreal pegaptanib (IVP) 0.3 mg was administered at intervals of 6 weeks until the exudation disappeared prospectively. All patients were examined with the following tests: best-corrected visual acuity (BCVA) and central retinal thickness (CRT), determined at the initial visit, before the first IVP (baseline), and at 12 months. The factors responsible for achieving dry macula with IVP were examined statistically.The rate of persistent cases with intravitreal ranibizumab (IVR) and/or PDT was 17.0%. The mean number of IVPs administered was 5.4 (range, 2-9). Logarithm of the minimal angle of resolution BCVA at 12 months was stable or improved by ≥ 0.3 in 49 eyes (98.0%), with a significant improvement noted between the baseline and final BCVA (P=0.01, paired t test). The CRT (mean ± standard deviation) was 446.9 ± 150.6 µm at the initial visit, 414.5 ± 146.5 µm at baseline, and 318.7 ± 99.0 µm at 12 months. There was a significant decrease in the mean CRT between the measurements at baseline and at 12 months after the first IVP (P=0.002, Bonferroni correction). At 12 months, the exudative change was completely resolved in 27 eyes (54.0%) and reduced in 21 eyes (42.0%). The number of previous IVR treatments was significantly correlated with dry macula at 12 months.After switching therapy to pegaptanib in persistent cases of AMD, most patients maintained or improved their BCVA and exhibited a positive treatment response at 12 months.


Effect of Alirocumab on Mortality After Acute Coronary Syndromes.
Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.


Potentiation of cardiac vagal action by cold.
The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated guinea pig atrial preparation. During cardiac output measurements in unanaesthetized sheep, by the thermodilution method, bradycardia was evoked on injection of cold indicator in eight of 12 sheep studied. This bradycardia was consistently evoked when blood pressure was increased, but not at normal blood pressure levels. In the guinea pig atrial preparation, which has one vagus nerve attached, bradycardia was evoked by electrical stimulation of the vagus nerve. When the preparation was cooled this bradycardia was potentiated. In anaesthetized dogs, the cut peripheral end of one vagus was stimulated electrically at different frequencies. The linear relationship between pulse interval and vagal frequency was then compared at deep body temperatures of 35, 37, 39 and 41 degrees C. This comparison showed that the vagus prolonged pulse interval more effectively when the animal was cool (35 degrees C) than when it was warm (41 degrees C).


Role of corpus callosum integrity in arm function differs based on motor severity after stroke.
While the corpus callosum (CC) is important to normal sensorimotor function, its role in motor function after stroke is less well understood. This study examined the relationship between structural integrity of the motor and sensory sections of the CC, as reflected by fractional anisotropy (FA), and motor function in individuals with a range of motor impairment level due to stroke. Fifty-five individuals with chronic stroke (Fugl-Meyer motor score range 14 to 61) and 18 healthy controls underwent diffusion tensor imaging and a set of motor behavior tests. Mean FA from the motor and sensory regions of the CC and from corticospinal tract (CST) were extracted and relationships with behavioral measures evaluated. Across all participants, FA in both CC regions was significantly decreased after stroke (p < 0.001) and showed a significant, positive correlation with level of motor function. However, these relationships varied based on degree of motor impairment: in individuals with relatively less motor impairment (Fugl-Meyer motor score > 39), motor status correlated with FA in the CC but not the CST, while in individuals with relatively greater motor impairment (Fugl-Meyer motor score ≤ 39), motor status correlated with FA in the CST but not the CC. The role interhemispheric motor connections play in motor function after stroke may differ based on level of motor impairment. These findings emphasize the heterogeneity of stroke, and suggest that biomarkers and treatment approaches targeting separate subgroups may be warranted.


The Utility of Ambulatory Electrocardiographic Monitoring for Detecting Silent Arrhythmias and Clarifying Symptom Mechanism in an Urban Elderly Population with Heart Failure and Hypertension: Clinical Implications.
Background: Atrial and ventriclar tachyarrhythmias, as well as bradyarrhythmias, in the elderly with heart failure (HF) and/or hypertension (HTN) have been well documented. However, the frequency of these arrhythmias, whether silent or symptomatic, and their association with subsequent cardiac events has not been well defi ned in patients 65 years or older with HF and other cardiovascular risk factors. Objective: To assess the value of 2 weeks of remote, transtelephonic cardiac monitoring for detecting arrhythmias in an elderly, urban population living with HF. Methods: Fi" y-four patients with a history of systolic HF and/or HTN were consented and enrolled. All wore an auto triggered cardiac loop monitor for 2 weeks that captures EKG data and both silent and symptomatic arrhythmias were recorded. Results: Mean age was 73 ± 6 years with 59% of subjects were females, 74% Hispanic, 22% black, and 4% white/other. All patients had HF and 94% had HTN. From the cardiac monitoring, 72% demonstrated ectopic atrial and ventricular activity, and 1 paroxysmal episode of atrial fi brillation was documented. In addition, 3 subjects had signifi cant non-sustained ventricular tachycardia, and 4 individuals had severe bradycardia recorded on cardiac monitoring. These 7 individuals underwent placement of an implantable cardioverter defi brillator (ICD) or pacemaker based on the documented arrhythmias which may have otherwise gone undetected. Conclusions: A substantial proportion of patients exhibited cardiac arrhythmias. Future morbidity was prevented because of the detection of arrhythmias on monitoring that led to specifi c therapies such as pacemaker or ICD implantation which otherwise may not have been implemented.


Heroes against homophobia: does elevation uniquely block homophobia by inhibiting disgust?
Homophobia has decreased in past decades, but gut-level disgust towards gay men lingers. It has been suggested that disgust can be reduced by inducing its proposed opposite emotion, elevation. Research suggests elevation might reduce homophobia, but only general elevation (not elevation evoked by gay people) and general attitudes (rather than disgust) have been studied. Nor has elevation's effect on homophobia been differentiated from effects of related emotions, such as admiration or surprise. We pretested a series of news stories featuring either a gay man or a man of unspecified sexuality that were intended to distinctly elicit elevation, admiration, or surprise. We pre-registered the prediction that an elevation-inducing story would reduce negative attitudes by reducing disgust. In Study 1 (N = 593), participants who read elevation-inducing stories did not express more positive attitudes or less disgust towards gay men than those who read stories inducing admiration or surprise. The admiration stories elicited similar or lower levels of disgust than the elevation stories. Study 2 (N = 588), replicated the findings of Study 1 with improved stimuli and measures. Both studies suggest that elevation may not uniquely reduce homophobia, as elevation and admiration have similar effects on this prejudice.


Treatment of patients with acute nonlymphocytic leukemia in relapse: a Leukemia Intergroup study.
Forty patients with acute nonlymphocytic leukemia (ANLL) in first relapse were treated at eight member institutions of the Leukemia Intergroup with a 10-day continuous intravenous infusion of cytosine arabinoside and an anthracycline antibiotic administered on days 1, 2, and 3. Twenty of the 40 patients achieved a complete response. Seven of the patients who did not enter remission were drug-resistant failures, while 13 patients failed to enter remission for reasons other than persistent leukemia. Pretreatment parameters such as age, presence of infection, platelet count, and liver function tests were important predictors of survival. The percent bone marrow cellularity, the percent circulating abnormal (leukemic) cells, and the height of the white blood cell count prior to treatment were helpful in distinguishing patients who would enter remission from those who would not enter remission because of persistent leukemia.


In vitro assessment of antimicrobial properties of rifampin-coated Titan(®) Coloplast penile implants and comparison with Inhibizone(®).
It is a common practice to soak Titan(®) Coloplast penile implants in antibiotic solution prior to implantation. Aim. The aim of this study is to identify an ideal solution for soaking the Titan(®) Coloplast penile implants prior to implantation. Titan(®) strips were soaked in a different combination of antibiotics and the zone of inhibition was studied against Staphylococcus epidermidis and Escherichia coli. This zone of inhibition was compared against zone of inhibition produced by Inhibizone(®) -coated silicone strips. Zones of inhibitions were also compared for different components of Inhibizone(®) implant such as cylinder, tubing, connector, rear tip extender, and reservoir, and compared with similar components of Titan(®) Coloplast penile implants. The zone of inhibition against S. epidermidis and E. coli for Titan strips dipped in Rifampin and Gentamicin was compared against other antibiotics. The clinical significance of dipping Titan(®) -coated Coloplast implant in Rifampin and Gentamicin solution was determined. Rifampin 10mg/mL+gentamicin 1mg/mL (R10/G1) and rifampin 1mg/mL+gentamicin 1mg/mL (R1/G1) had excellent coverage against S. epidermidis and E. coli. The zone of inhibition (utilizing the Titan(®) coating) produced by both these solutions exceeds that produced by Inhibizone(®) by 40% to 56% for S. epidermidis and 33% for E. coli. Components of the American Medical System implant (tubing connectors and rear tip extenders) are not coated with antibiotics and had no zone of inhibition. Soaking Titan(®) -coated Coloplast implants in R10/G1 solution produces a zone of inhibition greater than that produced by Inhibizone(®) -coated penile implants. The clinical significance of this increased zone of inhibition can only be determined by a separate clinical study.


