Assessment of viral presence in semen and reproductive function of frozen-thawed spermatozoa from Pallas' cats (Otocolobus manul) infected with feline herpesvirus.
Although herpesviruses are known to contaminate the semen of several mammalian species, the occurrence of feline herpesvirus type 1 (FHV-1) in semen of infected cats has not been reported. Our objectives in this study were to investigate the presence of FHV-1 DNA in seminal fluid and frozen-thawed spermatozoa from FHV-1 infected Pallas' cats (Otocolobus manul) and assess the functionality of their frozen-thawed spermatozoa in vitro. Over a 3-yr period, semen (n = 33 ejaculates) was collected periodically via electroejaculation from four Pallas' cats chronically infected with FHV-1. Spermic ejaculates were frozen by pelleting on dry ice and stored in liquid nitrogen. After thawing, sperm motility and acrosome status were assessed over time during in vitro culture. For vitro fertilization (IVF), viable domestic cat (Felis silvestris catus) oocytes were inseminated with frozen-thawed Pallas' cat spermatozoa and evaluated for embryo cleavage. For FHV-1 polymerase chain reaction (PCR) analysis, DNA was extracted from seminal fluid, frozen-thawed spermatozoa, inseminated oocytes, heterologous IVF embryos, and conjunctival biopsies and analyzed for presence of a 322-base pair region of the FHV-1 thymidine kinase gene. Immediately post-thaw, sperm motility and percentage of intact acrosomes were decreased (P < 0.05) compared to fresh samples, and declined further (P < 0.05) during culture. However, all frozen-thawed IVF samples were capable of fertilizing domestic cat oocytes (overall, 46.1 +/- 6.0% cleavage). PCR analysis did not identify FHV-1 DNA in any reproductive sample despite the repeated detection of FHV-1 DNA in conjunctival biopsies. These results suggest that semen collected from Pallas' cats infected with FHV-1 does not contain cell-associated or non-cell-associated virus and that frozen-thawed spermatozoa exhibit adequate function for potential genetic rescue with minimal risk of FHV-1 transmission.


The role and significance of nurses in managing transitions to palliative care: a qualitative study.
Nurses are generally present, and often influential, in supporting patient and family acceptance of medical futility and in assisting doctors in negotiating referral to palliative care. Yet the specificities of the nursing role and how nurses may contribute to timely and effective referrals is not well understood. This study aimed to systematically explore hospital-based nurses' accounts of the transition to palliative care, and the potential role of nurses in facilitating more effective palliative care transitions. Qualitative study using semistructured interviews. Two health services with public as well as private clinical environments in a major metropolitan area of Australia. Hospital-based nurses (n=20) who regularly work with patients at the point of referral and in managing transitions to palliative care. Four significant themes emerged from thematic analysis. These include: (1) professional dynamics and the roles played by nurses in initiating the transition to palliative care; (2) the value of nurses' informal interactions in timely and effective transitions; (3) the emerging challenge of managing task-oriented nursing versus intense emotional nursing work at the point of medical futility and (4) the emotional burden experienced by nurses within this clinical context. Nurses self-reported occupying critical albeit complex roles in the management of medical futility and the transition to palliative care. They reported experiencing significant emotional burden in balancing interpersonal and interprofessional relationships during this time. The results suggest that nurses may be utilised in a more formalised and systematic fashion in the context of managing medical futility and the need to topicalise the transition, with the focus shifted away from medical referrals towards more team-based and patient-centred timely transitions. Further research focused on the experiences of doctors, allied health professionals, patients and families is required to provide a broader interdisciplinary understanding of futility and contributions to the negotiation of palliative care.


Changes in Pelvic Incidence, Pelvic Tilt, and Sacral Slope in Situations of Pelvic Rotation.
Digitally reconstructed radiograph-based study. Using a computer-based method to determine what degree of pelvic rotation is acceptable for measuring the pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). The effectiveness of a geometrical formula used to calculate the angle of pelvic rotation proposed in a previous article was assessed. It is unclear whether PI, PT, and SS are valid with pelvic rotation while acquiring a radiograph. Ten 3-dimensionally reconstructed models were established with software and placed in a neutral orientation to orient all of the bones in a standing position. Next, 140 digitally reconstructed radiographs were obtained by rotating the models around the longitudinal axis of each pelvis in the software from 0 to 30 degrees at 2.5-degree intervals. PI, PT, and SS were measured. The rotation angle was considered to be acceptable when the change in the measured angle (compared with the "correct" position) was <6 degrees. The rotation angle (α) on the images was calculated by a geometrical formula. Consistency between the measured value and the set angle was assessed. The acceptable maximum angle of rotation for reliable measurements of PI was 17.5 degrees, and the changes in PT and SS were within an acceptable range (<6 degrees) when the pelvic rotation increased from 0 to 30 degrees. The effectiveness of the geometrical formula was shown by the consistency between the set and the calculated rotation angles of the pelvis (intraclass correlation coefficient=0.99). Our study provides insight into the influence of pelvic rotation on the PI, PT, and SS. PI changes with pelvic rotation. The acceptable maximum angle for reliable values of PI, PT, and SS was 17.5 degrees, and the rotation angle of the pelvis on a lateral spinopelvic radiograph can be calculated reliably.


Return to work following a distal biceps repair: a systematic review of the literature.
Among an active aging population, distal biceps tendon ruptures are becoming increasingly common. Typically, they are the result of an acute heavy eccentric load being placed on an already contracted muscle, and surgery is the gold standard treatment for optimal clinical and functional outcomes. Although improved strength has been shown after operative repair, there is little evidence available regarding a timeframe for return to work-related activity. The purpose of this study was to conduct a systematic review of the literature to provide guidance for return to work after a distal biceps repair. The authors searched online databases (EMBASE, MEDLINE) from inception until October 11, 2018, for literature pertaining to functional outcomes after distal biceps repair. Study inclusion and exclusion criteria were established a priori and applied in duplicate independently by 2 reviewers. Of the 480 initial studies, 40 papers satisfied full text inclusion criteria (19 case control studies, 12 retrospective reviews, 9 prospective reviews). A total of 1270 patients with 1280 distal bicep ruptures were included in the study. The mean age of patients was 45.38 years, and 97% (n = 1067) of reported patients were male. The mean follow-up time was 30 months (range, 6-84 months). After distal biceps repair, 1128 (89%) of patients were able to fully return to work without any modification of duties. Time to return to work was reported in 17 of the included studies with a mean of 14.37 ± 0.52 weeks. The average time to return to work after distal biceps repair in the literature was just beyond 14 weeks. Patients and employers may be given a range between 3 and 4 months, with variation dependent on job demands. Further studies are needed to establish whether the surgical approach or repair technique has any impact on time to return to work.


Role and potentials of low-flow CO(2) removal system in mechanical ventilation.
An analysis of the technological implementation of extracorporeal CO(2) removal (ECCO(2)R) techniques and of its clinical application. A new classification of ECCO(2)R, based on technological aspects, clinical properties and physiological performance, is proposed. The use of a ventilation with lower tidal volumes has been proved successful in acute respiratory distress syndrome (ARDS) patients but can be extremely problematic, especially when dealing with respiratory acidosis. The implementation of ECCO(2)R devices can represent the missing link between the prevention of ventilator-induced lung injury and pH control. ECCO(2)R has attracted increasing interest because of new less-invasive approaches allowing an easier management of ARDS patients. Recent studies have also shown that ECCO(2)R can also be used in patients with exacerbation of chronic obstructive pulmonary disease (COPD) and as a bridge to lung transplantation. The future ventilatory management of patients with acute respiratory failure may include a minimally invasive extracorporeal carbon dioxide removal circuit associated with the least amount of ventilatory support (noninvasive in COPD and/or invasive in ARDS) to minimize sedation, prevent ventilator-induced acute lung injury and nosocomial infections. Randomized clinical trials in the pipeline will confirm this fascinating hypothesis.


Management and future directions in non-small cell lung cancer with known activating mutations.
Lung cancer accounts for a quarter of all cancer deaths. Non-small cell lung cancer (NSCLC) is currently segregated by the presence of actionable driver oncogenes. This review will provide an overview of molecular subsets of lung cancer, including descriptions of the defining oncogenes (EGFR, ALK, KRAS, ROS1, RET, BRAF, ERBB2, NTRK1, FGFR, among others) and how these predict for response to small molecule tyrosine kinase inhibitors (TKIs) that are either clinically available or in clinical trial development for advanced NSCLC. Particular focus will be placed on subsets with EGFR mutated and ALK rearranged NSCLC. Somatic TKI-sensitizing EGFR mutations (such as exon 19 deletions and L858R substitutions) are the most robust predictive biomarker for symptom improvement, radiographic response, and increment in progression-free survival (PFS) when EGFR TKIs (gefitinib, erlotinib, and afatinib) are used for patients with advanced NSCLC. However, the palliative benefits that EGFR TKIs afford are limited by multiple biologic mechanisms of tumor adaptation/resistance (such as the EGFR-T790M mutation and oncogene bypass tracks), and future efforts toward delaying, preventing, and treating resistance are underway. Similar to EGFR mutations, ALK rearrangements exemplify an oncogene-driven NSCLC that can be effectively palliated with a precision TKI therapy (the multitargeted ALK/MET/ROS1 TKI crizotinib). When resistance to first-line crizotinib therapy occurs, multiple second generation ALK TKIs have demonstrated impressive rates of disease control in clinical trials, and these may modify long-term outcomes for patients with ALK-positive NSCLC. The development of TKIs for other oncogene-driven NSCLCs may expand the portfolio of precision therapies for this recalcitrant cancer.


