Quality of recovery from two types of general anesthesia for ambulatory dental surgery in children: a double-blind, randomized trial.
Pediatric dental procedures are increasingly performed under general anesthesia because of the inability to cooperate, situational anxiety, or other behavioral problems. Volatile anesthetics have been associated with emergence delirium in children, whereas the use of propofol for anesthetic maintenance has been shown to reduce the incidence of emergence delirium after other types of surgeries. The aim of this study is to compare a sevoflurane-based anesthetic with a propofol-based technique as it relates to the incidence of emergence delirium and the quality of recovery after pediatric dental surgery, in patients who present with risk factors for perioperative behavioral issues. We prospectively collected data of 179 pediatric patients scheduled for ambulatory dental surgery using a double-blind and randomized trial design. Subjects were anesthetized following standardized protocols for either a sevoflurane- or a propofol-based technique. The incidence of emergency delirium, as measured by the Pediatric Anesthesia Emergence Delirium score, was the primary outcome. Secondary outcomes included the incidence of postoperative nausea and vomiting (PONV), number of nursing interventions in the recovery room, time to discharge readiness, and parental satisfaction. We found no difference in the incidence of emergence delirium after both types of anesthesia. However, use of sevoflurane significantly increased both the risk of PONV and the number of postoperative nursing interventions. Discharge criteria were met about 10 min earlier in patients anesthetized with sevoflurane. Parental satisfaction was equally high with both anesthesia regimens. A propofol-based anesthetic technique did not lead to a lower incidence of emergence delirium after dental surgery in children but did result in significantly less PONV and fewer postoperative nursing interventions.


Differential amino acid utilization by Chlamydia psittaci (strain guinea pig inclusion conjunctivitis) and its regulatory effect on chlamydial growth.
The effect of omission of individual amino acids from growth medium on the multiplication of Chlamydia psittaci (strain guinea pig inclusion conjunctivitis) in cycloheximide-treated McCoy cells has been examined. Marked differences were observed in the amounts of particular amino acids required for normal chlamydial multiplication: omission of either leucine, phenylalanine or valine completely inhibited multiplication, whereas absence of any one of another 10 amino acids had no effect on numbers of cells infected. Threshold concentrations of 80, 80 and approx. 8 nmol ml-1 for leucine, valine and phenylalanine, respectively, were needed for normal chlamydial multiplication. These requirements could not be related either to unusually high content in the whole organism, to degradation in the medium, or, from studies with leucine, to deficient association of leucine with host cells. Leucine deprivation at late stages of the developmental cycle also appeared to regulate multiplication. Possible mechanisms responsible for these effects are discussed.


Evaluation of antidiabetic activity of Ipomoea batatas L. extract in alloxan-induced diabetic rats.
Different allopathic drugs are being used for the treatment of diabetes mellitus but more emphasis are being placed on the use of medicinal plants, herbs, and natural extracts of fruits and vegetables due to their easy availability, easy consummation with low cost, and with no well-reported side effects. White skinned sweet potato (WSSP; Ipomoea batatas L.) peel-off was selected to find out its antidiabetic potential as well as to explore the effects on selected biochemical parameters in diabetes-induced Wistar rats. In young (3-4 months) and old (up to 1 year) diabetic Wistar rats, it was found that WSSP ( I. batatas L.) peel-off significantly ( P < 0.05) decreased blood glucose level, protein glycation level, total cholesterol, triglycerides, and low-density lipoprotein (LDL)-cholesterol. A significant ( P < 0.05) increase in high-density lipoprotein (HDL)-cholesterol level after treatment was also reported. Furthermore, it was also found that WSSP peel-off also had beneficial effects on total protein concentration, albumin, globulin, and liver enzymes (serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT)). It might be concluded that antidiabetic potential of WSSP extract is due to the presence of bioactive compounds like glycoprotein, anthocyanins, alkaloids, and flavonoids, which act as insulin-like molecules or insulin secretagogues constituents in sweet potatoes peel-off and these antidiabetic proteins were extracted out in more concentration in methanol due to its organic nature. Further research is needed to purify and quantify the antidiabetic components responsible for antidiabetic effects of WSSP and it should be available in compact dose form for the treatment of diabetic patients.


Brain cortical and subcortical morphology in adolescents with depression and a history of suicide attempt.
Suicidal behaviours are a major source of mortality and morbidity among adolescents. Given the maturational changes that occur in cortical and subcortical structures during adolescence, we tested whether atypical brain structural measurements were associated with a history of suicide attempt. We assessed 3 groups of adolescents (n = 92; 79% female, mean age 15.9 years, range 11.6-18.1 years): patients with a depressive disorder and a history of suicide attempt (n = 28); patient controls, who had a depressive disorder but no history of suicide attempt (n = 34); and healthy controls (n = 30). We derived regional cortical thickness and surface area, and subcortical volumes, from T1-weighted anatomic MRI scans acquired at 3 T. We found significant group differences in surface area in the prefrontal, temporal and parietal regions, as well as in the volume of several subcortical nuclei (pFDR ≤ 0.05), but not in cortical thickness. Post hoc analyses indicated that morphological alterations primarily differentiated patients with a history of suicide attempt from healthy controls, but not from patient controls. However, patients with a history of suicide attempt exhibited positive correlations between age and cortical thickness in the temporal cortices and right insula, and between age and right putamen volume (i.e., thicker regional cortex and larger subcortical volumes with age). These correlations were negative in both patient controls and healthy controls (i.e., thinner regional cortex and smaller subcortical volumes). Sample sizes, cross-sectional findings and psychiatric heterogeneity were limitations of this study. Macroscopic structural differences in several brain regions differentiated adolescents with a history of suicide attempt from healthy controls, but not from patient controls. However, adolescents with a history of suicide attempt may present with atypical maturation of specific cortical and subcortical regions that might contribute to the risk of suicidal behaviour.