The complement of protein kinases of the microsporidium Encephalitozoon cuniculi in relation to those of Saccharomyces cerevisiae and Schizosaccharomyces pombe.
Microsporidia, parasitic fungi-related eukaryotes infecting many cell types in a wide range of animals (including humans), represent a serious health threat in immunocompromised patients. The 2.9 Mb genome of the microsporidium Encephalitozoon cuniculi is the smallest known of any eukaryote. Eukaryotic protein kinases are a large superfamily of enzymes with crucial roles in most cellular processes, and therefore represent potential drug targets. We report here an exhaustive analysis of the E. cuniculi genomic database aimed at identifying and classifying all protein kinases of this organism with reference to the kinomes of two highly-divergent yeast species, Saccharomyces cerevisiae and Schizosaccharomyces pombe. A database search with a multi-level protein kinase family hidden Markov model library led to the identification of 29 conventional protein kinase sequences in the E. cuniculi genome, as well as 3 genes encoding atypical protein kinases. The microsporidian kinome presents striking differences from those of other eukaryotes, and this minimal kinome underscores the importance of conserved protein kinases involved in essential cellular processes. Approximately 30% of its kinases are predicted to regulate cell cycle progression while another approximately 28% have no identifiable homologues in model eukaryotes and are likely to reflect parasitic adaptations. E. cuniculi lacks MAP kinase cascades and almost all protein kinases that are involved in stress responses, ion homeostasis and nutrient signalling in the model fungi S. cerevisiae and S. pombe, including AMPactivated protein kinase (Snf1), previously thought to be ubiquitous in eukaryotes. A detailed database search and phylogenetic analysis of the kinomes of the two model fungi showed that the degree of homology between their kinomes of approximately 85% is much higher than that previously reported. The E. cuniculi kinome is by far the smallest eukaryotic kinome characterised to date. The difficulty in assigning clear homology relationships for nine out of the twentynine microsporidian conventional protein kinases despite its compact genome reflects the phylogenetic distance between microsporidia and other eukaryotes. Indeed, the E. cuniculi genome presents a high proportion of genes in which evolution has been accelerated by up to four-fold. There are no orthologues of the protein kinases that constitute MAP kinase pathways and many other protein kinases with roles in nutrient signalling are absent from the E. cuniculi kinome. However, orthologous kinases can nonetheless be identified that correspond to members of the yeast kinomes with roles in some of the most fundamental cellular processes. For example, E. cuniculi has clear orthologues of virtually all the major conserved protein kinases that regulate the core cell cycle machinery (Aurora, Polo, DDK, CDK and Chk1). A comprehensive comparison of the homology relationships between the budding and fission yeast kinomes indicates that, despite an estimated 800 million years of independent evolution, the two model fungi share approximately 85% of their protein kinases. This will facilitate the annotation of many of the as yet uncharacterised fission yeast kinases, and also those of novel fungal genomes.


Spectrally dependent linear depolarization and lidar ratios for nonspherical smoke aerosols.
We use the numerically exact T-matrix method to model light scattering and absorption by aged smoke aerosols at lidar wavelengths ranging from 355 to 1064 nm assuming the aerosols to be smooth spheroids or Chebyshev particles. We show that the unique spectral dependence of the linear depolarization ratio (LDR) and extinction-to-backscatter ratio (or lidar ratio, LR) measured recently for stratospheric Canadian wildfire smoke can be reproduced by a range of model morphologies, a range of spectrally dependent particle refractive indices, and a range of particle sizes. For these particles, the imaginary part of the refractive index is always less than (or close to) 0.035, and the corresponding real part always falls in the range [1.35, 1.65]. The measured spectral LDRs and LRs could be produced by nearly-spherical oblate spheroids or Chebyshev particles whose shapes resemble those of oblate spheroids. Their volume-equivalent effective radii should be large enough (r eff = 0.3 μm or greater) to produce the observed enhanced LDRs. Our study demonstrates the usefulness of triple-wavelength LDR measurements as providing additional size information for a more definitive characterization of the particle morphology and composition. Non-zero LDR values indicate the presence of nonspherical aerosols and are highly sensitive to particle shapes and sizes. On the other hand, the LR is a strong function of absorption and is very responsive to changes in the particle refractive index.


PET/CT: appropriate application in lymphoma.
Positron emission tomography (PET) integrated with computed tomography (CT) (PET/CT) provides both metabolic and morphologic information, and becomes the most sensitive and specific imaging armamentarium in patients with non-Hodgkin lymphoma (NHL) and HL. This multimodality is being routinely used in staging, response assessment, and end-of-treatment evaluation for most lymphoma subtypes with convincing data. However, there are still controversial issues in the clinical management of patients with lymphoma. This comprehensive review addresses the latest information regarding the appropriate application of Fluorine 18 fluorodeoxyglucose ((18)F-FDG) PET/CT, discusses the current dilemma in the prognostic value of interim PET/CT, and tries to clarify questions existing in PET/CT-navigated application.


Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes.
Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.


Feasibility of endoscopic submucosal dissection for colorectal neoplasia at anastomotic sites: a retrospective study.
Metachronous colorectal lesions sometimes occur at anastomotic sites following colorectal surgery, which increases the risk of developing colorectal cancer. However, these lesions are difficult to treat even with minimally invasive methods such as endoscopic submucosal dissection (ESD). Thus, we aimed to evaluate the outcomes of ESD for colorectal lesions at anastomotic sites following colorectal surgery. We retrospectively investigated 11 patients with post-surgical colorectal lesions at anastomotic sites who later underwent ESD from May 2010 to April 2019 at Keio University Hospital, Tokyo, Japan. We examined the patients' background (tumor location, macroscopic type, tumor size, histological type, and depth of invasion) and treatment outcomes (procedure duration, en bloc resection rate, R0 resection rate, and adverse events). The patients' mean age was 66 years. There were two lesions in the transverse colon, six in the rectum, one in the anal canal, and two in the ileal pouch. The median tumor size was 25 mm. The macroscopic types were the protruded type (1 lesion) and the flat or depressed type (10 lesions). The pathological diagnoses were adenoma (4 lesions), intramucosal cancer (corresponding to high-grade dysplasia) (6 lesions), and muscularis propria cancer (1 lesion). The median procedure duration was 50 min; en bloc resection rate was 88.9% and R0 resection rate was 66.7%. The only adverse event was delayed post-ESD bleeding. A high en bloc resection rate without perforation was achieved with ESD for lesions at anastomotic sites. Although ESD for lesions at anastomotic sites is a technically challenging procedure because of severe submucosal fibrosis, this approach could prevent the need for repeated surgical resection.


Is Senescence Reversible?
Senescence was originally identified by the finite lifespan of normal cells that is a consequence of telomere shortening with each cycle of DNA replication. Cells undergoing replicative senescence display pronounced morphological and biochemical changes such as flattening and/or enlargement, increases in p21(WAF1) and/or p16(INK4A), a senescence-associated secretory phenotype, and often senescence-associated heterochromatic foci. Senescence also occurs in tumor cells in response to various forms of chemotherapy or radiation (therapy-induced senescence), which could be the basis for prolonged or (ideally) permanent growth arrest. Alternatively, therapy-induced senescence could represent a means whereby tumor cells evade the potential toxicity of chemotherapy and radiation, allowing for the eventual re-emergence or escape from senescence that could lead to disease recurrence. This review discusses the experimental data in the literature that support the premise that senescence is potentially reversible through the inactivation of p53, p16(INK4A) and/or Rb, over-expression of Cdc2/cdk1 and survivin, the development of polyploidy, the survival of cancer stem cells and/or restoration of the nuclear landscape. If senescence is truly reversible, then the re-emergence of tumor cells from senescent arrest induced by chemotherapy or radiation could represent a barrier to the development of effective and curative cancer therapies.