A selection study on a laboratory-designed population of salmon lic (Lepeophtheirus salmonis) using organophosphate and pyrethroid pesticides.
Resistance towards antiparasitic agents in the salmon louse (Lepeophtheirus salmonis) is a widespread problem along the Norwegian coast, reducing treatments efficacies and slowing down the envisioned expansion of Norwegian salmon production. The present study was conducted in order to assess the efficacies of two of the most widely used anti-parasitic substances-azamethiphos and deltamethrin-as well as assessing the benefit of having a resistant genotype compared to being fully sensitive when exposed to one of these substances. Atlantic salmon were exposed to a mix of salmon lice copepodids from a fully sensitive, a double resistant and a multi-resistant strain. Once the lice reached pre-adult stages, one group was exposed to 100 μg/L azamethiphos for 60 minutes, the other to 2 μg/L deltamethrin for 30 minutes, and the last was kept in a seawater control. Detached lice were collected at a series of time points following exposure, and all lice (immobilized and surviving) were analysed for both pyrethroid (sensitive "S" and resistant "R") and azamethiphos (fully sensitive "SS", heterozygous resistant "RS" and fully resistant "RR") resistance markers. We found that the efficacies of deltamethrin on parasites with genotype S and R were 70.3 and 13.2%, respectively. The overall efficacy of the deltamethrin treatment was 32.3%. The efficacies of azamethiphos on parasites with genotype SS, RS and RR were 100, 80 and 19.1%, respectively. The overall efficacy of the azamethiphos treatment was 80.4%. Survival analyses revealed that the median survival time in deltamethrin-sensitive and-resistant parasites were 16.8 and >172 hours, respectively. The differences were even more pronounced in the azamethiphos-treated group, where SS, RS and RR parasites survived for 0.26, 6.6 and >172 hours, respectively. The substantial differences in survival between sensitive and resistant lice following treatment demonstrate the ability of medicinal treatments to drive genetic selection towards a much more resistant salmon lice population within a very short time span if there is no influx of sensitive genotypes.


Intestinal permeability in patients with coeliac disease and dermatitis herpetiformis.
Intestinal permeability was investigated in patients with coeliac disease and dermatitis herpetiformis by a 51Chromium-labelled ethylenediaminetetraacetate (51Cr-EDTA) absorption test and the results correlated with histomorphometric analysis and intraepithelial lymphocyte counts of jejunal biopsies. The mean (+/- SD) 24 hour urine excretion of 51Cr-EDTA in 34 healthy volunteers was 1.9 +/- 0.5% of the orally administered test dose. Patients with untreated coeliac disease (19) or untreated dermatitis herpetiformis (five) excreted significantly more 51Cr-EDTA than controls (5.9 +/- 2.7% and 4.6 +/- 2.1%, respectively, p less than 0.001) and all were outside the normal range of 1.0-2.6%. Patients with coeliac disease (42) treated for 6 months-23 years (mean 5 years) and patients with dermatitis herpetiformis (11) treated for 6 months-8 years (mean 3 years) excreted significantly more 51Cr-EDTA than controls, 4.2 +/- 2.4% p less than 0.0001 and 3.0 +/- 0.9% p less than 0.003 respectively. Eleven of 14 (79%) treated patients with coeliac disease with an entirely normal jejunal mucosae demonstrated abnormal intestinal permeability. Intestinal permeability did not correlate significantly with either the mucosal height/crypt depth ratio or intraepithelial lymphocyte counts in jejunal biopsies from patients with untreated or treated coeliac disease. The demonstration of a persistent increase in intestinal permeability in patients with both coeliac disease and dermatitis herpetiformis may suggest a common pathogenetic mechanism in both disorders. It is postulated that altered permeability may facilitate the entry of gluten or a fraction thereof into the lamina propria where it causes a cascade of immunological events.


Endoluminal stent placement and coil embolization for the management of carotid artery pseudoaneurysms.
To present a series of carotid artery pseudoaneurysms treated successfully using an endovascular approach. From April 1995 to November 1999, 5 patients with neurological symptoms not explained by computed tomography of the head were identified by carotid angiography as having internal carotid artery (ICA) pseudoaneurysms. Three patients had sustained blunt trauma, and 2 had previous elective carotid endarterectomies for atherosclerotic disease. The time between injury and treatment ranged from 3 days to 10 years. The patients were treated with endovascular stent placement for exclusion of the pseudoaneurysm, followed by filling of the cavity with multiple detachable coils. Patients were maintained on oral antiplatelet agents or anticoagulant therapy after the procedure. Primary technical success was 100%. No patient suffered permanent neurological sequelae. Postprocedure angiography demonstrated a patent ICA in all cases, with complete obliteration of the pseudoaneurysm. At a mean 8.4-month follow-up (range 2-21), all patients remained symptom free; angiograms in 3 patients at a mean 11.7 months demonstrated continued ICA patency. One patient had a 60% focal narrowing of the distal common carotid artery, which was treated successfully with balloon dilation and stenting. Endovascular treatment of carotid artery pseudoaneurysms is a useful alternative to standard surgical repair. This modality avoids the necessity for surgical exposure at the skull base with its inherent morbidity.


Early Detection of Circulating Antigen and IgM-Associated Immune Complexes during Experimental Mycobacterium bovis Infection in Cattle.
The presence of circulating antigen in cattle experimentally infected with Mycobacterium bovis was demonstrated using dual-path platform (DPP) technology. The antigen capture immunoassays employed rabbit polyclonal antibody recognizing predominantly M. tuberculosis complex-specific epitopes and were able to detect soluble substances and whole cells of mycobacteria. The antigen found in serum appeared to be mostly bound to IgM, but not to IgG, within the immune complexes formed at early stages of M. bovis infection. The antigen was also detected in bile and urine, indicating possible clearance pathways. The data correlation analyses supported the idea of the role of IgM responses in antigen persistence during M. bovis infection. The antigen was detectable in serum months prior to detectable antibody seroconversion. This proof-of-concept study suggested the potential for improved immunodiagnostics for bovine tuberculosis.


Stimulating oxytocin receptors in the basolateral amygdala enhances stimulus processing: Differential and consistent effects for stimuli paired with fear versus sucrose in extinction and reversal learning.
Oxytocin (OT) influences a range of social behaviors by enhancing the salience of social cues and regulating the expression of specific social behaviors (e.g., maternal care versus defensive aggression). We previously showed that stimulating OT receptors in the basolateral amygdala of rats also enhanced the salience of fear conditioned stimuli: relative to rats given vehicle infusions, rats infused with [Thr4,Gly7]-oxytocin (TGOT), a selective OT receptor agonist, showed greater discrimination between a cue predictive of danger, and one that signaled safety. In the present series of experiments using male rats, the effects of OT receptor activation in the basolateral amygdala on stimulus processing were examined further using conditioning protocols that consist of changes in stimulus-outcome contingencies (i.e., extinction and reversal), and with stimuli paired with aversive (i.e., foot shock) and appetitive (i.e., sucrose) outcomes. It was revealed that the effects of OTR stimulation diverge for aversive and appetitive learning - enhancing the former but not the latter. However, across both types of learning, OTR stimulation enhanced the detection of conditioned stimuli. Overall, these results are consistent with an emerging view of OT's effects on stimulus salience; facilitating the detection of meaningful stimuli while reducing responding to those that are irrelevant.


Neural Foundations of Creativity: A Systematic Review.
When considering the importance of the human cognitive function of creativity, we often overlook the fact that it is due to human creativity and to the constant search for new sensory stimuli that our world has, throughout the years, been one of innovation in every aspect of our existence -in the sciences, the humanities, and the arts. Almost everything that surrounds us is the result of human creativity, therefore it is not difficult to understand that although neuroscientific research has led to valuable perceptions into the probable underpinnings of this multifaceted ability, the precise neurological substrates that underlie creativity are yet to be determined. Despite the establishment of a strong link between creativity and divergent thinking, other brain networks have been implicated in this mental process. The following review underlines recent studies on the neural foundations of creativity. A comprehensive analysis of the upmost important facts will be presented, with emphasis on concepts, tests, and methods that have been used to study creativity, and how they have outlined a pathway to the key understanding of this unique human ability.


Elastic properties of Thiel-embalmed human ankle tendon and ligament.
Thiel embalming is recommended as an alternative to formalin-based embalming because it preserves tissue elasticity, color, and flexibility in the long term, with low infection and toxicity risk. The degree to which Thiel embalming preserves elasticity has so far been assessed mainly by subjective scoring, with little quantitative verification. The aim of this study is to quantify the effect of Thiel embalming on the elastic properties of human ankle tendons and ligament. Biomechanical tensile tests were carried out on six Thiel-embalmed samples each of the peroneus longus, peroneus brevis, and calcaneal tendons, and the calcaneofibular ligament, with strain rates of 0.25%s(-1), 2%s(-1), and 8%s(-1). The stress-strain relationship was calculated from the force-extension response with cross-sectional area and gauge length. Young's modulus was determined from the stress-strain curve. The results showed that the tendon and ligament elasticity were lower after Thiel embalming than the literature values for fresh nonembalmed tendons and ligament. The biomechanical tensile test showed that the measured elasticity of Thiel-embalmed tendons and ligaments increased with the strain rate. The Thiel embalming method is useful for preserving human ankle tendons and ligaments for anatomy and surgery teaching and research, but users need to be aware of its softening effects. The method retains the mechanical strain rate effect on tendons and ligament.


Right ventricular dysfunction in early systemic hypertension: a tissue Doppler imaging study in patients with high-normal and mildly increased arterial blood pressure.
To analyze the relationship between increasing systemic blood pressure (BP) and right ventricular (RV) function. Ninety-eight never-treated, nonobese patients with BP values varying from the optimal to the mild hypertensive range. Peak early diastolic (Em) and systolic (Sm) velocities were recorded at the tricuspid and mitral annuli by tissue Doppler imaging (TDI); global RV and left ventricular (LV) structure and function by conventional echo-Doppler sonography; insulin sensitivity by homeostasis model assessment (HOMA) index. Data were analyzed by 24-h systolic BP (cut-offs 117 and 130 mmHg), thus partitioning an optimal BP from an intermediate high-normal and an upper mildly increased BP stratum. Em decreased in the mid-third and decelerated further in association with reduced Sm in the upper BP tertile; both correlated negatively to septal thickness and positively to homologous TDI-derived LV indices. RV and LV indices of global ventricular function, estimated pulmonary pressure, HOMA did not differ by systemic BP. RV diastolic and systolic function deteriorates in response to slightly increased systemic BP. The process paralleled homologous changes at the LV side and was driven by interventricular septum remodeling, perhaps as a reflection of its role in RV function and biventricular interdependence. Insulin sensitivity seemed to play no relevant role.