Mannose-binding lectin polymorphisms are not associated with rheumatoid arthritis--confirmation in two large cohorts.
In RA, conflicting results have been described on the association between genotypes of the complement factor mannose-binding lectin (MBL) and disease susceptibility and severity. This might be due to underpowerment of previous research work and the fact that no confirmation cohorts were used. Therefore a different approach is warranted. MBL2 gene polymorphisms were determined in two RA cohorts (378 and 261 cases) and 648 controls. Considering MBL polymorphisms, cases and controls were categorized in groups of high, intermediate and low MBL production. The total sample size allows detection of a potential association between RA susceptibility and MBL groups with an odds ratio of 1.37 (alpha < 0.05; 1-beta > 0.8). Disease severity as defined by the need for anti-TNF therapy was also analysed for possible associations with MBL groups. There was no difference in the frequencies between MBL genotypes of RA cases and controls that are associated with high (cases 54.4%, controls 57.0%), intermediate (cases 28.9%, controls 27.5%) or low (cases 16.7%, controls 15.5%) MBL production. Furthermore, there was no association between MBL groups and disease severity. MBL genotype groups are not associated with RA disease susceptibility or severity in this large study including a confirmation cohort. Compared with previous smaller studies these results add to more definite conclusions.


Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate.
Survival among chronic myelogenous leukemia (CML) patients can be linked to the reduction in leukemic cell burden. Treatment with imatinib mesylate results in a high frequency of complete cytogenetic response, which can be further stratified using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We have serially monitored peripheral blood and bone marrow BCR-ABL transcripts using qRT-PCR in CML patients commencing imatinib therapy, and compared the results with bone marrow cytogenetics. Seventeen patients (aged 25-74 yr) with Philadelphia chromosome positive CML in first chronic phase were treated with imatinib targeting a dose of 400 mg/d. The median follow up is 30 mo (range 9-33 mo). Every third month the product of the BCR-ABL fusion gene was evaluated in both blood and bone marrow specimens by real-time RT-PCR using the TaqMan probe system. In 113 simultaneously obtained blood and bone marrow samples, the BCR-ABL transcript values agreed well with cytogenetic data. Blood and bone marrow specimens gave comparable values for BCR-ABL transcripts. Before start of imatinib therapy there was a considerable variation in BCR-ABL transcripts among the patients, ranging approximately one log (base 10). Similarly, patients with a complete cytogenetic response following imatinib therapy had variable BCR-ABL transcript levels, ranging at least three logs (base 10). The major decline in BCR-ABL transcripts occurred within 6 mo after start of imatinib therapy. The decline in BCR-ABL transcripts, following imatinib therapy, appears to level off at 12-15 mo. Two late responders were identified with a still decreasing level in BCR-ABL transcripts after 24 mo of treatment. It is concluded that BCR-ABL mRNA quantification in peripheral blood is suitable for routine monitoring of the response to treatment and long-term disease status in CML, especially in patients who have achieved a complete cytogenetic response. A plateau in BCR-ABL transcripts seems to have been reached after 12-15 mo of imatinib treatment; however, some "late responders" are seen.


Local health departments' mission to the uninsured.
It is often maintained that local health departments (LHDs) should not directly provide personal health services. However, our nationally representative sample revealed that most LHD directors (87%) believed LHDs must directly provide these services, primarily because they perceived a high level of unmet need among the uninsured. While only a minority believed LHDs should focus exclusively on the core functions, this proportion rose dramatically when we asked directors to assume that there were no uninsured people. Directors who perceived a high level of unmet need among the uninsured in their jurisdictions were much less likely to believe that LHDs should exclusively focus on the core functions. In theory, LHDs have a unique responsibility for assuring that the uninsured and vulnerable have access to personal health services. However, a majority of directors (67%) acknowledged that they have no enforceable means of assuring access to services the health department did not directly provide.


Characteristics of Mothers Admitted to Intensive Care Units During Hospitalization for Delivery of a Live-born Infant: United States, 2020-2022.
Although admission of a mother to an intensive care unit (ICU) during hospitalization for delivery is a relatively rare event, rates of mortality and severe morbidity are high for both mother and child when ICU care is necessary (1-4). Studies on maternal ICU admissions have generally focused on medical diagnoses related to admission, and most have been conducted using international data or data for a hospital or group of hospitals (4-10). Information on demographic characteristics of mothers admitted to ICUs is lacking at the national level. This report describes ICU admissions overall and by race and Hispanic origin, maternal age, live birth order, and plurality for mothers delivering live-born infants in the United States in 2020-2022.


Evaluating the integration of eye-tracking and motion capture technologies: Quantifying the accuracy and precision of gaze measures.
Integrating mobile eye tracking and optoelectronic motion capture enables point of gaze to be expressed within the laboratory co-ordinate system and presents a method not commonly applied during research examining dynamic behaviors, such as locomotion. This paper examines the quality of gaze data collected through the integration. Based on research suggesting increased viewing distances are associated with reduced data quality; the accuracy and precision of gaze data as participants (N = 11) viewed floor-based targets at distances of 1-6 m was investigated. A mean accuracy of 2.55 ± 1.12° was identified, however, accuracy and precision measures (relative to targets) were significantly (p < .05) reduced at greater viewing distances. We then consider if signal processing techniques may improve accuracy and precision, and overcome issues associated with missing data. A 4th-order Butterworth lowpass filter with cut-off frequencies determined via autocorrelation did not significantly improve data quality, however, interpolation via Quintic spline was sufficient to overcome gaps of up to 0.1 s. We conclude the integration of gaze and motion capture presents a viable methodology in the study of human behavior and presents advantages for data collection, treatment, and analysis. We provide considerations for the collection, analysis, and treatment of gaze data that may help inform future methodological decisions.