Chromaticity-discrimination thresholds with aperture and object colors: experimental results and predictions of some recent color-difference formulas.
Threshold-discrimination ellipses were obtained by three normal observers, at five color centers, by the use of two experimental devices, which provided light-surface colors, and the same method and experimental conditions. The ellipses obtained for each center in both devices were quite similar when the sample distributions were appropriate and slightly smaller for object color than for aperture color. The ellipses predicted by three recent color-difference formulas based on the CIE uniform color space (CIELAB) were compared with those experimentally obtained by us as well as by other researchers who analyzed a greater number of color centers. The color-difference formula proposed by the CIE Technical Committee 1-29 [Color Res. Appl. 18, 137 (1993)] provides the best prediction of the semiaxis relationship for all the experimental datasets used, confirming their good performance in previous works [Appl. Opt. 33, 8069 (1993)], although the differences with respect to the experimental results are higher than those attributable to the interobserver variability.


Ability of probiotic Lactobacillus casei DN 114001 to bind or/and metabolise heterocyclic aromatic amines in vitro.
Heterocyclic aromatic amines (HCA) are compounds with high mutagenic potential, formed when meat is cooked at high temperatures of 150-300 degrees C. These compounds contribute to development of colon and gastric cancer. Western diet provides a lot of HCA and influences the available substrates for the intestinal microbiota which can activate HCA to direct acting mutagens. On the other hand, lactic acid bacteria existing in the colon and ingested with food including probiotics, may exert an anti-carcinogenic action, but the mechanism is still poorly understood. In the present study we determined the ability of probiotic Lactobacillus casei DN 114001 (Actimel strain) to metabolise or adsorb three HCA: IQ, MelQx and PhIP in vitro. Lactobacilli were cultivated in MRS and in a modified MRS broth with reduced concentrations of nitrogen and carbon (MRS NC), with addition of 25 mug/ml of IQ, MelQx or PhIP. Their concentration after cultivation with L. casei DN 114001 was measured with high-performance liquid chromatography and the genotoxicity was evaluated by the alkaline comet assay. It was measured, that after 24 h cultivation in MRS (cell density was 10(9) cfu/ml), rapid decrease of IQ and PhIP (98-99%) was observed, and the peaks on chromatograms were almost completely reduced. In case of MeIQx the decrease was about 27%. In a modified MRS broth (cell density was 10(8) cfu/ml), the ability to decrease HCA concentration during prolonged cultivation (to 168 h) depended on the growth phase of bacteria, and it was about 51.5% for IQ and at about 11.2% for MeIQx. Non-growing cells (in phosphate buffer), could reduce the content of IQ and PhIP from 72 h to the end of incubation. L. casei DN 114001 reduced genotoxicity of HCA (IQ from 46 to 48%; MeIQx from 35 to 65% and PhIP from 32 to 81%), and the degree depended on the incubation time, cell growth and the medium used. It may suggest that bacteria can metabolise or adsorb HCA.


Analysis and experimental demonstration of novel 8PolSK-QPSK modulation at 5 bits/symbol for passive mitigation of nonlinear impairments.
We propose a new modulation format providing 5 bits of information per recovered symbol while maintaining constant the total optical power. The proposed format applies a simple power constrain to the DP-8QAM format. This modulation format provides a passive way to mitigate nonlinear impairments due to Kerr effects occurring during propagation, and most specifically in the first 40 km. This report presents, to the authors' knowledge, a new transmission format using solely phase and polarization as modulation methods. The performance of this format, named 8PolSK-QPSK, is experimentally compared with that of the DP-8QAM format as both require equal transmitter complexity and implementation penalty, at the expense of a 20% increase in signaling baud rate. The greater nonlinear tolerance of this format is experimentally demonstrated. Moreover, thorough analysis of the Manakov-PDM propagation equation applied to both formats provides analytic explanation of the 8PolSK-QPSK's improved performance. The constant power property of the symbol set of the proposed format mitigates self- and cross-phase modulation (SPM, XPM) nonlinear effects and is experimentally validated over a long-haul transmission system in a WDM scenario. A total throughput of 7 × 129 Gbps is maintained for the transmission format comparison. Simulation of the same transmission system allows separate analysis of the strength of SPM, XPM and Cross-Polarization Modulation (XPolM) nonlinear effects and demonstrate reduced nonlinear impairments for the proposed format in the first span. We show an experimental reduction of the required OSNR for a BER threshold of 1.4 × 10(-2) of 0.5 dB for 8PolSK-QPSK compared to DP-8QAM in back-to-back. After 1920 km of SMF fiber, we demonstrate a required OSNR (ROSNR) diminution for increasing launch power, allowing a ROSNR relief of 0.95 dB at optimal launch power of -1 dBm for the proposed format. Using the same threshold, we show an increased reach by more than 34%, or 975 km, at optimal launch power. We also demonstrate that the relative reach increase for 8PolSK-QPSK compared to DP-8QAM monotonically increases with increasing BER threshold and that the BER growth with distance, after the first span, is equal for both formats.


Comparison of the diagnostic performance of bacterial culture of nasopharyngeal swab and bronchoalveolar lavage fluid samples obtained from calves with bovine respiratory disease.
OBJECTIVE To compare predictive values, extent of agreement, and gamithromycin susceptibility between bacterial culture results of nasopharyngeal swab (NPS) and bronchoalveolar lavage fluid (BALF) samples obtained from calves with bovine respiratory disease (BRD). ANIMALS 28 beef calves with clinical BRD. PROCEDURES Pooled bilateral NPS samples and BALF samples were obtained for bacterial culture from calves immediately before and at various times during the 5 days after gamithromycin (6 mg/kg, SC, once) administration. For each culture-positive sample, up to 12 Mannheimia haemolytica, 6 Pasteurella multocida, and 6 Histophilus somni colonies underwent gamithromycin susceptibility testing. Whole-genome sequencing was performed on all M haemolytica isolates. For paired NPS and BALF samples collected 5 days after gamithromycin administration, the positive and negative predictive values for culture results of NPS samples relative to those of BALF samples and the extent of agreement between the sampling methods were determined. RESULTS Positive and negative predictive values of NPS samples were 67% and 100% for M haemolytica, 75% and 100% for P multocida, and 100% and 96% for H somni. Extent of agreement between results for NPS and BALF samples was substantial for M haemolytica (κ, 0.71) and H somni (κ, 0.78) and almost perfect for P multocida (κ, 0.81). Gamithromycin susceptibility varied within the same sample and between paired NPS and BALF samples. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated culture results of NPS and BALF samples from calves with BRD should be interpreted cautiously considering disease prevalence within the population, sample collection relative to antimicrobial administration, and limitations of diagnostic testing methods.


Blood culture confirmed bacterial sepsis in neonates in a North Indian tertiary care center: changes over the last decade.
The spectrum of organisms causing sepsis is different in developing countries. Data on the recent trends of organisms causing sepsis are limited. This study was conducted in a tertiary care neonatal unit in Northern India. All inborn babies with blood-culture-positive sepsis from 1995 to 2006 were divided into two epochs, viz. 1995 to 1998 (epoch I) and 2001 to 2006 (epoch II). Organisms were grouped into early (<72 h) and late onset (> or =72 h) sepsis groups. The overall incidence of sepsis, the incidence of sepsis stratified by weight groups, the organism profile on different days of life, sepsis-related mortality and pathogen-specific case fatality rate were calculated and compared between the two epochs. Out of 34,362 live births during the study period, organisms were isolated in 1,491 neonates. Out of these, 89% had bacterial sepsis. The incidence of neonatal bacterial sepsis increased from epoch I to epoch II (35.8/1,000 versus 40.1/1,000 live births, P<0.05). The incidence of early onset sepsis (EOS) did not change between the epochs, but the incidence of late onset sepsis (LOS) increased from 12 to 16.5 per 1,000 live births (P<0.001). The incidence of bacterial sepsis decreased significantly in the 1,000- to 1,999-g birth weight groups. Klebsiella pneumoniae and Enterobacter aerogenes decreased, whereas Staphylococcus aureus increased in incidence during epoch II. Non-fermenting Gram-negative bacilli emerged as a newly identified pathogen during epoch II. Sepsis-associated mortality decreased from 42 to 20%. The incidence of bacterial sepsis has decreased significantly in 1,000- to 1,999-g infants, with a significant reduction in sepsis-related mortality. New organisms have emerged in recent years. The organism profile in recent years has changed, with a significant overlap of organisms causing EOS and LOS.


A protocol for testing the stability of biochemical analytes. Technical document.
Stability of a measurand in a specimen is a function of the property variation over time in specific storage conditions, which can be expressed as a stability equation, and is usually simplified to stability limits (SLs). Stability studies show differences or even inconsistent results due to the lack of standardized experimental designs and heterogeneity of the chosen specifications. Although guidelines for the validation of sample collection tubes have been published recently, the measurand stability evaluation is not addressed. This document provides an easy guideline for the development of a stability test protocol based on a two-step process. A preliminary test is proposed to evaluate the stability under laboratory habitual conditions. The loss of stability is assessed by comparing measurement values of two samples obtained from the same patient and analyzed at different time points. One of them is analyzed under optimal conditions (basal sample). The other is stored under specific stability conditions for a time set by the laboratory (test sample). Differences are expressed using percentage deviation (PD%) to facilitate comparison with specifications. When the preliminary test demonstrates instability, a comprehensive test is proposed in order to define the stability equation and to specify SLs. Several samples are collected from a set of patients. The basal sample is analyzed under optimal conditions, whereas analysis of test samples is delayed at time intervals. For each patient PD% is calculated as the difference between measurements for every test sample and its basal one and represented in a coordinate graph versus time.