Characterizing gaze and postural stability deficits in people with multiple sclerosis.
People with Multiple Sclerosis (PwMS) experience a wide range of symptoms that can alter function and limit activity and community participation. Symptoms including sensory changes, weakness, fatigue and others have been well documented. However, symptoms related to changes in vestibular related function, including gaze and postural stability have not been fully explored. While some recent studies have begun to provide insight into these deficits in PwMS and have explored the use of rehabilitation paradigms for their management, much remains unknown about the full extent of these deficits. Therefore, this study aimed to characterize the presence of gaze and postural stability deficits in measures across the World Health Organization International Classification of Functioning, Disability, and Health (WHO ICF) and to examine how deficits in domains of body structure and function and activity contribute to participation level limitations. Baseline data from 41 PwMS (mean(SD) age = 53.9(11.2), 78% female) enrolled as part of a randomized clinical trial were used in this analysis. Measures of gaze and postural stability from the ICF domains of body structure and function (Vestibular ocular reflex [VOR] gain and postural sway area), activity (computerized dynamic visual acuity [cDVA] and MiniBEST test), and participation (Dizziness handicap inventory [DHI] and Activities Balance Confidence [ABC] scale) along with demographic data were used to characterize the sample. To explore relationships between ICF domains for gaze and postural stability, univariate correlations were performed between measures from each domain using Pearson's correlations. Separate multivariate regression models examined how measures from the body structure and function and activity domains contributed to the variance in the participation level outcomes. Variance explained by the models was quantified using R-squared statistic and contribution of the independent variables were quantified using the beta coefficient (p < 0.05). Correlation analysis demonstrated significant relationships in the postural stability measures across domains. Specifically, between postural sway area on a firm surface and MiniBEST test score (r = -.48;p < 0.01) and MiniBEST test score and ABC score (r = 0.5;p < 0.01). Significant correlations were also found between the gaze stability measures of horizontal and vertical VOR gain (r = .68;p < 0.001), horizontal VOR gain and dynamic visual acuity (r = .38;p = 0.02), and vertical VOR gain and dynamic visual acuity (r = .54;p < 0.001). Regression models assessing postural stability, found that only the MiniBEST score significantly contributed to the variance in ABC score (p = 0.01) and the full model explained 34% of the variance in ABC score. Regression modeling of gaze stability outcomes did not produce any variable that significantly contributed to the variance in DHI score and the full model explained 18% of the variance in DHI score. PwMS in this sample demonstrated deficits in gaze and postural stability across the domains of the WHO ICF compared to past samples of PwMS and healthy cohorts. Correlation between measures in the different domains were present, but no strong relationship between measures of body structure and function, activity and participation level outcomes were observed. This lack of relationship across the domains is likely contributed to the relatively small sample size, the high level of variability observed in the outcomes, and the diverse presentation often seen in PwMS.


Identification and methods for prevention of Enterococcus mundtii infection in silkworm larvae, Bombyx mori, reared on artificial diet.
Previously, it was reported that Enterococcus mundtii (E. mundtii) was associated with flacherie disease of silkworm larvae reared on artificial diet. In this study, we report that E. mundtii was isolated from diseased silkworm larvae, and validated as a pathogenic bacterium of the animal. When silkworm larva was infected with 1.04 × 10⁶ colony-forming units of E. mundtii via oral administration of diet, half population died within six days, indicating that the bacterium is pathogenic to silkworm. Less severe infection was found to cause anorexia and hamper the development of larvae. This pathogen was found to proliferate in both time- and dose-dependent manner in the gastrointestinal tract of the animal. The bacterium was isolated from powder of artificial diet made from mulberry leaves, and from mulberry leaves growing at a field. Minimum inhibitory concentration determination revealed that this bacterium was susceptible to tested antibiotics. Vancomycin treatment of diet significantly decreased the number of E. mundtii in intestine of silkworm larvae infected with the bacteria, compared to control. Furthermore, autoclaving or gamma ray irradiation of diet was also effective for exclusion of E. mundtii from the diet without the loss of its nutrient capacities. These results suggest that mulberry leaves used in making artificial diet for silkworm larvae is one of the sources of E. mundtii infection; and that antibiotic treatment, autoclaving or gamma ray irradiation of artificial diet can exclude the bacteria.


[Perception on and registration of alcohol abuse and alcohol-related diseases at a university general hospital].
The high frequency of alcohol related problems highlights the importance of its approach. The association of both the alcohol-abuse and alcohol related diseases has been pointed in the literature and are often the main reason for hospitalization. Physicians use different tools to detect abusive drinkers, and one of them is the CAGE-test, validated by Mayfield et al. in 1974. To study the association between the result of the CAGE-test and the perception and registration of alcohol abuse by the medical staff and the nurses in charge of inpatients of Hospital de Clínicas de Porto Alegre, southern Brazil. The design involved three phases. First, the application of the CAGE-test to the 385 eligible patients. Second, review of all 51 CAGE-positive patients' records as well the controlled evaluation of 51 randomized CAGE-negative patients, to seek alcoholic habits and alcohol-related diseases. Third, interview with the medical staff to find out their perception about these subjects. We found 51 patients CAGE-positive (prevalence = 13%). When evaluated through the registration and through a standardized interview, medical staff and nurses were not aware of more than half of CAGE-positive patients. No significant differences were found between medical staff registration and perception; the prevalence of alcohol related diseases was the same for both: 26 and 27% (p = .861). The prevalence of alcohol related diseases was higher among CAGE-positive patients (p = .0003). In spite of the high prevalence among our patients, alcohol abuse is not pursued by our health teams as it should be. As for the future, there is reason to envision a continuing alcoholism rapprochement.


[The influence of a low- and high-frequency electromagnetic fields on seeds].
It was shown that the exposure of seeds in the rest phase to a low-frequency pulse electromagnetic field leads to substantial changes in seed physiology during germination. The changes at the physiological level in sprouting seeds depend not only on the frequency of the external EMF and its power characteristics but also on the kind of seeds. Low- and high-frequency electromagnetic fields are able to produce a biostimulation effect; however, the mechanisms of its appearance are different in their nature. The biochemical studies of seeds after EMF treatment in the modes resulting in expressed biological effects showed an increase in the activity of alpha-amylase, which testifies an increase in the gibberellin output and in the activity of the hydrolytic enzyme sour phosphatase. The response of seeds to EMF treatment demonstrates the possibility of electromagnetic control of growth processes.


Quantification of punctate iron sources using magnetic resonance phase.
Iron-mediated tissue damage is present in cerebrovascular and neurodegenerative diseases and neurotrauma. Brain microbleeds are often present in these maladies and are assuming increasing clinical importance. Because brain microbleeds present a source of pathologic iron to the brain, the noninvasive quantification of this iron pool is potentially valuable. Past efforts to quantify brain iron have focused on content estimation within distributed brain regions. In addition, conventional approaches using "magnitude" images have met significant limitations. In this study, a technique is presented to quantify the iron content of punctate samples using phase images. Samples are modeled as magnetic dipoles and phase shifts due to local dipole field perturbations are mathematically related to sample iron content and radius using easily recognized geometric features in phase images. Phantoms containing samples of a chitosan-ferric oxyhydroxide composite (which serves as a mimic for hemosiderin) were scanned with a susceptibility-weighted imaging sequence at 11.7 T. Plots relating sample iron content and radius to phase image features were compared to theoretical predictions. The primary result is the validation of the technique by the excellent agreement between theory and the iron content plot. This research is a potential first step toward quantification of punctate brain iron sources such as brain microbleeds.


Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database.
The introduction of immune checkpoint inhibitors (ICIs) in clinical practice has brought significant benefits for patients. Seven ICIs are available in Europe: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, and ipilimumab. Despite their proven clinical efficacy, these innovative drugs may cause serious immune-related adverse drugs reactions (irADRs). Given the significance of these ADRs for patients' health, we analyzed individual case safety reports (ICSRs) related to ICIs, focusing on those reporting irADRs, collected in the Italian spontaneous reporting database. We analyzed ICI-induced irADRs collected in the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza [RNF]) from January 1, 2002, to February 28, 2019, focusing on those reported in the Campania Region. We retrieved from an open-access Italian pharmacovigilance system, the RAM system (for national safety data), and from the RNF (for Campania safety data) all ICSRs reporting ADRs related to ICIs authorized until the analysis date. Focusing on irADRs, we performed descriptive and disproportionality analyses through the reporting odds ratio (ROR) with 95% confidence interval. National results. Among 2,088 ICI-related ICSRs, 801 reported irADRs. The majority of such ADRs occurred in male patients reporting gastrointestinal and skin toxicities. Nivolumab and pembrolizumab were drugs most commonly reported as suspect drugs. Compared to other ICIs, ROR was statistically significant for pembrolizumab and ipilimumab.Campania Region results. Out of 253 ICI-related ICSRs sent to Regional Pharmacovigilance Center of Campania Region, 121 reported at least one ICI-induced irADR. These were serious in 37.2% of cases and had an unfavorable outcome in 32.2% of cases. Overall, out of 8 ICSRs reported ADR with a fatal outcome, four reported irADRs. From disproportionality analyses on Campania Region ICSRs, statistically significant ROR emerged only for ipilimumab. Our results showed that during the study period several serious irADRs were reported, some of which had fatal outcome. Given the clinical relevance of irADRs, further investigations in real-life context are necessary for a better characterization of ICIs safety profiles. Oncologists should be trained to early recognize and adequately manage irADRs. Patients should also be educated to immediately report any new symptom or worsening of pre-existed ones during the ICI treatment.