Occluding junctions as novel regulators of tissue mechanics during wound repair.
In epithelial tissues, cells tightly connect to each other through cell-cell junctions, but they also present the remarkable capacity of reorganizing themselves without compromising tissue integrity. Upon injury, simple epithelia efficiently resolve small lesions through the action of actin cytoskeleton contractile structures at the wound edge and cellular rearrangements. However, the underlying mechanisms and how they cooperate are still poorly understood. In this study, we combine live imaging and theoretical modeling to reveal a novel and indispensable role for occluding junctions (OJs) in this process. We demonstrate that OJ loss of function leads to defects in wound-closure dynamics: instead of contracting, wounds dramatically increase their area. OJ mutants exhibit phenotypes in cell shape, cellular rearrangements, and mechanical properties as well as in actin cytoskeleton dynamics at the wound edge. We propose that OJs are essential for wound closure by impacting on epithelial mechanics at the tissue level, which in turn is crucial for correct regulation of the cellular events occurring at the wound edge.


BIOCAT: a pattern recognition platform for customizable biological image classification and annotation.
Pattern recognition algorithms are useful in bioimage informatics applications such as quantifying cellular and subcellular objects, annotating gene expressions, and classifying phenotypes. To provide effective and efficient image classification and annotation for the ever-increasing microscopic images, it is desirable to have tools that can combine and compare various algorithms, and build customizable solution for different biological problems. However, current tools often offer a limited solution in generating user-friendly and extensible tools for annotating higher dimensional images that correspond to multiple complicated categories. We develop the BIOimage Classification and Annotation Tool (BIOCAT). It is able to apply pattern recognition algorithms to two- and three-dimensional biological image sets as well as regions of interest (ROIs) in individual images for automatic classification and annotation. We also propose a 3D anisotropic wavelet feature extractor for extracting textural features from 3D images with xy-z resolution disparity. The extractor is one of the about 20 built-in algorithms of feature extractors, selectors and classifiers in BIOCAT. The algorithms are modularized so that they can be "chained" in a customizable way to form adaptive solution for various problems, and the plugin-based extensibility gives the tool an open architecture to incorporate future algorithms. We have applied BIOCAT to classification and annotation of images and ROIs of different properties with applications in cell biology and neuroscience. BIOCAT provides a user-friendly, portable platform for pattern recognition based biological image classification of two- and three- dimensional images and ROIs. We show, via diverse case studies, that different algorithms and their combinations have different suitability for various problems. The customizability of BIOCAT is thus expected to be useful for providing effective and efficient solutions for a variety of biological problems involving image classification and annotation. We also demonstrate the effectiveness of 3D anisotropic wavelet in classifying both 3D image sets and ROIs.


Endoscopic and histologic findings in a cohort of uric acid and calcium oxalate stone formers.
To characterize the endoscopic and histologic renal papillary lesions in a cohort of uric acid (UA) stone formers (SF). Data were prospectively obtained during percutaneous nephrolithotomy between 2009 and 2013. Renal papillae were endoscopically analyzed to quantitate surface area occupied by plaque or plug, and biopsies were obtained. UA SF were compared with non-SF controls and patients with >50% calcium oxalate (CaOx) in the absence of UA. There were 23 UA SF; of which 19 stones (83%) were admixed with CaOx and 4 (17%) were pure. Compared with CaOx SF and controls, UA SF had a higher prevalence of diabetes and obesity, greater serum creatinine and UA levels, lower estimated glomerular filtration rate and urine pH, and elevated UA supersaturation. Characteristics of UA SF were compared with 95 CaOx SF and 19 controls. Overall, 23 (100%) UA SF had endoscopic plaque and 13 (57%) plugs. Endoscopically, UA SF displayed a greater incidence of plugging (57% vs 45% vs 11%; P = .006) relative to CaOx SF and controls. Likewise, UA SF had a greater percentage surface area of plugging (0.1 vs 0.0; P = .002) and plaque (2.0 vs 0.9; P = .006) than controls but similar amounts to CaOx SF. Histologic plugs were similar in UA and CaOx SF, although CaOx SF demonstrated greater interstitial inflammation on endoscopic biopsy. UA and CaOx SF have similar amounts of plaque, whereas UA SF have more endoscopic but not histologic collecting duct plugs. These data suggest an overlap between the pathogenesis of UA and CaOx stones. The anchoring site for UA stones remains uncertain.


JPH3 repeat expansions cause a progressive akinetic-rigid syndrome with severe dementia and putaminal rim in a five-generation African-American family.
We report the clinical, neuropsychological, genetic, and radiological features of a large five-generation African-American kindred from the southern USA presenting with a progressive akinetic-rigid syndrome and severe dementia, but clinically insignificant chorea, due to mutations in junctophillin 3 (JPH3). Overt disease onset was in the mid-20s to late 30s with cognitive decline, REM sleep disturbance, or psychiatric features, followed by development of a levodopa-unresponsive akinetic-rigid motor syndrome. Dystonia and myoclonus were present in some subjects. A bedridden, nonverbal severely akinetic-rigid state developed within 10 to 15 years after onset. CTG repeat expansions ranged from 47 to 53. Imaging revealed generalized cerebral atrophy with severe striatal involvement and putaminal rim hyperintensity. Analysis of our kindred indicates that JPH3 mutations should be considered in the differential diagnosis of early-onset dementia and hypokinetic-rigid syndromes in individuals of African descent. Moreover, chorea may not be overtly manifest at presentation or during significant parts of the disease course.