Growth, interaction, and positioning of microtubule asters in extremely large vertebrate embryo cells.
Ray Rappaport spent many years studying microtubule asters, and how they induce cleavage furrows. Here, we review recent progress on aster structure and dynamics in zygotes and early blastomeres of Xenopus laevis and Zebrafish, where cells are extremely large. Mitotic and interphase asters differ markedly in size, and only interphase asters span the cell. Growth of interphase asters occurs by a mechanism that allows microtubule density at the aster periphery to remain approximately constant as radius increases. We discuss models for aster growth, and favor a branching nucleation process. Neighboring asters that grow into each other interact to block further growth at the shared boundary. We compare the morphology of interaction zones formed between pairs of asters that grow out from the poles of the same mitotic spindle (sister asters) and between pairs not related by mitosis (non-sister asters) that meet following polyspermic fertilization. We argue growing asters recognize each other by interaction between antiparallel microtubules at the mutual boundary, and discuss models for molecular organization of interaction zones. Finally, we discuss models for how asters, and the centrosomes within them, are positioned by dynein-mediated pulling forces so as to generate stereotyped cleavage patterns. Studying these problems in extremely large cells is starting to reveal how general principles of cell organization scale with cell size.


Effects of hydrogen-rich saline treatment on polymicrobial sepsis.
Hydrogen has been reported to selectively reduce hydroxyl radicals and peroxynitrite anion in many pathologic processes. This study aimed to test the hypothesis that hydrogen-rich saline (HRS) may ameliorate organ dysfunction in a rat model of polymicrobial sepsis. Sepsis was induced in male Sprague-Dawley rats by cecal ligation and puncture (CLP). Twenty-four rats were equally assigned to Sham group, CLP group, and CLP + HRS group (n = 8). At 0, 6, and 18 h after CLP or sham operation, rats received an intraperitoneal injection of HRS (5 mL/kg) or the same volume of normal saline. Malondialdehyde, superoxide dismutase activities, inflammatory mediators, pulmonary nitric oxide, myeloperoxidase activities, wet-to-dry weight ratio, histologic scores, apoptotic analysis, alanine aminotransferase, creatinine, and blood urea nitrogen were assessed at 24 h after operation. The 7-d survival rate was also recorded. HRS administration significantly reduced the serum high-mobility group box, alanine aminotransferase, creatinine, and blood urea nitrogen levels; the pulmonary interleukin 6, high-mobility group box, nitric oxide, and malondialdehyde levels; and the wet-to-dry weight ratio, total histologic scores, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, whereas it increased the superoxide dismutase activities 24 h after CLP when compared with the CLP group. However, there was no significant difference in survival rate between the CLP + HRS and CLP groups. HRS has potential protective effects against sepsis by decreasing proinflammatory responses, oxidative stress, and apoptosis in a rat model of polymicrobial sepsis.


Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations.
We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with 4 different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine46 by arginine (H46R), leucine84 by valine (L84V), isoleucine104 by phenylalanine (I104F), and valine148 by isoleucine (V148I), in 5 Japanese families. Although features of progressive neurogenic muscular atrophy were common in patients of these families, patients of each family showed characteristic clinical features. FALS patients with the H46R mutation showed a benign clinical course and stereotype progression of muscular weakness and atrophy beginning from the legs. In FALS with the L84V mutation, while the clinical course of the disease was similar, the age at onset was younger in men than women. The patients with I104F showed wide ranges of age at onset and duration with ophthalmoparesis and sensory involvement in one patient. Those with the V148I mutation showed younger age at onset and variable first symptoms within the family. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and the Babinski sign was not observed in any case. Bulbar palsy was frequent with I104F, but not with H46R. SOD activity of the red blood cells was severely reduced with I104F and V148I, but was slightly reduced with H46R. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene each showed clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.


Mean total arsenic concentrations in chicken 1989-2000 and estimated exposures for consumers of chicken.
The purpose of this study was to estimate mean concentrations of total arsenic in chicken liver tissue and then estimate total and inorganic arsenic ingested by humans through chicken consumption. We used national monitoring data from the Food Safety and Inspection Service National Residue Program to estimate mean arsenic concentrations for 1994-2000. Incorporating assumptions about the concentrations of arsenic in liver and muscle tissues as well as the proportions of inorganic and organic arsenic, we then applied the estimates to national chicken consumption data to calculate inorganic, organic, and total arsenic ingested by eating chicken. The mean concentration of total arsenic in young chickens was 0.39 ppm, 3- to 4-fold higher than in other poultry and meat. At mean levels of chicken consumption (60 g/person/day), people may ingest 1.38-5.24 microg/day of inorganic arsenic from chicken alone. At the 99th percentile of chicken consumption (350 g chicken/day), people may ingest 21.13-30.59 microg inorganic arsenic/day and 32.50-47.07 microg total arsenic/day from chicken. These concentrations are higher than previously recognized in chicken, which may necessitate adjustments to estimates of arsenic ingested through diet and may need to be considered when estimating overall exposure to arsenic.


Eggs of Tylenchulus semipenetrans Inhibit Growth of Phytophthora nicotianae and Fusarium solani in vitro.
In previous greenhouse and laboratory studies, citrus seedlings infested with the citrus nematode Tylenchulus semipenetrans and later inoculated with the fungus Phylophthora nicotianae grew larger and contained less fungal protein in root tissues than plants infected by only the fungus, demonstrating antagonism of the nematode to the fungus. In this study, we determined whether eggs of the citrus nematode T. semipenetrans and root-knot nematode Meloidogyne arenaria affected mycelial growth of P. nicotianae and Fusarium solani in vitro. Approximately 35,000 live or heat-killed (60 degrees C, 10 minutes) eggs of each nematode species were surface-sterilized with cupric sulfate, mercuric chloride, and streptomycin sulfate and placed in 5-pl drops onto the center of nutrient agar plates. Nutrient agar plugs from actively growing colonies of P. nicotianae or F. solani were placed on top of the eggs for 48 hours after which fungal colony growth was determined. Live citrus nematode eggs suppressed mycelial growth of P. nicotianae and F. solani (P </= 0.05) compared to heat-killed eggs and water controls. Reaction of the fungi to heat-killed eggs was variable. Root-knot nematode eggs had no effect on either P. nicotianae or F. solani mycelial growth. The experiment demonstrated a species-specific, direct effect of the eggs of the citrus nematode on P, nicotianae and F. solani.


Physical activity and blood pressure in primary school children: a longitudinal study.
High blood pressure (BP) is becoming increasingly common during childhood. Regular physical activity (PA) reduces BP in adults, but limited studies have reported inconsistent results among children. The aim of this study is to examine, for the first time, the cross-sectional and longitudinal associations between BP and objectively measured PA in young children of predominantly South Asian background. Data from the Birmingham healthy Eating and Active lifestyle for CHildren Study were analyzed. Five hundred seventy-four children, aged 5 to 7 years, underwent a series of measures at baseline and were followed up 2 years later. PA was objectively measured using accelerometry and converted to counts per minute (total PA, cpm), and time spent in moderate-vigorous PA (minutes per day). BP was measured by trained staff using standard protocols. Data were available for 512 children at baseline (mean age 6.5 years, range 5.4-7.8 years), and 427 of these children were followed up. Baseline total PA was inversely associated with diastolic BP at both baseline (adjusted regression coefficient: -0.75 mm Hg [95% CI -1.33 to -0.18] per 20 cpm) and follow-up (-0.74 mm Hg [95% CI -1.40 to -0.08]). All associations remained unchanged after further adjustment for weight status. This study strengthens evidence of a causal association between higher PA and lower BP in children as young as 5, independent of weight status. The results provide support for development of interventions to increase PA in young children.