Explanatory model of help-seeking and coping mechanisms among depressed women in three ethnic groups of Fars, Kurdish, and Turkish in Iran.
As one of the most prevalent diseases globally and as an important cause of disability, depressive disorders are responsible for as many as one in every five visits to primary care doctors. Cultural variations in clinical presentation, sometimes make it difficult to recognize the disorder resulting in patients not being diagnosed and not receiving appropriate treatment. To address this issue, we conducted a qualitative pilot study on three ethnic groups including Fars, Kurdish, and Turkish in Iran to test the use of qualitative methods in exploring the explanatory models of help-seeking and coping with depression (without psychotic feature) among Iranian women. A qualitative study design was used based on an explanatory model of illness framework. Individual interviews were conducted with key informant (n=6), and depressed female patients (n=6). A hypothetical case vignette was also used in focus group discussions and individual interviews with lay people (three focus groups including 25 participants and six individual interviews; n=31). There were a few differences regarding help-seeking and coping mechanisms among the three ethnic groups studied. The most striking differences were in the area of treatment. Non-psychotic depressive disorder in all ethnicities was related to an external stressor, and symptoms of illness were viewed as a response to an event in the social world. Coping mechanisms involved two strategies: (1) solving problems by seeking social support from family and neighbors, religious practice, and engaging in pleasurable activities, and (2) seeking medical support from psychologists and family counselors. The Fars group was far more likely to recommend professional treatment and visiting psychiatrists whereas the other two ethnic groups (i.e., Turks and Kurds) preferred to consult family counselors, psychologists or other alternative care providers, and traditional healers. The study has educational and clinical implications. Cultural reframing of the patient's and family's perceptions about mental illness and depression may require community education. Family counseling, family therapy, and also religious practices can be used to empower the patient.


Microwave-assisted silylation followed by gas chromatography/mass spectrometry for rapid determination of ergosterol in cigarettes.
Ergosterol is one of the important precursors of tumorigenic polynuclear aromatic hydrocarbons. To the best of our knowledge, a large amount of ergosterol is present in moldy cigarettes, which derives from fungal contaminations. Thus, the development of a simple, fast, and efficient method for the analysis of ergosterol is in great demand. In this paper, GC/MS following microwave-assisted silylation (MAS) was developed for the rapid quantitative analysis of ergosterol in cigarettes for the first time. In our work, total ergosterol in cigarettes after NaOH saponification was extracted with hexane, and then was fast derivatized with bis(trimethylsilyl)trifluoroacetamide (BSTFA) under microwave irradiation. Finally, the ergosterol trimethylsilyl derivative was analyzed by GC/MS. Derivatization conditions including microwave reaction solvent, irradiation time, and power were investigated. Method validations (linear range, LOD, precision, and recovery) were also studied. The results showed that the proposed method provided a fast, simple, and sensitive approach for the determination of ergosterol in cigarettes. Finally it was successfully applied to the analysis of ergosterol in normal and mildewy cigarettes.


Experiences and Perceptions of Patients with Uncontrolled Hypertension Who are Dissatisfied with Their Hypertension Care.
Hypertension control has been decreasing recently. We compared the experience and attitudes toward care between patients with uncontrolled hypertension who are more and less satisfied with that care to identify ways to improve their care. Baseline survey of 3072 patients with diagnosed hypertension and repeated blood pressure measurements at or above 150/95 mmHg during clinic appointments at 21 primary care clinics of a large Midwestern multi-specialty medical group. Survey questions were about previous hypertension care satisfaction, the degree to which that care was patient-centered, their feelings of self-confidence and treatment burden in managing hypertension, and medication side effects. A total of 1697 patients completed surveys (response rate = 55%). Of the 1697 patients, the 24% who were most dissatisfied (scored 0 to 5 on a 0 to 10 scale of satisfaction) significantly differed from those most satisfied (scored 9 to 10) on all demographic and clinical characteristics as well as on every measure of care experience and health status. After adjusting for those characteristics, reports of patient-centered care, self-confidence, stopping the medication because of side effects, and the burdensomeness of treatment were all significantly worse (P <.01 to P <.001) than for those with a higher rating of their hypertension care. Correlations among these measures were low, so the people with each problem with care seem to be different. Many patients with uncontrolled hypertension are dissatisfied with their care, but that is associated with different problems for different people. Identifying and attending to these problems may provide opportunities to help them achieve better control.


Evolution of an Enzyme from a Noncatalytic Nucleic Acid Sequence.
The mechanism by which enzymes arose from both abiotic and biological worlds remains an unsolved natural mystery. We postulate that an enzyme can emerge from any sequence of any functional polymer under permissive evolutionary conditions. To support this premise, we have arbitrarily chosen a 50-nucleotide DNA fragment encoding for the Bos taurus (cattle) albumin mRNA and subjected it to test-tube evolution to derive a catalytic DNA (DNAzyme) with RNA-cleavage activity. After only a few weeks, a DNAzyme with significant catalytic activity has surfaced. Sequence comparison reveals that seven nucleotides are responsible for the conversion of the noncatalytic sequence into the enzyme. Deep sequencing analysis of DNA pools along the evolution trajectory has identified individual mutations as the progressive drivers of the molecular evolution. Our findings demonstrate that an enzyme can indeed arise from a sequence of a functional polymer via permissive molecular evolution, a mechanism that may have been exploited by nature for the creation of the enormous repertoire of enzymes in the biological world today.


Ventricular trabeculations in the chick embryo heart and their contribution to ventricular and muscular septal development.
Sixty-two chick embryo hearts were studied at incremental stages of development (Hamburger-Hamilton stages 16 to 39) by scanning electron microscopy following 3% glutaraldehyde fixation and critical point drying. Early in cardiac development, the primitive ventricle becomes homogeneously trabeculated with highly organized sheets of myocytes lined by endocardial cells, with the trabeculae generally oriented in the dorsoventral direction. Coalescence of these trabecular sheets begins at stage 26, initially at the area of the bulboventricular flange, and later proceeding caudally toward the floor of the ventricle. The fusion process is finished by stage 30, resulting in a muscular ventricular septum that has now divided the primitive ventricle into right and left ventricles. Further growth of the ventricular septum is by continued fusion of the adjoining trabecular sheets. Remnants of the apposing trabecular sheets are found in the solidified muscular septum in the form of endocardial channels. We suggest that persistent patency of these channels results in muscular ventricular septal defects.


Osteopetrosis: a rare cause of anemia.
Normocytic anaemia is caused either by hypoproliferation of haemopoietic tissue or increased destruction of red cells. Osteopetrosis is a rare cause of anaemia. Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. But it is the adult osteopetrosis (also called benign osteopetrosis) which is diagnosed in late adolescence or adulthood that present as anaemia which is difficult to diagnose and treat. Approximately one half of patients are asymptomatic, and the diagnosis is made incidentally, often in late adolescence because radiologic abnormalities start appearing only in childhood. In other patients, the diagnosis is based on family history. Still other patients might present with osteomyelitis or fractures. We are presenting here an unusual case of osteopetrosis which was referred to us for the evaluation of anaemia.


GDNF and endothelin 3 regulate migration of enteric neural crest-derived cells via protein kinase A and Rac1.
Enteric neural crest-derived cells (ENCCs) migrate from the anterior foregut in a rostrocaudal direction to colonize the entire gastrointestinal tract and to form the enteric nervous system. Genetic approaches have identified many signaling molecules regulating the migration of ENCCs; however, it remains elusive how the activities of the signaling molecules are regulated spatiotemporally during migration. In this study, transgenic mice expressing biosensors based on Förster resonance energy transfer were generated to video the activity changes of the signaling molecules in migrating ENCCs. In an organ culture of embryonic day 11.25 (E11.25) to E13 guts, ENCCs at the rostral wavefront migrated as a cellular chain faster than the following ENCCs that formed a network. The faster-migrating cells at the wavefront exhibited lower protein kinase A (PKA) activity than did the slower-migrating trailing cells. The activities of Rac1 and Cdc42 exhibited an inverse correlation with the PKA activity, and PKA activation decreased the Rac1 activity and migration velocity. PKA activity in ENCCs was correlated positively with the distribution of GDNF and inversely with the distribution of endothelin 3 (ET-3). Accordingly, PKA was activated by GDNF and inhibited by ET-3 in cultured ENCCs. Finally, although the JNK and ERK pathways were previously reported to control the migration of ENCCs, we did not find any correlation of JNK or ERK activity with the migration velocities. These results suggest that external cues regulate the migration of ENCCs by controlling PKA activity, but not ERK or JNK activity, and argue for the importance of live imaging of signaling molecule activities in developing organs.


EUROPEAN SCIENCE: Urgent Call for Research Overhaul.
The European Union is in danger of losing ground in the global research competition unless its member nations devote more resources to science, restructure the E.U.'s flagship research program, and develop a Europe-wide science strategy, an expert panel says. Framework 5--which provides $17 billion over 5 years for multinational research efforts and scientific networking--should be made more flexible to respond to hot new research fields, the report suggests, and its complex grant-application procedures should be made "much simpler and easier to understand."


Evaluation of three approaches for real-time monitoring of roller compaction with near-infrared spectroscopy.
Three different approaches have been evaluated for monitoring ribbon density through real-time near-infrared spectroscopy measurements. The roll compactor was operated to produce microcrystalline cellulose (MCC) ribbons of varying densities. The first approach used the slope of the spectra which showed a variation through the ribbon that could be attributed to density. A second qualitative approach was also developed with a principal component analysis (PCA) model with spectra taken in-line during the production of ribbons in an ideal roll pressure range. The PCA (i.e., real-time) density scans show that the model was able to qualitatively capture the density responses resulting from variation in process parameters. The third approach involved multivariate partial least squares (PLS) calibration models developed at wavelength regions of 1,120-1,310 and 1,305-2,205 nm. Also, various PLS models were developed using three reference methods: caliper, pycnometer, and in-line laser. The third approach shows a quantitative difference between the model-predicted and the measured densities. Models developed at high-wavelength region showed highest accuracy compared with models at low-wavelength region. All the PLS models showed a high accuracy along the spectra collected throughout the production of the ribbons. The three methods showed applicability to process control monitoring by describing the changes in density during in-line sampling.