Effect of the thiol-thiolate equilibrium on the photophysical properties of aqueous CdSe/ZnS nanocrystal quantum dots.
We study the effect of thiols on the emission efficiency of aqueous CdSe/ZnS core/shell nanocrystal quantum dots (NQDs). We observe that the impact of thiol addition on emission quantum yields (QYs) is time-, concentration-, and pH-dependent. Further, we use a combination of time-resolved spectroscopic methods to determine the mechanism by which thiol addition can cause either increases or decreases in QYs. Specifically, through transient absorption measurements, we show that thiol addition can improve passivation of electron traps, increasing QYs at low thiol concentrations. Further, using nanosecond photoluminescence (PL), we observe that at higher thiol concentrations, hole traps are introduced that reduce PL QYs. Last, through a combination of pH-dependence and control studies (e.g., addition of 2-methyl thioethanol to an aqueous NQD solution and addition of dodecanethiol to a hexane NQD solution), we demonstrate that it is the ability of thiols in aqueous solution to generate thiolate that is the source of both favorable and adverse QY changes. Our results contribute to the understanding of the role of surface ligands, which is critical to the design of stable, high-quantum-yield, nonblinking NQDs.


New Vistas on the Pathomechanism of Charcot-Marie-Tooth and Related Peripheral Neuropathies.
A gene-dosage mechanism in CMT1A and HNPP has been postulated previously. Here, recent findings are discussed concerning (i) the functional consequences of altered PMP22 expression on Schwann cell growth regulation and on the capacity of genetically modified Schwann cells to myelinate peripheral axons, (ii) the cell physiological effects caused by the expression of certain disease-related missense mutations of PMP22 that are known to alter the Schwann cell phenotype and impair myelination in vivo, and (iii) the pathomechanism of CMT1 in light of findings on a novel association between PMP22 and P0 in PNS myelin.


Structural origin for vibration-induced accelerated aging and rejuvenation in metallic glasses.
Glassy materials are nonequilibrium and their energy states have crucial influences on properties. Recent studies have shown that oscillating deformations (vibrations) can cause either accelerated aging (lowering energy) or rejuvenation (elevating energy); however, the underlying atomic mechanisms remain elusive. Using metallic glasses (MGs) as model systems, we show that the vibration-induced accelerated aging is correlated with the strain field of the stringlike atomic motions stemming from the Johari-Goldstein (β) relaxation, whereas the rejuvenation is associated with nonlinear response and the formation of nanoscale shear bands attributing to the activation of α relaxation. Both processes are affected by thermal fluctuations, which result in an optimal temperature for accelerated aging. These results suggest intrinsic correlations among relaxation dynamics, mechanical properties, and the vibration induced structural rearrangements in MGs.


[Pathology of the organ of vision in chronic fatigue syndrome].
218 patients were examined and the chronic fatigue syndrome (CFS) was diagnosed in them on the basis of clinical-and-immunologic data. 126 somatically healthy persons of the same age and sex were in the control group. Vascular pathology of the vision organ was found in 153 (70.2%) persons, and dystrophic pathology was found in 115 (52.8%) persons. A combination of vascular and dystrophic pathologies of the vision organ was diagnosed in 46 (21.1%) patients. The detection of vision pathology in the CFS patients essentially exceeded the morbidity of similar pathology in the controls. No reliable differences of refraction anomalies were found between the CFS patients and the controls.


Health Status of Female and Male Vegetarian and Vegan Endurance Runners Compared to Omnivores-Results from the NURMI Study (Step 2).
Health effects of vegetarian and vegan diets are well known. However, data is sparse in terms of their appropriateness for the special nutritional demands of endurance runners. Therefore, the aim of this study was to investigate the health status of vegetarian (VER) and vegan endurance runners (VGR) and compare it to omnivorous endurance runners (OR). A total of 245 female and male recreational runners completed an online survey. Health status was assessed by measuring health-related indicators (body weight, mental health, chronic diseases, and hypersensitivity reactions, medication intake) and health-related behavior (smoking habits, supplement intake, food choice, healthcare utilization). Data analysis was performed by using non-parametric ANOVA and MANOVA. There were 109 OR, 45 VER and 91 VGR. Significant differences (p < 0.05) were determined for the following findings: (i) body weight for VER and VGR was less than for OR, (ii) VGR had highest food choice scores, and (iii) VGR reported the lowest prevalences of allergies. There was no association (p > 0.05) between diet and mental health, medication intake, smoking habits, supplement intake, and healthcare utilization. These findings support the notion that adhering to vegetarian kinds of diet, in particular to a vegan diet, is associated with a good health status and, thus, at least an equal alternative to an omnivorous diet for endurance runners.


Lifetime socioeconomic position and twins' health: an analysis of 308 pairs of United States women twins.
Important controversies exist about the extent to which people's health status as adults is shaped by their living conditions in early life compared to adulthood. These debates have important policy implications, and one obstacle to resolving them is the relative lack of sufficient high-quality data on childhood and adult socioeconomic position and adult health status. We accordingly compared the health status among monozygotic and dizygotic women twin pairs who lived together through childhood (until at least age 14) and subsequently were discordant or concordant on adult socioeconomic position. This comparison permitted us to ascertain the additional impact of adult experiences on adult health in a population matched on early life experiences. Our study employed data from a cross-sectional survey and physical examinations of twins in a population-based twin registry, the Kaiser Permanente Women Twins Study Examination II, conducted in 1989 to 1990 in Oakland, California, United States. The study population was composed of 308 women twin pairs (58% monozygotic, 42% dizygotic); data were obtained on childhood and adult socioeconomic position and on blood pressure, cholesterol, post-load glucose, body mass index, waist-to-hip ratio, physical activity, and self-rated health. Health outcomes among adult women twin pairs who lived together through childhood varied by their subsequent adult occupational class. Cardiovascular factors overall differed more among monozygotic twin pairs that were discordant compared to concordant on occupational class. Moreover, among the monozygotic twins discordant on adult occupational class, the working class twin fared worse and, compared to her professional twin, on average had significantly higher systolic blood pressure (mean matched difference = 4.54 mm Hg; 95% confidence interval [CI], 0.10-8.97), diastolic blood pressure (mean matched difference = 3.80 mm Hg; 95% CI, 0.44-7.17), and low-density lipoprotein cholesterol (mean matched difference = 7.82 mg/dl; 95% CI, 1.07-14.57). By contrast, no such differences were evident for analyses based on educational attainment, which does not capture post-education socioeconomic position. These results provide novel evidence that lifetime socioeconomic position influences adult health and highlight the utility of studying social plus biological aspects of twinship.