Porphyromonas gingivalis Lipopolysaccharide Damages Mucosal Barrier to Promote Gastritis-Associated Carcinogenesis.
Recent epidemiological studies suggested correlation between gastric cancer (GC) and periodontal disease. We aim to clarify involvement of lipopolysaccharide of Porphyromonas gingivalis (Pg.), one of the red complex periodontal pathogens, in the GC development. To evaluate barrier function of background mucosa against the stimulations, we applied biopsy samples from 76 patients with GC using a Ussing chamber system (UCs). K19-Wnt1/C2mE transgenic (Gan) mice and human GC cell-lines ± THP1-derived macrophage was applied to investigate the role of Pg. lipopolysaccharide in inflammation-associated carcinogenesis. In the UCs, Pg. lipopolysaccharide reduced the impedance of metaplastic and inflamed mucosa with increases in mRNA expression of toll-like receptor (TLR) 2, tumor necrosis factor (TNF) α, and apoptotic markers. In vitro, Pg. lipopolysaccharide promoted reactive oxidative stress (ROS)-related apoptosis as well as activated TLR2-β-catenin-signaling on MKN7, and it increased the TNFα production on macrophages, respectively. TNFα alone activated TLR2-β-catenin-signaling in MKN7, while it further increased ROS and TNFα in macrophages. Under coculture with macrophages isolated after stimulation with Pg. lipopolysaccharide, β-catenin-signaling in MKN7 was activated with an increase in supernatant TNFα concentration, both of which were decreased by adding a TNFα neutralization antibody into the supernatant. In Gan mice with 15-week oral administration of Pg. lipopolysaccharide, tumor enlargement with β-catenin-signaling activation were observed with an increase in TNFα with macrophage infiltration. Local exposure of Pg. lipopolysaccharide may increase ROS on premalignant gastric mucosa to induce apoptosis-associated barrier dysfunction and to secrete TNFα from activated macrophages, and both stimulation of Pg. lipopolysaccharide and TNFα might activate TLR2-β-catenin-signaling in GC.


A neural substrate for behavioral inhibition in the risk for major depressive disorder.
Behavioral inhibition (BI) is an early developing trait associated with cautiousness and development of clinical depression and anxiety. Little is known about the neural basis of BI and its predictive importance concerning risk for internalizing disorders. We looked at functional connectivity of the default-mode network (DMN) and salience network (SN), given their respective roles in self-relational and threat processing, in the risk for internalizing disorders, with an emphasis on determining the functional significance of these networks for BI. We used functional magnetic resonance imaging to scan, during the resting state, children and adolescents 8 to 17 years of age who were either at high familial risk (HR; n = 16) or low familial risk (LR; n = 18) for developing clinical depression and/or anxiety. Whole-brain DMN and SN functional connectivity were estimated for each participant and compared across groups. We also compared the LR and HR groups on levels of BI and anxiety, and incorporated these data into follow-up neurobehavioral correlation analyses. The HR group, relative to the LR group, showed significantly decreased DMN connectivity with the ventral striatum and bilateral sensorimotor cortices. Within the HR group, trait BI increased as DMN connectivity with the ventral striatum and sensorimotor cortex decreased. The HR and LR groups did not differ with respect to SN connectivity. Our findings show, in the risk for internalizing disorders, a negative functional relation between brain regions supporting self-relational processes and reward prediction. These findings represent a potential neural substrate for behavioral inhibition in the risk for clinical depression and anxiety.


Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO.
Myelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor beta 1 (TGF-beta 1) in the pathogenesis of myelofibrosis has been documented, but the mechanisms mediating osteosclerosis remain unclear. Here, we used mice deficient in osteoprotegerin (OPG), a secreted inhibitor of bone resorption, to determine whether osteosclerosis occurs through a deregulation of osteoclastogenesis. Marrow cells from opg-deficient mice (opg(-/-)) or wild-type (WT) littermates were infected with a retrovirus encoding TPO and engrafted into an opg(-/-) or WT background for long-term reconstitution. The 4 combinations of graft/host (WT/WT, opg(-/-)/opg(-/-), opg(-/-)/WT, and WT/opg(-/-)) were studied. Elevation of TPO and TGF-beta 1 levels in plasma was similar in the 4 experimental groups and all the mice developed a similar myeloproliferative syndrome associated with severe myelofibrosis. Osteosclerosis developed in WT hosts engrafted with WT or opg(-/-) hematopoietic cells and was associated with increased OPG levels in plasma and decreased osteoclastogenesis. In contrast, opg(-/-) hosts exhibited an osteoporotic phenotype and a growth of bone trabeculae was rarely seen. These findings suggest that osteosclerosis in mice with TPO overexpression occurs predominantly via an up-regulation of OPG in host stromal cells leading to disruption of osteoclastogenesis.


Trisomy of 8q22.3 approximately q23-qter following an unbalanced 1;8 translocation in a boy with multiple anomalies.
An 11-month-old boy was first referred with global developmental delay, pallor and heart defects (ASD, VSD, mitral and tricuspid valve insufficiency). He also had facial abnormalities. Standard karyotyping showed additional material on one chromosome 1p homolog, and fluorescence in situ hybridization (FISH) indicated an unbalanced translocation of 1pter approximately p36.33 and 8q22.3 approximately q23. The breakpoint on p was found to reside very close to the telomere, making this a rare case of "almost pure" trisomy of 8q22.3 approximately q23-qter, without a significant partial 1p36 monosomy by FISH technique. The patient's face resembled the peculiar face in previously reported cases of 8q23-qter duplication. This report supports that critical gene(s) for cardiac septum formation reside on distal chromosome 8q.


The gay adolescent: stressors, adaptations, and psychosocial interventions.
Social stigmatization hinders the ability of gay adolescents to achieve the tasks of adolescence. Because their sexual identity is denigrated by society, these youth have difficulty forming a positive identity and establishing healthy peer and intimate relationships. Family relations are often painful, and gay adolescents are susceptible to loneliness, isolation, depression, and suicide. Validation of these adolescents' affectional and erotic feelings helps to normalize their adolescence, as does providing them with a peer group of other gay youth.


Trends in paediatric clinical pharmacology data in US pharmaceutical labelling.
There is often a lack of safety and efficacy data in the paediatric population at the time of drug approval. Legislative efforts have promoted clinical pharmacology research in this underserved population. We sought to determine the quantity and quality of paediatric clinical pharmacology data in US drug labelling at the time of initial approval and to evaluate trends over time. The labelling data of 213 new molecular entities approved between 2003 and 2012 were systematically reviewed. The type of paediatric pharmacology data present at the time of approval was recorded and stratified by age group. Labelling revisions were analysed for updated paediatric data. The presence of paediatric-specific black-box warnings was noted. Of the 213 drugs evaluated, 48 had adult-specific indications. Of the remaining 165 medicines, only 47 (28%) had paediatric study data at the time of initial labelling. The number of approved drugs with paediatric data was the greatest in 2005 (8, 44%) and was at its lowest point in 2012 (3, 11%). Only five medicines had neonatal data, with none of the anti-infective agents presenting neonatal information. Seven medications had a paediatric-specific black-box warning. Additional 16 medicines presented paediatric data during general labelling updates. Despite efforts to improve the quality of paediatric clinical pharmacology data, there was not a significant increase in drugs with paediatric data at the time of approval over this 10-year study period. Paediatric drug approvals and labelling revisions continue to lag behind their adult counterparts.


A Versatile Ultrasound Simulation System for Education and Training in High-Fidelity Emergency Scenarios.
Point of care ultrasonography and the related focused assessment with sonography for trauma protocol, if performed by experienced physicians, is a highly sensitive examination, and specific for the detection of free fluids. Different systems and methods have been proposed for training, including simulation as one of the most efficient. This paper presents an ultrasound training system, specifically designed to be used during bedside high fidelity simulation scenarios, that could facilitate the learning process. The development of the proposed system exploited novel rapid prototyping electronic boards as a means to obtain good performances with a low cost. Moreover, the design of the data structure permits the construction of a library that caters for individual needs, with the possibility of adding emergency scenarios, collecting pictures or videos, as well as 3-D volumes. The device has been compared with currently commercial ultrasound simulators and its innovative aspects have been highlighted. Finally, it has been tested during a training session in order to evaluate features, such as realism and user-friendliness.


Risk stratification and dental management of the patient with thyroid dysfunction.
The thyroid gland produces hormones critical to the maintenance of the cellular metabolic rate. The actions of these hormones are far-reaching, affecting thermoregulation and calorigenesis; the metabolism of carbohydrates, fats, and proteins; and oxygen utilization. Thyroid hormones also appear to act synergistically with epinephrine and enhance tissue sensitivity to catecholamines. Signs and symptoms of hypothyroidism include listlessness, fatigue, cold intolerance, dry skin, hair loss, constipation, weight gain, muscle soreness, and slow heart rate. Signs and symptoms of hyperthyroidism include irritability, heat intolerance, tremors, increased sweating, frequent bowel movements, and quickened heart rate. The effect of inadequately treated or undiagnosed hyperthyroidism on the heart carries perioperative risks. To provide competent dental care to patients with thyroid dysfunction, clinicians must understand the disease, its treatment, and the impact the disease and its treatment may have on the patient's ability to undergo and respond to dental care.