Quantitative EEG analysis in Encephalopathy related to Status Epilepticus during slow Sleep.
Since its first description, quantifying the burden of epileptiform abnormalities in sleep EEG has played a fundamental role in the diagnosis of Encephalopathy related to Status Epilepticus during slow Sleep (ESES). In fact, in the 1971 seminal paper by Tassinari's group and in the following studies on this syndrome, the amount of epileptiform discharges (EDs) was calculated as the percentage of slow sleep occupied by spike-and-waves and referred to as "spike and wave index" (SWI). However, nowadays it is becoming increasingly clear that the SWI alone does not explain the whole clinical course of patients affected by ESES. In this paper, we aim to provide a state-of-the-art summary of the quantitative EEG methods currently used in the ESES/CSWS literature, highlighting the possible pitfalls and discrepancies explaining the unsatisfactory correlation between SWI and clinical course. Furthermore; we illustrate a number of methodological refinements - taking into account inter-individual, intra-individual, and temporal variability of EDs - alongside "new" quantitative variables -including ED-related and sleep-related features - potentially useful to reach a reliable electro-clinical correlation in patients with ESES.


Body mass index and all-cause mortality among people age 70 and over: the Longitudinal Study of Aging.
To assess the relationship between body mass index (BMI; kg/m2) and mortality in a large nationally representative sample of US adults over age 70 years. Prospective longitudinal cohort study, the Longitudinal Study of Aging (LSOA). Subjects were all those 7260 black and white people (2769 men, 4491 women) initially interviewed in 1984 for whom height and weight were available. These subjects were followed through to 1990. Measurements included self-reported height and weight, date of death if subjects died, sex, age, race, measures of socio-economic status, number of living first degree relatives, and responses to questions asking whether the subject had retired due to poor health, had difficulty eating, worried about their health, and felt their health was worse than during the prior year. Smoking status was not assessed. When analyzed via Cox proportional hazard regression, the relationship between BMI and mortality, represented by means of hazard ratio, was clearly U-shaped for both men and women. The base of the curves was fairly wide suggesting that a broad range of BMIs are well tolerated by older adults. The minimum mortality (estimated from the fitted proportional hazard models) occurred at a BMI of approximately 31.7 for women and 28.8 for men. The results were essentially unchanged, if analyses were weighted, if various disease states were controlled for, and if apparently unhealthy subjects were excluded. The finding of the relatively high BMI (27-30 for men, 30-35 for women) associated with minimum hazard in persons older than seventy years supports some previously documented findings and opposes others and, if confirmed in future research, has implications for public health and clinical recommendations.


Defective cerebral glucose utilization in diet-induced obese rats.
A neural mechanism may underlie the divergent weight gain patterns of rats fed a high-energy diet; half develop diet-induced obesity (DIO), whereas the rest are diet resistant (DR). Male rats were fed chow (n = 14) or a high-energy diet for 3 mo with the development of DIO (n = 11) or DR (n = 12). DIO rats had 159-219% heavier retroperitoneal fat pads and 158% higher plasma insulin levels than chow-fed and DR rats, but plasma glucose levels were equal. Rats were trained to drink glucose after an overnight fast and were tested for local cerebral glucose utilization using 2-deoxy-D-[14C]glucose autoradiography in the presence or absence of 0.15% saccharin substituted for glucose. Saccharin intake increased 2-deoxyglucose uptake in the rostral nucleus tractus solitarius of DR but not DIO or chow-fed rats. Also, DIO rats had reduced basal 2-deoxyglucose uptake in the central amygdaloid nucleus. High-energy diet intake was associated with saccharin-induced depression of 2-deoxyglucose uptake in the inferior olive and increased utilization in the medial amygdaloid nucleus of both DR and DIO rats. Thus DIO rats have diminished basal and food-related neuronal activity in certain brain areas involved in food intake and autonomic function. Furthermore, dietary content affects glucose utilization in areas not usually associated with these functions.


Drug-drug interactions of triazole antifungal agents in multimorbid patients and implications for patient care.
Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.


Exercise interventions for smoking cessation.
Taking regular exercise may help people give up smoking by moderating nicotine withdrawal and cravings, and by helping to manage weight gain. To determine whether exercise-based interventions alone, or combined with a smoking cessation programme, are more effective than a smoking cessation intervention alone. We searched the Cochrane Tobacco Addiction Group Specialized Register in April 2014, and searched MEDLINE, EMBASE, PsycINFO, and CINAHL Plus in May 2014. We included randomized trials which compared an exercise programme alone, or an exercise programme as an adjunct to a cessation programme, with a cessation programme (which we considered the control in this review). Studies were required to recruit smokers or recent quitters and have a follow-up of six months or more. Studies that did not meet the full inclusion criteria because they only assessed the acute effects of exercise on smoking behaviour, or because the outcome was smoking reduction, are summarised but not formally included. We extracted data on study characteristics and smoking outcomes. Because of differences between studies in the characteristics of the interventions used we summarized the results narratively, making no attempt at meta-analysis. We assessed risk of selection and attrition bias using standard methodological procedures expected by The Cochrane Collaboration. We identified 20 trials with a total of 5,870 participants. The largest study was an internet trial with 2,318 participants, and eight trials had fewer than 30 people in each treatment arm. Studies varied in the timing and intensity of the smoking cessation and exercise programmes offered. Only one included study was judged to be at low risk of bias across all domains assessed. Four studies showed significantly higher abstinence rates in a physically active group versus a control group at end of treatment. One of these studies also showed a significant benefit for exercise versus control on abstinence at the three-month follow-up and a benefit for exercise of borderline significance (p = 0.05) at the 12-month follow-up. Another study reported significantly higher abstinence rates at six month follow-up for a combined exercise and smoking cessation programme compared with brief smoking cessation advice. One study showed significantly higher abstinence rates for the exercise group versus a control group at the three-month follow-up but not at the end of treatment or 12-month follow-up. The other studies showed no significant effect for exercise on abstinence. Only two of the 20 trials offered evidence for exercise aiding smoking cessation in the long term. All the other trials were too small to reliably exclude an effect of intervention, or included an exercise intervention which may not have been sufficiently intense to achieve the desired level of exercise. Trials are needed with larger sample sizes, sufficiently intense interventions in terms of both exercise intensity and intensity of support being provided, equal contact control conditions, and measures of exercise adherence and change in physical activity in both exercise and comparison groups.


Influence of trigger factors on the efficacy of almotriptan as early intervention for the treatment of acute migraine in a primary care setting: the START study.
In a large observational general practice study (the Standardized Study with Almotriptan in Early Treatment of Migraine [START]), 12.5 mg almotriptan administered within 1 h of pain onset and when pain was mild significantly improved pain-related outcomes, compared with later treatment or when pain was more severe. Migraine triggers at baseline and during treatment were recorded, and it was examined whether trigger factors could affect almotriptan-induced headache improvement. More than 400 patients were enrolled, and 1174 attacks were assessed. At baseline, patients reported a mean of 2.6 types of triggers related to the start of their previous migraine attacks. During the trial, a mean of 1.5 trigger factors for each attack was recorded. The most frequent trigger during the study was stress (37% of migraine attacks), with poor sleep (34%), fatigue (32%) and menses (19%) also being widely reported. Stress and fatigue and/or poor sleep were the most frequent trigger combinations. Early treatment with almotriptan improved clinical outcomes, regardless of the trigger factors involved. Similar results were observed for nonearly administration, although this was less efficacious than early intervention. An exception in the nonearly group was that migraines triggered by poor sleep had better responses than attacks in which sleep disorder was not a factor. Almotriptan maintained its efficacy irrespective of trigger factors in migraine patients treated in everyday clinical practice and, as shown in other studies, it was most effective in reducing pain-free rates when administered early, when pain was still mild.


Tf2O-Mediated Tandem Reaction of Enaminones for the Synthesis of Functionalized Conjugated-Enals/β-Naphthalaldehydes.
A highly efficient and regioselective method for constructing functionalized conjugated enals via the Tf2O-mediated tandem reaction of enaminones with thiophenols has been described. Chain products with excellent stereoselectivity could be obtained through substrate regulation. Additionally, a feasible method for synthesizing β-naphthalaldehydes through PhSO2Na/DABCO promoting hydrogen atom transfer process has also been reported here. Mechanism studies have shown that 2-formyl vinyl triflate 8 and sulfonylated enal 9 were the key intermediates in this process.


Multivalent Ultrasensitive Interfacing of Supramolecular 1D Nanoplatforms.
Multivalent display on linear platforms is used by many biomolecular systems to effectively interact with their corresponding binding partners in a dose-responsive and ultrasensitive manner appropriate to the biological system at hand. Synthetic supramolecular multivalent displays offer a matching approach for the modular and bottom-up construction and systematic study of dynamic 1D materials. Fundamental studies into multivalent interactions between such linear, 1D materials have been lacking because of the absence of appropriate modular nanoplatforms. In this work we interfaced two synthetic multivalent linear nanoplatforms based on a dynamic supramolecular polymer, formed by hybrid discotic-oligonucleotide monomers, and a series of complementary DNA-duplex-based multivalent ligands, also with appended short oligonucleotides. The combination of these two multivalent nanoplatforms provides for the first time entry to study multivalent effects in dynamic 1D systems, of relevance for the conceptual understanding of multivalency in biology and for the generation of novel multivalent biomaterials. Together the two nanoscaffolds provide easy access to libraries of multivalent ligands with tunable affinities. The DNA scaffold allows for exact control over valency and spatial ligand distribution, and the discotic supramolecular polymer allows for dynamic adaptation and control over receptor density. The interaction between the two nanoplatforms was studied as a function of ligand interaction strength, valency, and density. Usage of the enhancement parameter β allowed quantification of the effects of ligand valency and affinity. The results reveal a generalized principle of additive binding increments. Receptor density is shown to be crucially and nonlinearly correlated to complex formation, leading to ultrasensitive responses. The results reveal that, not unlike biomolecular signaling, high density multivalent display of receptors is crucial for functionally increased affinities.