Influencing the decline of lung function in COPD: use of pharmacotherapy.
Chronic obstructive pulmonary disease (COPD) is a common and deadly disease. One of the hallmarks of COPD is an accelerated decline in lung function, as measured by spirometry. Inflammation, oxidative stress and other pathways are hypothesized to be important in this deterioration. Because progressive airflow obstruction is associated with considerable morbidity and mortality, a major goal of COPD treatment has been to slow or prevent the accelerated decline in lung function. Until recently, the only known effective intervention was smoking cessation. However, newly reported large clinical trials have shown that commonly used medications may help slow the rate of lung function decline. The effect of these medications is modest (and thus required such large, expensive trials) and to be of clinical benefit, therapy would likely need to start early in the course of disease and be prolonged. Such a treatment strategy aimed at preservation of lung function would need to be balanced against the side effects and costs of prolonged therapy. A variety of newer classes of medications may help target other pathophysiologically important pathways, and could be used in the future to prevent lung function decline in COPD.


Tuneable Giant Magnetocaloric Effect in (Mn,Fe)₂(P,Si) Materials by Co-B and Ni-B Co-Doping.
The influence of Co (Ni) and B co-doping on the structural, magnetic and magnetocaloric properties of (Mn,Fe) 2 (P,Si) compounds is investigated by X-ray diffraction (XRD), differential scanning calorimetry, magnetic and direct temperature change measurements. It is found that Co (Ni) and B co-doping is an effective approach to tune both the Curie temperature and the thermal hysteresis of (Mn,Fe) 2 (P,Si) materials without losing either the giant magnetocaloric effect or the positive effect of the B substitution on the mechanical stability. An increase in B concentration leads to a rapid decrease in thermal hysteresis, while an increase in the Co or Ni concentration hardly changes the thermal hysteresis of the (Mn,Fe) 2 (P,Si) compounds. However, the Curie temperature decreases slowly as a function of the Co or Ni content, while it increases dramatically for increasing B concentration. Hence, the co-substitution of Fe and P by Co (Ni) and B, respectively, offers a new control parameter to adjust the Curie temperature and reduce the thermal hysteresis of the (Mn,Fe) 2 (P,Si) materials.


Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases.
One general principle of gene regulation is that DNA-binding transcription factors modulate transcription by recruiting cofactors that modify histones and chromatin structure. A second implicit principle is that a particular cofactor is necessary at all the target genes where the cofactor is recruited. Increasingly, these principles do not appear to be absolute, as experimentally defined relationships between transcription, cofactors and chromatin modification grow in complexity. The KAT3 histone acetyltransferases CREB binding protein (CBP) and p300 have at least 400 interacting protein partners, thereby acting as hubs in gene regulatory networks. Studies using mutant primary cells indicate that the occurrence of CBP and p300 at any given target gene sometimes correlates with, rather than dictates transcription. This suggests that there are unexpected levels of redundancy between CBP/p300 and other unrelated coactivators, or that CBP/p300 recruitment may sometimes be coincidental. A transcription factor may therefore recruit the same group of coactivators as part of its "toolbox", but it is the characteristics of the individual target gene that determine which coactivation "tools" are required for its transcription.


BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method.
Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene-mutation-cell-behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and ∼40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants. Analysis of simultaneous multiple patch-clamp recordings from 6068 pairs of rat neurons with validation in additional mouse and human neurons and multiple learning tests from 1486 rats identified BRaf as the key missing signaling effector in the common synaptic NMDA-R-CaMKII-SynGap-Ras-BRaf-MEK-ERK transduction cascade. Moreover, the analysis creates the original big data unveiling three general features of BRaf signaling. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.


Inflammatory and coagulatory markers and exposure to different size fractions of particle mass, number and surface area air concentrations in Swedish iron foundries, in particular respirable quartz.
To study the relationship between inhalation of airborne particles and quartz in Swedish iron foundries and markers of inflammation and coagulation in blood. Personal sampling of respirable dust and quartz was performed for 85 subjects in three Swedish iron foundries. Stationary measurements were used to study the concentrations of respirable dust and quartz, inhalable and total dust, PM10 and PM2.5, as well as the particle surface area and the particle number concentrations. Markers of inflammation, namely interleukins (IL-1β, IL-6, IL-8, IL-10 and IL-12), C-reactive protein, and serum amyloid A (SAA) were measured in plasma or serum, together with markers of coagulation including fibrinogen, factor VIII (FVIII), von Willebrand factor and D-dimer. Complete sampling was performed on the second or third day of a working week after a work-free weekend, and follow-up samples were collected 2 days later. A mixed model analysis was performed including sex, age, smoking, infections, blood group, sampling day and BMI as covariates. The average 8-h time-weighted average air concentrations of respirable dust and quartz were 0.85 mg/m3 and 0.052 mg/m3, respectively. Participants in high-exposure groups with respect to some of the measured particle types exhibited significantly elevated levels of SAA, fibrinogen and FVIII. These observed relationships between particle exposure and inflammatory markers may indicate an increased risk of cardiovascular disease among foundry workers with high particulate exposure.


Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia.
Long non-coding RNAs (lncRNAs) have emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. However, the role and expression pattern of lncRNAs in molecular subtypes of B cell acute lymphoblastic leukemia (BCP-ALL) have not yet been investigated. Here, we assess to what extent lncRNA expression and DNA methylation is driving the progression of relapsed BCP-ALL subtypes and we determine if the expression and DNA methylation profile of lncRNAs correlates with established BCP-ALL subtypes. We performed RNA sequencing and DNA methylation (Illumina Infinium microarray) of 40 diagnosis and 42 relapse samples from 45 BCP-ALL patients in a German cohort and quantified lncRNA expression. Unsupervised clustering was applied to ascertain and confirm that the lncRNA-based classification of the BCP-ALL molecular subtypes is present in both our cohort and an independent validation cohort of 47 patients. A differential expression and differential methylation analysis was applied to determine the subtype-specific, relapse-specific, and differentially methylated lncRNAs. Potential functions of subtype-specific lncRNAs were determined by using co-expression-based analysis on nearby (cis) and distally (trans) located protein-coding genes. Using an integrative Bioinformatics analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific and 942 relapse-specific lncRNAs and the methylation profile of three subtypes of BCP-ALL. The 1235 subtype-specific lncRNA signature represented a similar classification of the molecular subtypes of BCP-ALL in the independent validation cohort. We identified a strong correlation between the DUX4-specific lncRNAs and genes involved in the activation of TGF-β and Hippo signaling pathways. Similarly, Ph-like-specific lncRNAs were correlated with genes involved in the activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we found 23 promoter methylated lncRNAs epigenetically facilitating their expression levels. Here, we describe a set of subtype-specific and relapse-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. The subtype-specific lncRNAs are reproducible and can effectively stratify BCP-ALL subtypes. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining which lncRNAs are involved in the pathogenesis of disease and are relevant for the stratification of BCP-ALL subtypes.


Motives for Studying and Student Wellbeing: Validation of the Motivational Mindset Model.
Research on the joint effect of multiple motives for studying was recently given a push in a new direction with the introduction of the motivational mindset model (MMM). This model contributes to a better understanding of study success and student wellbeing in higher education. The aim of the present study is to validate the newly developed model and the associated mindset classification tool (MCT). To this end, 662 first-year university students were classified in one of the four types of motivational mindset using the classification tool and three exploratory validation procedures were conducted through sense of purpose, study engagement, and students' background characteristics in terms of gender and ethnicity. Both purpose and study engagement are central dimensions of student wellbeing and predictors of study success. The results show that (1) sense of purpose and study engagement differ across the four types of mindset, (2) students in the low-impact mindset show the least optimal pattern of study engagement and sense of purpose, (3) sense of purpose and study engagement are positively related and this relationship is consistent across mindsets, and (4) overall differences in purpose and study engagement between gender and ethnic subgroups stem from one specific type of motivational mindset. The results provide support for the validity of the MMM and the usefulness of the MCT. The implications of the findings are discussed as well as promising avenues for future research.


PLK1 regulates spindle formation kinetics and APC/C activation in mouse zygote.
Polo-like kinase 1 (PLK1) is involved in essential events of cell cycle including mitosis in which it participates in centrosomal microtubule nucleation, spindle bipolarity establishment and cytokinesis. Although PLK1 function has been studied in cycling cancer cells, only limited data are known about its role in the first mitosis of mammalian zygotes. During the 1-cell stage of mouse embryo development, the acentriolar spindle is formed and the shift from acentriolar to centrosomal spindle formation progresses gradually throughout the preimplantation stage, thus providing a unique possibility to study acentriolar spindle formation. We have shown previously that PLK1 activity is not essential for entry into first mitosis, but is required for correct spindle formation and anaphase onset in 1-cell mouse embryos. In the present study, we extend this knowledge by employing quantitative confocal live cell imaging to determine spindle formation kinetics in the absence of PLK1 activity and answer the question whether metaphase arrest at PLK1-inhibited embryos is associated with low anaphase-promoting complex/cyclosome (APC/C) activity and consequently high securin level. We have shown that inhibition of PLK1 activity induces a delay in onset of acentriolar spindle formation during first mitosis. Although these PLK1-inhibited 1-cell embryos were finally able to form a bipolar spindle, not all chromosomes were aligned at the metaphase equator. PLK1-inhibited embryos were arrested in metaphase without any sign of APC/C activation with high securin levels. Our results document that PLK1 controls the onset of spindle assembly and spindle formation, and is essential for APC/C activation before anaphase onset in mouse zygotes.


Favorable evolution of severe paraquat poisoning. Treatment with gastric lavage, activated charcoal, cyclophosphamide + corticoids, and conventional daily hemodialysis: case study at the Franck Joly Hospital Center in french Guiana
We report the observations of two patients, having voluntarily ingested lethal doses of paraquat with suicidal intent, with an unfavorable prognostic score. The treatment consisted of gastric lavage, administration of activated charcoal, n-acetylcysteine and cyclophosphamide + methylprednisolone + dexamethasone. The installation of acute renal failure motivated the initiation of daily conventional hemodialysis (HD) over 10 to 14 days, with a favorable evolution. The following complications were recorded: anemia, bacteremia and deep vein thrombosis. These observations raise three questions in the treatment of paraquat intoxication: the effectiveness of HD, the interest of its association with the above therapies in the prevention of pulmonary fibrosis, and the need for infectious prevention and thromboembolism. Furthermore, the absence of a paraquatemia assay cannot constitute a limitation for management, and hemoperfusion on an inaccessible charcoal column can be replaced by an HD usually available.