Challenges in the Management of Geriatric Obesity in High Risk Populations.
The global prevalence of obesity in the older adult population is growing, an increasing concern in both the developed and developing countries of the world. The study of geriatric obesity and its management is a relatively new area of research, especially pertaining to those with elevated health risks. This review characterizes the state of science for this "fat and frail" population and identifies the many gaps in knowledge where future study is urgently needed. In community dwelling older adults, opportunities to improve both body weight and nutritional status are hampered by inadequate programs to identify and treat obesity, but where support programs exist, there are proven benefits. Nutritional status of the hospitalized older adult should be optimized to overcome the stressors of chronic disease, acute illness, and/or surgery. The least restrictive diets tailored to individual preferences while meeting each patient's nutritional needs will facilitate the energy required for mobility, respiratory sufficiency, immunocompentence, and wound healing. Complications of care due to obesity in the nursing home setting, especially in those with advanced physical and mental disabilities, are becoming more ubiquitous; in almost all of these situations, weight stability is advocated, as some evidence links weight loss with increased mortality. High quality interdisciplinary studies in a variety of settings are needed to identify standards of care and effective treatments for the most vulnerable obese older adults.


Diagnostic Potential of Anti-RTE30 Polyclonal Antibodies In A Blocking Elisa For Toxocara canis Detection.
The main etiologic agent of human toxocariasis, a zoonotic disease, is the helminth Toxocara canis. Among the diagnostics used for human toxocariasis, ELISA using T. canis excretion and secretion antigen (TES) is considered as a standard technique. TES antigen requires the cultivation of T. canis larvae, which makes its production difficult. Besides this, the use of TES antigen does not eliminate the cross-reactions with other similar proteins that are produced by other intestinal worms. In this context, recombinant antigens are being tested to improve the diagnosis of human toxocariasis. Herein, we describe the production of polyclonal antibodies against recombinant protein TES30 (pAb-rTES30) and evaluate its use in a blocking ELISA (b-ELISA) using human sera. The b-ELISA showed 95.6% sensitivity and 94.4% specificity. Thus, the b-ELISA using pAb-rTES30 offers a viable option for toxocariasis diagnosis owing to its configuration, which prevents cross-reactivity with non-species-specific antibodies.


Treating and reducing anxiety and pain in the paediatric emergency department-TIME FOR ACTION-the TRAPPED quality improvement collaborative.
In 2013, the TRAPPED-1 survey reported inconsistent availability of pain and distress management strategies across all 15 Canadian paediatric emergency department (PEDs). The objective of the TRAPPED-2 study was to utilize a procedural pain quality improvement collaborative (QIC) and evaluate the number of newly introduced pain and distress-reducing strategies in Canadian PEDs over a 2-year period. A QIC was created to increase implementation of new strategies, through collaborative information sharing among PEDs. In 2015, 11 of the 15 Canadian PEDs participated in the TRAPPED QIC. At the end of the year, the TRAPPED-2 survey was electronically sent to a representative member at each of the 15 PEDs. The successful introduction of the chosen strategies by the QIC was assessed as well as the addition of new strategies per site. The number of new strategies introduced in the participating and nonparticipating QIC sites were described. All 15 PEDs (100%) completed the TRAPPED-2 survey. Overall, 10/11 of QIC-participating sites implemented the strategy they had initially identified. All 15 Canadian PEDs implemented some new strategies during the study period; participants in the QIC reported a mean of 5.2 (1-11) new strategies compared to 2.5 (1-4) in the nonactively participating sites. While all PEDs introduced new strategies during the study, QIC-participating sites successfully introduced the majority of their previously identified new strategies in a short time period. Sharing deadlines and information between centres may have contributed to this success.


The hedgehog morphogen and gradients of cell affinity in the abdomen of Drosophila.
The adult abdomen of Drosophila is a chain of anterior (A) and posterior (P) compartments. The engrailed gene is active in all P compartments and selects the P state. Hedgehog enters each A compartment across both its anterior and posterior edges; within A its concentration confers positional information. The A compartments are subdivided into an anterior and a posterior domain that each make different cell types in response to Hedgehog. We have studied the relationship between Hedgehog, engrailed and cell affinity. We made twin clones and measured the shape, size and displacement of the experimental clone, relative to its control twin. We varied the perceived level of Hedgehog in the experimental clone and find that, if this level is different from the surround, the clone fails to grow normally, rounds up and sometimes sorts out completely, becoming separated from the epithelium. Also, clones are displaced towards cells that are more like themselves: for example groups of cells in the middle of the A compartment that are persuaded to differentiate as if they were at the posterior limit of A, move posteriorly. Similarly, clones in the anterior domain of the A compartment that are forced to differentiate as if they were at the anterior limit of A, move anteriorly. Quantitation of these measures and the direction of displacement indicate that there is a U-shaped gradient of affinity in the A compartment that correlates with the U-shaped landscape of Hedgehog concentration. Since affinity changes are autonomous to the clone we believe that, normally, each cell's affinity is a direct response to Hedgehog. By removing engrailed in clones we show that A and P cells also differ in affinity from each other, in a manner that appears independent of Hedgehog. Within the P compartment we found some evidence for a U-shaped gradient of affinity, but this cannot be due to Hedgehog which does not act in the P compartment.


Central respiratory failure during acute organophosphate poisoning.
Organophosphate (OP) pesticide poisoning is a global health problem with over 250,000 deaths per year. OPs affect neuronal signaling through acetylcholine (Ach) neurotransmission via inhibition of acetylcholinesterase (AChE), leading to accumulation of Ach at the synaptic cleft and excessive stimulation at post-synaptic receptors. Mortality due to OP agents is attributed to respiratory dysfunction, including central apnea. Cholinergic circuits are integral to many aspects of the central control of respiration, however it is unclear which mechanisms predominate during acute OP intoxication. A more complete understanding of the cholinergic aspects of both respiratory control as well as neural modification of pulmonary function is needed to better understand OP-induced respiratory dysfunction. In this article, we review the physiologic mechanisms of acute OP exposure in the context of the known cholinergic contributions to the central control of respiration. We also discuss the potential central cholinergic contributions to the known peripheral physiologic effects of OP intoxication.


Ontogenetic Change in Behavioral Responses to Structural Enrichment From Fry to Parr in Juvenile Atlantic Salmon (Salmo salar L.).
Enrichment is widely used as a tool for studying how changes in environment affect animal behavior. Here, we report an experimental study investigating if behaviors shaped by stimuli from environmental enrichment depending on the stage animals are exposed to enrichment. We used juvenile Atlantic salmon (Salmo salar) in their first autumn. This is a species commonly reared for conservation purposes. Previous work has shown that environmental enrichment had no effect on long-term survival when the fry stage (smaller than 70 mm) was released, but that if late parr stages (larger than 70 mm) are released, enrichment is reported to have a positive effect on smolt migration survival. Here, we explored the effect of enrichment at two different stages of development. Both stages were reared and treated for 7 weeks (fry at 11-18 weeks and parr at 24-31 weeks after hatching) before tested for behavior. Responses known to be associated with exploratory behavior, activity, and stress coping were quantified by testing 18-week-old fry and 31-week-old parr in a six-chamber maze on 7 successive days after rearing in structurally enriched (plastic plants and tubes) or plain impoverished rearing environments. The data show that Atlantic salmon are sensitive to stimuli from structural enrichment when they are parr, but not when in the fry stage. Parr deprived of enrichment (control treatment) were reluctant to start exploring the maze, and when they did, they spent a longer time frozen than enriched parr, suggesting that deprivation of enrichment at this life can be stressful. Our data suggest that structural enrichment could have the potential to improve welfare for salmonids in captivity and for survival of released juvenile salmon if structural enrichment is provided at the parr stage and the fish reared for conservation are released at the parr stage.


Forensic observations and recommendations on sexual and gender based violence in Kenya.
Sexual and Gender Based Violence (SGBV) in Kenya is highly complex requiring a multi-sectoral approach for comprehensive management. This complexity is worsened by the acceptance of Sexual Violence within a patriarchal society, harmful traditional and cultural practices, breakdown of law and order especially during electoral periods, all heightened by abject poverty. There are numerous programs on interventions costing millions in local and foreign currency, however grave gaps still exist at key levels across all sectors even after years of continued intervention. The overall lack of specialist forensic knowledge required to strengthen key service provision contributes to the rise of many parallel and poor quality approaches. The challenges that victims face in accessing justice are tremendous while suspects' rights to a fair trial requires serious evaluation. The value of specialist forensic service provision in achieving Sustainable Development Goal number 16 in Kenya or in a developing country context cannot be underestimated.