[Degradation of purines in leukocytes in acute nonlymphoblastic leukemias].
Activities of the enzymes, responsible for degradation of purine nucleotides in leukocytes, were distinctly dissimilar in M1, M2, M4 and M6 variants of acute non-lymphoblastic leukosis studied in 34 patients. Differentiation of leukemic cells was shown to be due to alterations in activity of adenosine deaminase and purine nucleoside phosphorylase, which were oppositely directed as compared with those observed in lymphoblasts under conditions of acute lymphoblast leukosis. Evaluation of activities of adenosine deaminase, purine nucleoside phosphorylase and 5'-nucleotidase is of importance for characteristics of individual variants of acute non-lymphoblastic leukosis and for elucidation of the state of leukemic clone differentiation, which may affect the efficiency of the therapeutic measures used.


Munchausen Syndrome by Proxy: balancing ethical and clinical challenges for healthcare professionals Ethical consideration in factitious disorders.
Munchausen syndrome by proxy is a relatively rare behavioral disorder affecting a child's primary caregiver, typically the mother. Ethical dilemmas that physicians may face in such situations mainly concern the medical options for best protecting the child's welfare, that are important, in clinical pediatric practice, because critical conflicts might arise between health professionals and parents. In such cases, the physician's primary obligation is to protect the children involved, whose family environment may be essential to their wellbeing. Ev- ery ethical choice should be tailored to a given child's story, which should be viewed as a whole, considering the possible consequences for the family balance, and taking the complexity of the emotional and psychological dimensions of children's relationship with their parents into account. Specific protocols, discussion of clinical cases, open communi- cation of feelings will help doctors to deal more effectively with the families involved and ensure that treatment decisions are made in the child's best interest.


Semaphorin 4A exerts a proangiogenic effect by enhancing vascular endothelial growth factor-A expression in macrophages.
The axon guidance cues semaphorins (Semas) and their receptors plexins have been shown to regulate both physiological and pathological angiogenesis. Sema4A plays an important role in the immune system by inducing T cell activation, but to date, the role of Sema4A in regulating the function of macrophages during the angiogenic and inflammatory processes remains unclear. In this study, we show that macrophage activation by TLR ligands LPS and polyinosinic-polycytidylic acid induced a time-dependent increase of Sema4A and its receptors PlexinB2 and PlexinD1. Moreover, in a thioglycollate-induced peritonitis mouse model, Sema4A was detected in circulating Ly6C(high) inflammatory monocytes and peritoneal macrophages. Acting via PlexinD1, exogenous Sema4A strongly increased macrophage migration. Of note, Sema4A-activated PlexinD1 enhanced the expression of vascular endothelial growth factor-A, but not of inflammatory chemokines. Sema4A-stimulated macrophages were able to activate vascular endothelial growth factor receptor-2 and the PI3K/serine/threonine kinase Akt pathway in endothelial cells and to sustain their migration and in vivo angiogenesis. Remarkably, in an in vivo cardiac ischemia/reperfusion mouse model, Sema4A was highly expressed in macrophages recruited at the injured area. We conclude that Sema4A activates a specialized and restricted genetic program in macrophages able to sustain angiogenesis and participates in their recruitment and activation in inflammatory injuries.


Large-scale expression and purification of a soluble form of the pleckstrin homology domain of the human protooncogenic serine/threonine protein kinase PKB (c-akt) in Escherichia coli.
The protooncogenic serine/threonine protein kinase PKB contains an amino-terminal pleckstrin homology (PH) domain which binds phosphatidylinositides. The PH domain, composed of approximately 100 loosely conserved amino acids, is found in many proteins, including kinases, phospholipases C, GTPases, GTPase-activating proteins, GTPase-exchange factors, "adaptor" proteins, cytoskeletal proteins, and kinase substrates. We have developed an expression system in Escherichia coli that can produce large quantities of a soluble form of the PKB PH domain and have purified it to apparent homogeneity. Expression of the PKB PH domain as a (His)(6)-tagged fusion with the addition of 3 lysines at the carboxyl-terminus facilitated the production of soluble protein. Induction of expression at 24 degrees C as opposed to 37 degrees C also significantly increased solubility of the PH domain. Large-scale purification was easily achieved by exploiting the (His)(6) tag and the high isoelectric point of the protein attributable to the additional 3 carboxyl-terminal lysines.


Automated analysis of differential interference contrast microscopy images of the foveal cone mosaic.
An algorithm is presented for processing and analysis of differential interference contrast (DIC) microscopy images of the fovea to study the cone mosaic. The algorithm automatically locates the cones and their boundaries in such images and is assessed by comparison with results from manual analysis. Additional algorithms are presented that analyze the cone positions to extract information on cone neighbor relationships as well as the short-range order and domain structure of the mosaic. The methods are applied to DIC images of the human fovea.


Effect of procainamide and N-acetylprocainamide on atrial flutter: studies in vivo and in vitro.
We studied the effects of procainamide and N-acetylprocainamide (NAPA) in a conscious dog preparation of atrial flutter resulting from circus movement around the tricuspid orifice. We also recorded transmembrane potentials of atrial tissues from the circus path in vitro. In 12 instrumented dogs, average flutter cycle length was 157 msec, the duration of the excitable gap was 73 msec, and conduction velocity was 0.75 m/sec. At 4 and 8 mg/kg, procainamide moderately prolonged cycle length, but did not terminate the flutter. At a cycle length of 300 msec procainamide increased effective refractory period (ERP) by 12% and 20% and conduction time by 8% and 19%. At 16 and 32 mg/kg procainamide prolonged cycle length, ERP, and conduction time by 60% to 80% and stopped the flutter in all trials. NAPA, at 16, 32, and 64 mg/kg, increased flutter cycle length by 16%, 16%, and 31%, ERP by 14%, 28%, and 41%, and conduction time by less than 15%. NAPA terminated the flutter in two of six dogs given 32 mg/kg, and three of five dogs given 64 mg/kg. The excitable gap was lengthened by both procainamide and NAPA. Transmembrane potentials showed that at a cycle length from 1000 to 300 msec procainamide (10 mg/liter) increased action potential duration and decreased the first time derivative of phase O of the action potential (Vmax), whereas NAPA (20 mg/liter) increased action potential duration without changing Vmax. These findings show the difficulty of relating drug effects on transmembrane potentials to efficacy in vivo since the former do not necessarily indicate which changes in cellular electrical activity are responsible for efficacy against a particular arrhythmogenic mechanism.


[Typifying foci of tick-borne encephalitis in the pre-Baikal].
The existence of tick-borne encephalitis foci of several landscape types was revealed in the Prebaikalye. Of particular interest were foci of the forest-steppe type, in which virus strains of the Western serological type circulated along with the Eastern serological type strain of the tick-borne encephalitis virus. It was shown that infection of man was possible not only by transmissive, but also by the almientary route--through cow milk.


A PLP-dependent polyketide chain releasing mechanism in the biosynthesis of mycotoxin fumonisins in Fusarium verticillioides.
Fumonisins are polyketide-derived mycotoxins produced by several plant pathogenic fungi. The toxins cause several fatal diseases in domestic animals and are associated with esophageal cancer and neural tube defects in humans. Fumonisins contain a highly reduced, acyclic 18-carbon chain, which is synthesized by an iterative polyketide synthase (PKS). This PKS does not contain a thioesterase or cyclase domain that is found in other PKSs for the release of the covalently linked polyketide chain. In this study, we expressed the acyl carrier protein (ACP) of FUM1 and in vitro loaded acyl chains to the ACP from acyl-CoA using a promiscuous 4'-phosphopantetheinyl transferase. We then expressed FUM8, which is homologous to 2-oxoamine synthase genes, in yeast and showed that the enzyme is able to offload the acyl chains from ACP. Products resulted from the decarboxylative condensation between l-alanine and acyl-S-ACP were detected by GC-MS. The enzyme activity was dependent on pyridoxal 5'-phosphate (PLP), and C18-S-ACP was the preferred substrate. The results revealed a novel polyketide chain-releasing mechanism, in which a PLP-dependent enzyme catalyzes the termination and offloading of the polyketide chain as well as the introduction of a new carbon-carbon bond and an amino group to the chain. The mechanism is fundamentally different from the thioesterase/cyclase-catalyzed polyketide chain release found in bacterial and other fungal polyketide biosyntheses.


Ethics in sentinel node biopsy in breast cancer: an open question.
The sentinel node concept agrees with the modern principles of surgical oncology in breast cancer, which are related to lymphatic dissection, accurate axillary study, and less traumatic surgery. After publication of many series, it has proven its capacity to correctly stage axilla and select patients who need axillary dissection. The Brazilian Society of Senology established the current norms for its practice. However, the transportation of new surgical techniques from research to practice always occurs with some ethical dilemmas related to its introduction in clinical practice. The aim of this study was to analyze the ethical challenges of the sentinel node technique and problems with its implementation.