Characterization of anti-CCR5 ribozyme-transduced CD34+ hematopoietic progenitor cells in vitro and in a SCID-hu mouse model in vivo.
The cellular entry of HIV is mediated by the specific interaction of viral envelope glycoproteins with the cell-surface marker CD4 and a chemokine receptor (CCR5 or CXCR4). Individuals with a 32-base-pair (bp) deletion in the CCR5 coding region, which results in a truncated peptide, show resistance to HIV-1 infection. This suggests that the downregulation of CCR5 expression on target cells may prevent HIV infection. Therefore, ribozymes that inhibit the CCR5 expression offer a novel approach for anti-HIV gene therapy. To assess the effect of an anti-CCR5 ribozyme (R5Rbz) on macrophage differentiation, CD34+ hematopoietic progenitor cells were transduced with a retroviral vector carrying RSRbz and allowed to differentiate in the presence of appropriate cytokines. R5Rbz-transduced CD34+ cells differentiated normally into mature macrophages that carried CD14 and CD4 surface markers, expressed the anti-CCR5 ribozyme, and showed significant resistance to viral infection upon challenge with the HIV-1 BaL strain. Using an in vivo thymopoiesis model, the effect of RSRbz on stem cell differentiation into thymocytes was evaluated by reconstituting SCID-hu mice thymic grafts with ribozyme-transduced CD34+ cells. FACS analysis of cell biopsies at 4 and 6 weeks postengraftment for HLA, CD4, and CD8 markers showed comparable levels of reconstitution and similar percentages of subpopulations of thymocytes between grafts receiving R5Rbz-transduced and control CD34+ cells. RT-PCR assays demonstrated the expression of the anti-CCR5 ribozyme in CD4+, CD8+, and CD4+/CD8+ thymocyte subsets derived from RSRbz-transduced CD34+ cells. These results indicate that anti-CCR5 ribozyme can be introduced into hematopoietic stem cells without adverse effects on their subsequent lineage-specific differentiation and maturation. The expression of anti-CCR5 ribozymes in HIV-1 target cells offers a novel gene therapy strategy to control HIV infection.


Failed laser trabeculoplasty requiring surgery in open-angle glaucoma.
Argon laser trabeculoplasty (ALT) has been successful in controlling open-angle glaucoma, but a significant number of patients still require filtration surgery. Concern that post-laser inflammatory changes or alterations of structural anatomy with damage to the trabecular meshwork may adversely affect the outcome of filtration surgery prompted a retrospective review of 87 consecutive eyes with open-angle glaucoma that required filtration surgery following failed ALT. The follow-up period was at least 6 months, with a mean of 18 months (6 to 38 months). Posterior lip sclerectomy was chosen for 69 eyes and trabeculectomy for 18 eyes. The overall success rate of filtration surgery during the follow-up period was 92%. There was no recognized difference in the response to filtration surgery following ALT.


Recurrent antitopographic inhibition mediates competitive stimulus selection in an attention network.
Topographically organized neurons represent multiple stimuli within complex visual scenes and compete for subsequent processing in higher visual centers. The underlying neural mechanisms of this process have long been elusive. We investigate an experimentally constrained model of a midbrain structure: the optic tectum and the reciprocally connected nucleus isthmi. We show that a recurrent antitopographic inhibition mediates the competitive stimulus selection between distant sensory inputs in this visual pathway. This recurrent antitopographic inhibition is fundamentally different from surround inhibition in that it projects on all locations of its input layer, except to the locus from which it receives input. At a larger scale, the model shows how a focal top-down input from a forebrain region, the arcopallial gaze field, biases the competitive stimulus selection via the combined activation of a local excitation and the recurrent antitopographic inhibition. Our findings reveal circuit mechanisms of competitive stimulus selection and should motivate a search for anatomical implementations of these mechanisms in a range of vertebrate attentional systems.


Anatomical distribution and daily profile of gper1b gene expression in brain and peripheral structures of goldfish (Carassius auratus).
The functional organization of the circadian system and the location of the main circadian oscillators vary through phylogeny. Present study investigates by in situ hybridization the anatomical location of the clock gene gPer1b in forebrain and midbrain, pituitary, and in two peripheral locations, the anterior intestine and liver, in a teleost fish, the goldfish (Carassius auratus). Moreover, the daily expression profiles of this gene were also studied by quantitative Real Time-PCR. Goldfish were maintained under a 12L-12D photoperiod and fed daily at 2 h after lights were switched on. A wide distribution of gPer1b mRNA in goldfish brain and pituitary was found in telencephalon, some hypothalamic nuclei (including the homologous to mammalian SCN), habenular nucleus, optic tectum, cerebellum and torus longitudinalis. Moreover, gPer1b expression was observed, for the first time in teleosts, in the pituitary, liver and anterior intestine. Day/night differences in gper1b mRNA abundance were found by in situ hybridization, with higher signal at nighttime that correlates with the results obtained by RT-PCR, where a rhythmic gPer1b expression was found in all tissues with acrophases at the end of the night. Amplitudes of gper1b rhythms vary among tissues, being higher in liver and intestine than in the brain, maybe because different cues entrain clocks in these locations. These results support the existence of functional clocks in many central and peripheral locations in goldfish coordinated, ticking at the same time.


Time to revisit arsenic regulations: comparing drinking water and rice.
Current arsenic regulations focus on drinking water without due consideration for dietary uptake and thus seem incoherent with respect to the risks arising from rice consumption. Existing arsenic guidelines are a cost-benefit compromise and, as such, they should be periodically re-evaluated. Literature data was used to compare arsenic exposure from rice consumption relative to exposure arising from drinking water. Standard risk assessment paradigms show that arsenic regulations for drinking water should target a maximum concentration of nearly zero to prevent excessive lung and bladder cancer risks (among others). A feasibility threshold of 3 μg As l(-1) was determined, but a cost-benefit analysis concluded that it would be too expensive to target a threshold below 10 μg As l(-1). Data from the literature was used to compare exposure to arsenic from rice and rice product consumption relative to drinking water consumption. The exposure to arsenic from rice consumption can easily be equivalent to or greater than drinking water exposure that already exceeds standard risks and is based on feasibility and cost-benefit compromises. It must also be emphasized that many may disagree with the implications for their own health given the abnormally high cancer odds expected at the cost-benefit arsenic threshold. Tighter drinking water quality criteria should be implemented to properly protect people from excessive cancer risks. Food safety regulations must be put in place to prevent higher concentrations of arsenic in various drinks than those allowed in drinking water. Arsenic concentrations in rice should be regulated so as to roughly equate the risks and exposure levels observed from drinking water.