Separating fact from fiction: an examination of deceptive self-presentation in online dating profiles.
This study examines self-presentation in online dating profiles using a novel cross-validation technique for establishing accuracy. Eighty online daters rated the accuracy of their online self-presentation. Information about participants' physical attributes was then collected (height, weight, and age) and compared with their online profile, revealing that deviations tended to be ubiquitous but small in magnitude. Men lied more about their height, and women lied more about their weight, with participants farther from the mean lying more. Participants' self-ratings of accuracy were significantly correlated with observed accuracy, suggesting that inaccuracies were intentional rather than self-deceptive. Overall, participants reported being the least accurate about their photographs and the most accurate about their relationship information. Deception patterns suggest that participants strategically balanced the deceptive opportunities presented by online self-presentation (e.g., the editability of profiles) with the social constraints of establishing romantic relationships (e.g., the anticipation of future interaction).


The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.
Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.


Effect of amiloride and some of its analogues of cation transport in isolated frog skin and thin lipid membranes.
The inhibition of short-circuit current (Isc) in isolated frog skin and the induction of surface potentials in lipid bilayer membranes produced by the diuretic drug amiloride and a number of its chemical analogues was studied. The major conclusions of our study are: (a) The charged form of amiloride is the biologically active species. (b) Both the magnitude of Isc and the amiloride inhibitory effect are sensitive to the ionic milieu bathing the isolated skin, and these two features are modulated at separate and distinct regions on the transport site. (c) Amiloride is very specific in its inhibitory interaction with the Na+ transport site since slight structural modifications can result in significant changes in drug effectiveness. We found that substitutions at pyrazine ring position 5 greatly diminish drug activity, while changes at position 6 are less drastic. Alterations in the guanidinium moiety only diminish activity if the result is a change in the spatial orientation of the amino group carrying the positive charge. (d) Amiloride can bind to and alter the charge on membrane surfaces, but this action cannot explain its highly specific effects in biological systems.


Preferential entry of botulinum neurotoxin A Hc domain through intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine.
Botulism, characterized by flaccid paralysis, commonly results from botulinum neurotoxin (BoNT) absorption across the epithelial barrier from the digestive tract and then dissemination through the blood circulation to target autonomic and motor nerve terminals. The trafficking pathway of BoNT/A passage through the intestinal barrier is not yet fully understood. We report that intralumenal administration of purified BoNT/A into mouse ileum segment impaired spontaneous muscle contractions and abolished the smooth muscle contractions evoked by electric field stimulation. Entry of BoNT/A into the mouse upper small intestine was monitored with fluorescent HcA (half C-terminal domain of heavy chain) which interacts with cell surface receptor(s). We show that HcA preferentially recognizes a subset of neuroendocrine intestinal crypt cells, which probably represent the entry site of the toxin through the intestinal barrier, then targets specific neurons in the submucosa and later (90-120 min) in the musculosa. HcA mainly binds to certain cholinergic neurons of both submucosal and myenteric plexuses, but also recognizes, although to a lower extent, other neuronal cells including glutamatergic and serotoninergic neurons in the submucosa. Intestinal cholinergic neuron targeting by HcA could account for the inhibition of intestinal peristaltism and secretion observed in botulism, but the consequences of the targeting to non-cholinergic neurons remains to be determined.


Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression.
Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D2 receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.


hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation.
Human telomerase reverse transcriptase (hTERT) plays an important role in cancer invasion, but the relevant mechanism is not well known. This study aims to investigate the role and mechanism of hTERT in gastric cancer metastasis. Proteomics analysis, qPCR and western blotting were used to screen for hTERT-regulated candidate molecules in gastric cancer invasion. Chromatin immunoprecipitation (ChIP) qPCR was performed to identify the binding sites of hTERT at the regulatory region of the integrin β1 (ITGB1) gene. ChIP assays were further applied to elucidate the transcription factors that bound to the regulatory region. The interactions between hTERT and the transcription factors were tested by co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down experiments. Moreover, the revealed pathway was verified in tumour-bearing nude mice and human gastric cancer tissues. ITGB1 was identified as a downstream gene of hTERT, and there were two hTERT-binding regions within this gene. hTERT alleviated the binding of forkhead box O3 (FOXO3a) to FOXO3a binding element (+9972∼+9978), but it enhanced the binding of forkhead box M1 (FOXM1) to FOXM1 binding element (-1104∼-1109) in ITGB1 gene. Importantly, FOXO3a played a major role in hTERT-induced ITGB1 expression, and the hTERT/murine double minute 2 (MDM2) complex promoted the ubiquitin-mediated degradation of FOXO3a. Moreover, hTERT increased ITGB1 expression in xenograft gastric cancer, and the level of hTERT was positively correlated with that of ITGB1 in human gastric cancer tissues. The hTERT/MDM2-FOXO3a-ITGB1 pathway markedly contributes to hTERT-promoted gastric cancer invasion, suggesting that this pathway might be a novel target for the prevention and treatment of gastric cancer metastasis.


A class of two-sample nonparametric statistics for binary and time-to-event outcomes.
We propose a class of two-sample statistics for testing the equality of proportions and the equality of survival functions. We build our proposal on a weighted combination of a score test for the difference in proportions and a weighted Kaplan-Meier statistic-based test for the difference of survival functions. The proposed statistics are fully non-parametric and do not rely on the proportional hazards assumption for the survival outcome. We present the asymptotic distribution of these statistics, propose a variance estimator, and show their asymptotic properties under fixed and local alternatives. We discuss different choices of weights including those that control the relative relevance of each outcome and emphasize the type of difference to be detected in the survival outcome. We evaluate the performance of these statistics with small sample sizes through a simulation study and illustrate their use with a randomized phase III cancer vaccine trial. We have implemented the proposed statistics in the R package SurvBin, available on GitHub (https://github.com/MartaBofillRoig/SurvBin).


Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
Unexplained left ventricular hypertrophy often prompts the diagnosis of hypertrophic cardiomyopathy, a sarcomere-protein gene disorder. Because mutations in the gene for AMP-activated protein kinase gamma2 (PRKAG2) cause an accumulation of cardiac glycogen and left ventricular hypertrophy that mimics hypertrophic cardiomyopathy, we hypothesized that hypertrophic cardiomyopathy might also be clinically misdiagnosed in patients with other mutations in genes regulating glycogen metabolism. Genetic analyses performed in 75 consecutive unrelated patients with hypertrophic cardiomyopathy detected 40 sarcomere-protein mutations. In the remaining 35 patients, PRKAG2, lysosome-associated membrane protein 2 (LAMP2), alpha-galactosidase (GLA), and acid alpha-1,4-glucosidase (GAA) genes were studied. Gene defects causing Fabry's disease (GLA) and Pompe's disease (GAA) were not found, but two LAMP2 and one PRKAG2 mutations were identified in probands with prominent hypertrophy and electrophysiological abnormalities. These results prompted the study of two additional, independent series of patients. Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, > or =30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2. Genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations. Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of two serum proteins. LAMP2 mutations typically cause multisystem glycogen-storage disease (Danon's disease) but can also present as a primary cardiomyopathy. The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation.


Calcium uptake and release by isolated cortices and microsomes from the unfertilized egg of the sea urchin Strongylocentrotus droebachiensis.
Isolated cortices from unfertilized sea urchin eggs sequester calcium in an ATP-dependent manner when incubated in a medium containing free calcium levels characteristic of the resting cell (approximately 0.1 microM). This ATP-dependent calcium uptake activity was measured in the presence of 5 mM Na azide to prevent mitochondrial accumulation, was increased by oxalate, and was blocked by 150 microM quercetin and 50 microM vanadate (known inhibitors of calcium uptake into the sarcoplasmic reticulum). Cortical regions preloaded with 45Ca in the presence of ATP were shown to dramatically increase their rate of calcium efflux upon the addition of (a) the calcium ionophore A23187 (10 microM), (b) trifluoperazine (200 microM), (c) concentrations of free calcium that activated cortical granule exocytosis, and (d) the calcium mobilizing agent inositol trisphosphate. This pool of calcium is most likely sequestered in the portion of the egg's endoplasmic reticulum that remains associated with the cortical region during its isolation. We have developed a method for obtaining a high yield of purified microsomal vesicles from whole eggs. This preparation also demonstrates ATP-dependent calcium sequestering activity which increases in the presence of oxalate and has similar sensitivities to calcium transport inhibitors; however, the isolated microsomal vesicles did not show any detectable release of calcium when exposed to inositol trisphosphate.