Improved Diagnosis of Prosthetic Joint Infection by Culturing Periprosthetic Tissue Specimens in Blood Culture Bottles.
Despite known low sensitivity, culture of periprosthetic tissue specimens on agars and in broths is routine. Culture of periprosthetic tissue samples in blood culture bottles (BCBs) is potentially more convenient, but it has been evaluated in a limited way and has not been widely adopted. The aim of this study was to compare the sensitivity and specificity of inoculation of periprosthetic tissue specimens into blood culture bottles with standard agar and thioglycolate broth culture, applying Bayesian latent class modeling (LCM) in addition to applying the Infectious Diseases Society of America (IDSA) criteria for prosthetic joint infection. This prospective cohort study was conducted over a 9-month period (August 2013 to April 2014) at the Mayo Clinic, Rochester, MN, and included all consecutive patients undergoing revision arthroplasty. Overall, 369 subjects were studied; 117 (32%) met IDSA criteria for prosthetic joint infection, and 82% had late chronic infection. Applying LCM, inoculation of tissues into BCBs was associated with a 47% improvement in sensitivity compared to the sensitivity of conventional agar and broth cultures (92.1 versus 62.6%, respectively); this magnitude of change was similar when IDSA criteria were applied (60.7 versus 44.4%, respectively; P = 0.003). The time to microorganism detection was shorter with BCBs than with standard media (P < 0.0001), with aerobic and anaerobic BCBs yielding positive results within a median of 21 and 23 h, respectively. Results of our study demonstrate that the semiautomated method of periprosthetic tissue culture in blood culture bottles is more sensitive than and as specific as agar and thioglycolate broth cultures and yields results faster. Prosthetic joint infections are a devastating complication of arthroplasty surgery. Despite this, current microbiological techniques to detect and diagnose infections are imperfect. This study examined a new approach to diagnosing infections, through the inoculation of tissue samples from around the prosthetic joint into blood culture bottles. This study demonstrated that, compared to current laboratory practices, this new technique increased the detection of infection. These findings are important for patient care to allow timely and accurate diagnosis of infection.


Integrating Adolescents and Young Adults into Adult-Centered Care for IBD.
Planned healthcare transition, initiated in pediatric care, is a gradual process aimed at fostering the adolescent patient's disease knowledge and skills with the ultimate objective of preparing patients and families for adult-centered care. The process is critical in inflammatory bowel diseases (IBD) where there is an increased risk of non-adherence, hospitalizations, and emergency department use as young adult patients graduate from pediatric to adult-centered care. While evidence for healthcare transition in IBD is mounting, important gaps remain in the understanding of this process from the perspective of the adult gastroenterologist. This paper summarizes what is known about healthcare transition in IBD and explores the unanswered questions-a conceptual and methodological framework for transition interventions, relevant outcomes that define successful transition, and key stakeholder perspectives. For the adult gastroenterologist managing the young adult patient population, this paper presents the paradigm of "care integration"-a process of ongoing, multi-modality support for the patient, initiated in the adult care setting, with the goal of improving self-management skills and active participation in medical decision-making.


Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors.
In the accompanying paper (K. Tanabe, Y. Ikegami, R. Ishida, and T. Andoh, Cancer Res., 51: 4903-4908, 1991), we showed that ICRF-154 and -193, dioxopiperazine derivatives, inhibited the activity of purified topoisomerase II, without formation of a cleavable DNA-protein complex. In order to see whether ICRF-154 and ICRF-193 affect cellular topoisomerase II in situ or not, we examined the effect of these drugs on etoposide (VP-16)-induced, topoisomerase II-mediated DNA breaks in RPMI 8402 cells by alkaline sedimentation analysis. When RPMI 8402 cells were exposed to VP-16 in the presence of ICRF-154 or ICRF-193 for 1 h, VP-16-induced DNA strand breaks were greatly inhibited by both ICRF compounds. In parallel with this observation, VP-16-induced growth inhibition was also reversed by ICRF-193. Exposure of cells to ICRF-154 resulted in a progressive accumulation of cells with 4C DNA content. Although mitotic index did not significantly increase, mitotic abnormalities were seen in cells exposed to ICRF-193 or ICRF-154: all mitotic cells exhibited early mitotic figures with fewer condensed and entangled chromosomes. The most sensitive phase of the cell cycle to ICRF-154 was the G2-M. ICRF-154 did not affect the spindle formation. However, abnormally oriented spindles were observed in drug-treated cells in parallel with the appearance of multinucleated cells. The results suggest that ICRF-154 and -193 inhibit topoisomerase II activity in RPMI 8402 cells, and this effect resulted in the appearance of cells in G2 and early M phase with fewer condensed and entangled chromosomes and of cells with multilobed nuclei.


Insights for Realizing Ultrasensitive Colorimetric Detection of Glucose Based on Carbon/Silver Core/Shell Nanodots.
On-site and instant glucose sensing is essential for objectively monitoring the change of glucose content that has decisive effects on the normal regulation of carbon metabolism. Colorimetric synergy based on indicators for real-time sensing seemed to be the potential route, but so far it has remained quite challenge to shift down the detection limit in a stable manner. Also, the lack of a direct identification of the underlying detection mechanism especially on the exhibited color change limited their practical use. In this study, the strategy is to employ the carbon nanodots with silver shells functioning as the highly sensitive indicators that enabled realization of the colorimetric sensing of glucose which is caused by oxidation of the surface silver shell observed by the naked eye. These were based on the robust core/shell architectures that allowed an ultralow limit of detection of 87.3 nM for glucose detection through the formation of Ag2O that led to the obvious particle aggregations, and the results were found to be superior than other reported colorimetric-based glucose sensors by the glucose-oxidase-mediated strategy. Moreover, the reliability tests verified their long-term stability and high resistance for the alteration of environmental pH from 3 to 10 on glucose detection. These features associated with the sound crystalline quality of core/shell nanostructures that could be attributed to the compensation of lattice defects existed in the original carbon nanodots by the Ag-O-C bonding while Ag shells were formed.


[Studying of hepatoprotective properties of dry extract from apricot leaves on the model of liver lesion by tetrachloromethane].
The results of the pharmacological investigation of the properties of apricot leaves dry extract are indicated in the article. It is proved that the extract belongs to the group of "relatively harmless" substances, exclusion of the ulcerogenic effect on the stomach, local irritating and allergenic effect on animals. It is found minimal reacting dose of the extract, which is 70 mg/kg of body weight. On the model of liver lesion by tetrachlormethane it is proved the antioxidant properties of the extract, which is manifested by the decreasing of the activity of oxidative processes and the resumption of the activity of the endogenous antioxidant system. At the studying of the bile formation and bile secretion functions in the conditions of the toxic tetrachlormethane lesion the hepatoprotective effect of the dosage form was confirmed, which was realized by the increasing of the speed of bile secretion and its volume. It is proved a positive effect of the extract on the detoxification function of the liver, that is confirmed by the reducing of the hexenal sleep in rats after toxicant exposure.


Analysis of unexpected disruptive effects of contingent food reinforcement on automatically maintained self-injury.
Research has identified treatment-responsive and treatment-resistant subtypes of automatically maintained self-injurious behavior (ASIB) based on patterns of responding in the functional analysis (FA) reflecting its sensitivity to disruption by alternative reinforcement, and the presence of self-restraint. Rooker et al. (2019) unexpectedly observed reductions in treatment-resistant self-injury while participants performed an operant task. The current study further examined this in nine participants with treatment-resistant ASIB in an example of discovery-based research. An operant task engendering high rates of responding (switch-pressing) to produce food, reduced self-injury across all participants, and eliminated self-injury for some participants under certain schedules. Although this finding must be replicated and evaluated over longer time periods, it provides some evidence that alternative reinforcement can disrupt self-injury in these treatment-resistant subtypes under some conditions. Reinforcer and response competition are discussed as possible mechanisms underlying these disruptive effects, as are the potential implications of these findings regarding treatment.


Ex Vivo Organ Cultures as Models to Study Bone Biology.
The integrity of the skeleton is maintained by the coordinated and balanced activities of the bone cells. Osteoclasts resorb bone, osteoblasts form bone, and osteocytes orchestrate the activities of osteoclasts and osteoblasts. A variety of in vitro approaches has been used in an attempt to reproduce the complex in vivo interactions among bone cells under physiological as well as pathological conditions and to test new therapies. Most cell culture systems lack the proper extracellular matrix, cellular diversity, and native spatial distribution of the components of the bone microenvironment. In contrast, ex vivo cultures of fragments of intact bone preserve key cell-cell and cell-matrix interactions and allow the study of bone cells in their natural 3D environment. Further, bone organ cultures predict the in vivo responses to genetic and pharmacologic interventions saving precious time and resources. Moreover, organ cultures using human bone reproduce human conditions and are a useful tool to test patient responses to therapeutic agents. Thus, these ex vivo approaches provide a platform to perform research in bone physiology and pathophysiology. In this review, we describe protocols optimized in our laboratories to establish ex vivo bone organ cultures and provide technical hints and suggestions. In addition, we present examples on how this technical approach can be employed to study osteocyte biology, drug responses in bone, cancer-induced bone disease, and cross-talk between bone and other organs © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.


Using Online Respondent Driven Sampling for Vietnamese Youths' Alcohol Use and Associated Risk Factors.
The average alcohol consumption per capita among Vietnamese adults has consistently increased. Although alcohol-related disorders have been extensively studied, there is a paucity of research shedding light on this issue among Internet users. The study aimed to examine the severity of alcohol-related disorders and other associated factors that might predispose individuals towards alcohol usage in a sample of youths recruited online. An online cross-sectional study was conducted with 1,080 Vietnamese youths. A standardized questionnaire was used. Respondent-driven sampling was applied to recruit participants. Multivariate logistic and Tobit regressions were utilized to identify the associated factors. About 59.5% of the males and 12.7% of the total youths declared that they were actively using alcohol. From the total sample, a cumulative total of 32.3% of the participants were drinking alcohol, with 21.8% and 25.0% of the participants being classified as drinking hazardously and binge drinkers, respectively. The majority of the participants (60.7%) were in the pre-contemplative stage. A high prevalence of hazardous drinking was recognized among online Vietnamese youths. In addition, we found relationships between alcohol use disorder and other addictive disorders, such as tobacco smoking and water-pipe usage. Our results highlighted that the majority of the individuals are not receptive to the idea of changing their alcohol habits, and this would imply that there ought to be more government effort towards the implementation of effective alcohol control policies.