t-PA, but not desmoteplase, induces plasmin-dependent opening of a blood-brain barrier model under normoxic and ischaemic conditions.
Tissue-type plasminogen activator (t-PA) is the only thrombolytic treatment available for patients with acute ischaemic stroke. However, t-PA can increase permeability of the blood-brain barrier (BBB). Desmoteplase is a plasminogen activator derived from the common vampire bat, currently under clinical development for ischaemic stroke. We compared how t-PA and desmoteplase influenced BBB permeability using a human in vitro model where primary brain endothelial cells (BEC) and astrocytes are co-cultured on the opposite sides of a porous membrane. Permeability changes were evaluated 6 or 24h post-stimulation by passage of fluorescent albumin across the membrane. Under normoxic conditions, t-PA, but not desmoteplase, increased BBB permeability. Surprisingly, the ability of t-PA to affect the barrier was lost under conditions of oxygen-glucose deprivation (OGD). Addition of plasminogen re-sensitised the BBB to the action of t-PA under both normoxia and OGD, but did not affect the inert behaviour of desmoteplase, even when digested fibrinogen was added to ensure optimal plasmin generation. These observations coincided with plasmin-dependent changes in astrocyte and BEC morphology and disruption of tight junction proteins in BECs, specifically initiated by t-PA but not by desmoteplase. Finally, inhibition of plasmin post-stimulation with t-PA and plasminogen, especially within 2h, protected the BBB against t-PA-mediated barrier opening. Hence t-PA, but not desmoteplase, increases BBB permeability under both normoxic and OGD conditions in a reversible, plasmin-dependent process. The inability of desmoteplase to increase permeability despite its capacity to generate plasmin provides further support for its use as thrombolytic in patients with ischaemic stroke.


Evidence for second metabolic pathway for O2 from PtiO2 measurements in denervated cat carotid body.
O2 microelectrode studies were conducted in the cat carotid body (CB) to investigate the hypothesis that there is a second, low affinity metabolic pathway for O2 in addition to classical oxidative metabolism. Tissue PO2 (PtiO2) and O2 disappearance rates (dPO2/dt) after brief blood flow occlusion were measured with recessed cathode microelectrodes (tip diameter less than 5 microns) at 150 sites in 15 normal cats (controls) and at 154 sites in 5 cats in which one CB had been denervated 2 or 3 days before the experiments. Mean PtiO2 was slightly higher in denervated CBs: 79.6 +/- 1.6 (SE) Torr compared with 76.4 +/- 2.0 Torr for controls (P = not significant). Mean dPO2/dt was 8.4% faster: -8.42 +/- 0.28 Torr/s compared with -7.77 +/- 0.43 Torr/s for controls (P less than 0.05). The O2 consumption rate (VO2), calculated from dPO2/dt correcting for cat oxyhemoglobin, was 7.5% higher: 1.62 and 1.51 ml.100 g-1.min-1, respectively, for denervated and control CBs (P less than 0.05). The apparent Michaelis-Menten constant, Kmapp (defined as the PtiO2 where dPO2/dt decreased by 50% from the initial rate during the first 3 s after occlusion) was determined for each O2 disappearance curve. After denervation, Kmapp decreased significantly by -47%: 12.0 +/- 1.3 Torr compared with 22.6 +/- 2.5 Torr for controls (P less than 0.01). The data provide evidence for a second metabolic pathway for O2 in the CB that loses its influence on VO2 after denervation.


Internet-based interventions for behavioral addictions: A systematic review.
Behavioral addictions are a public health problem that causes harm to both individuals and society. Internet-based interventions offer potential benefits over face-to-face therapy for the treatment of behavioral addictions, including their accessibility, perceived anonymity, and low costs. We systematically reviewed the characteristics and effectiveness of these interventions. A systematic literature search was conducted in: PubMed, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials. A standardized methodological quality assessment was performed on all identified studies via the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool. Twenty-nine studies were assessed in this systematic review. Between them, considerable heterogeneity was noted in various study characteristics, including screening tools, inclusion criteria, and outcome measures. Attrition rates also ranged widely (9-89%), as did study quality, with three of the 29 studies rated strong, 12 moderate, and 14 weak methodologically. Twenty-two studies focused on gambling disorder, most revealing significant within-group effects for the assessed intervention on gambling-related symptoms and four of these studies identified significant between-group effects. Behavioral addictions studied in the remaining studies included gaming disorder, internet use disorder, hoarding disorder, and pornography use disorder, revealing generally-promising, albeit limited results. Internet-based interventions seem promising at reducing gambling problems, but too few studies have been published, to date, for conclusions to be drawn for other behavioral addictions. Internet-based interventions targeting other behavioral addictions - like gaming disorder, internet use disorder, hoarding disorder, and pornography use disorder - remain under-examined, warranting considerable additional research to assess their effectiveness.


An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients.
Validating prognostic or predictive candidate genes in appropriately powered breast cancer cohorts are of utmost interest. Our aim was to develop an online tool to draw survival plots, which can be used to assess the relevance of the expression levels of various genes on the clinical outcome both in untreated and treated breast cancer patients. A background database was established using gene expression data and survival information of 1,809 patients downloaded from GEO (Affymetrix HGU133A and HGU133+2 microarrays). The median relapse free survival is 6.43 years, 968/1,231 patients are estrogen-receptor (ER) positive, and 190/1,369 are lymph-node positive. After quality control and normalization only probes present on both Affymetrix platforms were retained (n = 22,277). In order to analyze the prognostic value of a particular gene, the cohorts are divided into two groups according to the median (or upper/lower quartile) expression of the gene. The two groups can be compared in terms of relapse free survival, overall survival, and distant metastasis free survival. A survival curve is displayed, and the hazard ratio with 95% confidence intervals and logrank P value are calculated and displayed. Additionally, three subgroups of patients can be assessed: systematically untreated patients, endocrine-treated ER positive patients, and patients with a distribution of clinical characteristics representative of those seen in general clinical practice in the US. Web address: www.kmplot.com . We used this integrative data analysis tool to confirm the prognostic power of the proliferation-related genes TOP2A and TOP2B, MKI67, CCND2, CCND3, CCNDE2, as well as CDKN1A, and TK2. We also validated the capability of microarrays to determine estrogen receptor status in 1,231 patients. The tool is highly valuable for the preliminary assessment of biomarkers, especially for research groups with limited bioinformatic resources.


[Examination of formula for enhanced dynamic wedge factors in symmetric and asymmetric fields].
We proposed a formula for the enhanced dynamic wedge (EDW) factor in the half-field (HF) that combined the formula proposed by Liu et al. in 1998 and their formula in 2003. When the EDW was used for irradiation to the tangent line of the HF breast, the values calculated by our formula and the measured values were consistent within 0.5%. We showed that our proposed formula was useful, easy to use, and more accurate than the conventional formula. The purpose of this study was to examine the available range of the wedge factor of symmetrical and asymmetric EDW calculated by our formula. As a result of the examination, the values calculated by our formula and the measured values were consistent within 2% except for highly asymmetric EDW. We created a spreadsheet to calculate the wedge factor easily and accurately. We will examine the reason why the calculated and measured values were greater than 2%, and improve our formula so that it can be used in a wider range.


Direction discrimination thresholds of vestibular and cerebellar nuclei neurons.
To understand the roles of the vestibular system in perceptual detection and discrimination of self-motion, it is critical to account for response variability in computing the sensitivity of vestibular neurons. Here we study responses of neurons with no eye movement sensitivity in the vestibular (VN) and rostral fastigial nuclei (FN) using high-frequency (2 Hz) oscillatory translational motion stimuli. The axis of translation (i.e., heading) varied slowly (1 degrees /s) in the horizontal plane as the animal was translated back and forth. Signal detection theory was used to compute the threshold sensitivity of VN/FN neurons for discriminating small variations in heading around all possible directions of translation. Across the population, minimum heading discrimination thresholds averaged 16.6 degrees +/- 1 degrees SE for FN neurons and 15.3 degrees +/- 2.2 degrees SE for VN neurons, severalfold larger than perceptual thresholds for heading discrimination. In line with previous studies and theoretical predictions, maximum discriminability was observed for directions where firing rate changed steeply as a function of heading, which occurs at headings approximately perpendicular to the maximum response direction. Forward/backward heading thresholds tended to be lower than lateral motion thresholds, and the ratio of lateral over forward heading thresholds averaged 2.2 +/- 6.1 (geometric mean +/- SD) for FN neurons and 1.1 +/- 4.4 for VN neurons. Our findings suggest that substantial pooling and/or selective decoding of vestibular signals from the vestibular and deep cerebellar nuclei may be important components of further processing. Such a characterization of neural sensitivity is critical for understanding how early stages of vestibular processing limit behavioral performance.