Seasonal Risk Assessment of Water-Electricity Nexus Systems under Water Consumption Policy Constraint.
Previous studies have estimated power plant cooling water consumption based on the long-term average cooling water consumption intensity (WI: water consumption per unit of electricity generation) at an annual scale. However, the impacts of the seasonality of WI and streamflow on electricity generation are less well understood. In this study, a risk assessment method is developed to explore the seasonal risk of water-electricity nexus based on the Integrated Environmental Control Model, which can simulate variable WIs in response to daily weather conditions and avoid underestimation in WIs as well as nexus risk during dry seasons. Three indicators, reliability, maximum time to recovery, and total power generation loss, are proposed to quantify the seasonal nexus risk under water consumption policy constraint represented by the allowed maximum percentage of water consumption to streamflow. The applications of the method in two representative watersheds demonstrate that the nexus risk is highly seasonal and is greatly impacted by the seasonal variability of streamflow rather than annual average water resources conditions on which most previous studies are based. The nexus is found more risky in the watershed with almost double mean annual streamflow and greater streamflow variability, compared with the watershed with less streamflow variability.


Brief Report: Infants Developing with ASD Show a Unique Developmental Pattern of Facial Feature Scanning.
Infants are interested in eyes, but look preferentially at mouths toward the end of the first year, when word learning begins. Language delays are characteristic of children developing with autism spectrum disorder (ASD). We measured how infants at risk for ASD, control infants, and infants who later reached ASD criterion scanned facial features. Development differed across groups. The preference for the eyes region decreased with age in infants who were at risk of ASD. For the control group the change in feature preference was marginally significant for a quadratic model, reflecting a decrease in the preference for eyes at 9 months followed by a recovery. The infants who later reached ASD criterion did not show a significant change across time.


The influence of age on in vitro plasmin generation in the presence of fibrin monomer.
The components of the fibrinolytic system interact to generate plasmin from its zymogen form, plasminogen. At birth, all the components of the fibrinolytic system are present but with differing plasma concentrations. The present study was undertaken to explore the effect of physiological, age-dependent factors of the fibrinolytic system during childhood on the capacity to generate plasmin. Total plasmin generation was measured in venous plasma from umbilical cords and adults, on plastic and cell surfaces, in the presence of fibrin monomer, Desafib. Plasminogen, its inhibitors alpha2-antiplasmin and plasminogen activator inhibitor type 1, and plasmin-alpha2-antiplasmin complex in the time samples were assayed by enzyme-linked immunosorbent assay. The effect of addition of plasminogen on the plasmin generation in cord plasma and the effect of lipoprotein on adult and cord plasmin generation were measured. On the surface of human umbilical vein endothelial cells, onset of plasmin generation was earlier (40 min) compared to plastic (60 min) but total plasmin generation was similar on both surfaces. The addition of plasminogen to cord plasma increased plasmin generation. Supplementation of lipoprotein in adult plasma had an inhibitory effect, but there was no significant effect in cord plasma. Plasmin generation is reduced in newborn compared to adult plasma. Decreased plasmin generation in cord plasma is likely due to decreased plasminogen concentration. The antifibrinolytic effect of lipoprotein is more pronounced in adults as compared to newborns due to the presence of higher plasminogen concentration.


Effects of thyroid deficiency on the vasopressin receptors in the kidney of developing and adult rats. A comparative study of hormonal binding and adenylate cyclase activation.
The effects of propylthiouracil (PTU) treatment on renal vasopressin sensitive adenylate cyclase in young and adult rats were studied by measuring the binding of tritiated vasopressin and adenylate cyclase activation by vasopressin in kidney medulla plasma membranes. Thyroxine therapy completely corrected the effects of PTU treatment on the vasopressin-adenylate cyclase system. Thus, the abnormalities observed after a such treatment are directly related to thyroid deficiency and not to toxic effects of PTU. The inability of the kidney to normally concentrate urine in developing and adult animals with induced hypothyroidism was mainly related to the reduction of the number of binding sites without significant changes in the basal and guanylyl-imidodiphosphate (Gpp(NH)p)-stimulated adenylate cyclase activities, the apparent dissociation constant (Kbind) of labeled vasopressin from its specific receptor and the apparent activation constant (Kact) of vasopressin for adenylate cyclase. These results also show that thyroid deficiency has more effect on the ontogenesis of receptors than on their turnover, and demonstrate that a normal antidiuretic response occurs at very low receptor occupancy. Since, on the one hand, the hypothyroidism-induced abnormalities in renal medulla responsiveness to vasopressin were reversible and, on the other, only a permanent therapy consisting of two daily physiological doses of thyroxine from birth to the age of sacrifice fully restored them, the responsiveness of developing kidney to thyroid hormones appears to be fundamentally different from that of the CNS.


Hidden Markov Models and their Applications in Biological Sequence Analysis.
Hidden Markov models (HMMs) have been extensively used in biological sequence analysis. In this paper, we give a tutorial review of HMMs and their applications in a variety of problems in molecular biology. We especially focus on three types of HMMs: the profile-HMMs, pair-HMMs, and context-sensitive HMMs. We show how these HMMs can be used to solve various sequence analysis problems, such as pairwise and multiple sequence alignments, gene annotation, classification, similarity search, and many others.


Induced fatigue effects on velopharyngeal closure force.
This investigation studied the effects of induced velopharyngeal fatigue in speakers with normal mechanisms. Five adult female and 5 adult male subjects were used. A force sensing bulb was placed in the velopharynx to measure velopharyngeal closure force and intramuscular electrodes were inserted in the levator veli polatini muscle to sample muscle activation levels. The subjects' task was to repeat the syllable /si/100 times while an external load was placed on the velopharyngeal mechanism. The external load consisted of various levels of air pressure (0 as a control, 5, 15, 25, and 35 cm H2O relative to atmospheric pressure) delivered to the nasal passages via a tube and nasal mask assembly. Fatigue was defined as a declination of force across the series of syllables within a pressure condition and was depicted as the slope of a linear regression line that was fit to the data. The more negative the slope, the greater was the rate of fatigue. Within each experimental pressure condition, small cyclic variations in force were noted about each regression line that corresponded to individual breath groups. This type of declination, within breath groups, has been reported in the literature previously. Overall declination in force over an entire series of syllables and over several breath groups is a new finding. It was possible to induce such fatigue in most subjects, and greater rates of fatigue generally occurred at the higher levels of external loading, i.e., at 25 and 35 cm H2O. Two subjects, 1 male and 1 female, reached exhaustion. The female subject could not perform the syllable repetition task at 25 cm H2O, and the male subject could not complete the task at 35 cm H2O. Three subjects, 1 female and 2 males, exhibited virtually no force declination even at the highest level (35 cm H2O) of external loading. There were no discernable differences in patterns of fatigue or in initial velopharygeal closure force values between the male and female subjects.


A study of human lens cell growth in vitro. A model for posterior capsule opacification.
After intraocular lens (IOL) implant surgery for cataract, cell growth on the posterior capsule is responsible for renewed visual impairment in approximately 30% of patients. The authors have, therefore, developed a human lens capsule system to study this growth in vitro. Sham cataract surgery, including anterior capsulorhexis, nucleus hydroexpression, and aspiration of lens fibers, was performed on donor eyes. In some cases, a polymethylmethacrylate IOL implant was placed in the capsular bag. The capsular bag was dissected free, pinned flat on a plastic culture dish, covered with Eagle's minimum essential medium supplemented with 10% fetal calf serum and observed by phase-contrast and dark-field microscopy for as long as 100 days. At the end-point, capsules were examined by fluorescence microscopy for actin, vimentin, and chromatin. Within 24 hours, there was evidence of cell growth in the equatorial region. After 2 to 3 days, cells were normally observed growing from the rhexis onto the posterior capsule and across the anterior surface of the IOL, if present. Growth proceeded rapidly so that the posterior capsule, for example, was totally covered by a confluent monolayer of cells at 5.8 +/- 0.6 days and 7.2 +/- 0.7 days for capsules aged < 40 years and > 60 years, respectively. Total cover of the anterior IOL surface generally followed 4 to 5 days behind that of the capsule. Capsular wrinkles became increasingly apparent as time progressed, causing a marked rise in light scatter. An increase in capsular tension also occurred, and the actin filaments became more polarized near the wrinkles. The model presented here for posterior capsule opacification shows many of the changes seen in vivo, including rapid lens cell growth, wrinkling, tensioning, and light scatter in the posterior capsule. It will be possible to develop strategies for inhibiting cell growth with this system.


Few-shot learning approach with multi-scale feature fusion and attention for plant disease recognition.
Image-based deep learning method for plant disease diagnosing is promising but relies on large-scale dataset. Currently, the shortage of data has become an obstacle to leverage deep learning methods. Few-shot learning can generalize to new categories with the supports of few samples, which is very helpful for those plant disease categories where only few samples are available. However, two challenging problems are existing in few-shot learning: (1) the feature extracted from few shots is very limited; (2) generalizing to new categories, especially to another domain is very tough. In response to the two issues, we propose a network based on the Meta-Baseline few-shot learning method, and combine cascaded multi-scale features and channel attention. The network takes advantage of multi-scale features to rich the feature representation, uses channel attention as a compensation module efficiently to learn more from the significant channels of the fused features. Meanwhile, we propose a group of training strategies from data configuration perspective to match various generalization requirements. Through extensive experiments, it is verified that the combination of multi-scale feature fusion and channel attention can alleviate the problem of limited features caused by few shots. To imitate different generalization scenarios, we set different data settings and suggest the optimal training strategies for intra-domain case and cross-domain case, respectively. The effects of important factors in few-shot learning paradigm are analyzed. With the optimal configuration, the accuracy of 1-shot task and 5-shot task achieve at 61.24% and 77.43% respectively in the task targeting to single-plant, and achieve at 82.52% and 92.83% in the task targeting to multi-plants. Our results outperform the existing related works. It demonstrates that the few-shot learning is a feasible potential solution for plant disease recognition in the future application.