Sporting activity following colic surgery in horses: a retrospective study.
There is a paucity of studies addressing sporting activity and horse owners' satisfaction after horses have undergone colic surgery. To determine 1) survival rate after colic surgery, 2) prevalence of horses returning to, or starting, sporting activities and 3) assess the owners' satisfaction regarding colic surgery. Cases that underwent exploratory celiotomy for colic between January 2005 and August 2010 were reviewed. All horses that had one or more celiotomies and were discharged after colic surgery were included in a telephone questionnaire survey. Only horses that survived at least 6 months after colic surgery were included in the sporting activity analysis. Data extracted from the records included case details, intra-operative diagnosis and surgical treatment. Information from a telephone questionnaire included the horses' post surgical details (horse alive or subjected to euthanasia, post operative complications, pre- and post surgical use, return to sporting activity, sporting performance, behavioural changes, management changes and recommendation by owner for colic surgery). A logistic regression model was used for the statistical analysis of post hospitalisation performance and an ordinal regression model used for analysis of post colic complications and of owner's recommendation of surgery. A Kaplan-Meier survival curve was computed to show survival of horses discharged after colic surgery. The survival rates (%) at 6, 12, 24, 36, 48 and 60 months were 95.3, 86.6, 80.9, 76.9, 62.1 and 57.6, respectively. A large majority of horses (86.1%) resumed or started sporting activities after colic surgery. The proportion of horses that the owners believed to achieve the same or better performance after surgery was 83.5%. In 89.9% of the cases, owners stated that they would recommend colic surgery. Horses discharged after colic surgery had a high long-term survival rate. A high prevalence of horses resumed or started sporting activities with a high proportion of horses at their presurgical performance level. The large majority of owners of discharged horses were satisfied with colic surgery performed on their horses.


Competing with kreteks: transnational tobacco companies, globalisation, and Indonesia.
To examine the strategies employed by transnational tobacco companies (TTCs) to compete more effectively compete with the dominant kretek manufacturers in Indonesia, and to consider implications of their failure. Systematic analysis of corporate documents obtained from British American Tobacco's (BAT's) Guildford depository and from industry and tobacco control websites document collections. The limited progress of the TTCs in Indonesia is best explained by the distinctive political economy of its tobacco industry. Though effective when collaborating on regulatory issues of mutual interest, TTCs have been less able than kretek manufacturers to exercise political influence where their interests conflict. Global strategies of TTCs have undergone significant local adaptation in attempting to compete in this distinctive environment. While maintaining uniformity in core brand attributes, TTCs have sought to reconcile international imagery with local norms, particularly to appeal to women. BAT unsuccessfully attempted to develop clove based products that imitated the appeal of kreteks, withdrawn following concerns about exposing the company to charges of operating double standards. The documents presented highlight the complexity of the global tobacco industry. Tobacco control efforts need to address more effectively the ongoing impact of kreteks while recognising the distinctive threats posed by TTCs.


Chronic Granulomatous Invasive Fungal Sinusitis: A Case Series and Literature Review.
Chronic granulomatous invasive fungal sinusitis (CGIFS) is a peculiar disease of the paranasal sinuses due to its rarity, patient subset, and disease course. We describe 7 cases of histopathologically confirmed CGIFS with different treatment plans and varying outcomes. Of particular note was that one of these patients developed allergic fungal rhinosinusitis after complete resolution of his primary invasive disease, a finding that has never been reported in the literature. Another patient had an atypical fungal species (Aspergillus nidulans) on fungal stain and culture, while one immunodeficient patient had a large intracerebral disease component and died after 2 months of treatment. We also present a review of the pertinent literature investigating this rare disease.


Beta-hydroxy-gamma-lactones as chiral building blocks for the enantioselective synthesis of marine natural products.
The enantioselective synthesis of trans-(+)-laurediol, (2S,3S,5R)-5-[(1R)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol, and (2S,3S,5S)-5-[(1S)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol are described. In addition, a formal synthesis of trans-(-)-kumausyne is also developed. All the synthetic procedures have in common the use of enantiomerically enriched beta-hydroxy-gamma-lactones, easily available by Sharpless asymmetric dihydroxylation (AD) from the suitable beta,gamma-unsaturated ester. The use of Katsuki-Sharpless asymmetric epoxidation (AE) as an additional enantioselective reaction provides cyclic compounds of high enantiomeric purity.


Regulation of lung fibroblast activation by annexin A1.
Annexin-A1 (AnxA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The contribution of AnxA1 to human cell biology is not well understood. We investigated the contribution of AnxA1 and its receptor, formyl-peptide receptor 2 (FPR2), to the regulation of inflammatory responses in human normal lung fibroblasts (NLF). Silencing constitutive AnxA1 expression in NLF using small interfering RNA (siRNA) was associated with moderate but significant increases in tumor necrosis factor (TNF)-induced proliferation and interleukin (IL)-6 production, accompanied by reduction of ERK and NF-κB activity. AnxA1 regulation of ERK and NF-κB activation was associated with effects on proliferation. Blocking FPR2 using the specific antagonist WRW4 mimicked the effects of AnxA1 silencing on TNF-induced proliferation, IL-6, ERK, and NF-κB activation. AnxA1 silencing also impaired inhibitory effects of glucocorticoid on IL-6 production and on the expression of glucocorticoid-induced leucine zipper (GILZ), but blocking FPR2 failed to mimic these effects of AnxA1 silencing. These data suggest that AnxA1 regulates TNF-induced proliferation and inflammatory responses in lung fibroblasts, via effects on the ERK and NF-κB pathways, which depend on FPR2. AnxA1 also mediates effects of glucocorticoids and GILZ expression, but these effects appear independent of FPR2. These findings suggest that mimicking AnxA1 actions might have therapeutic potential in chronic inflammatory lung diseases.


Identification and prevalence of swine pasivirus 1 in eastern Romanian pig farms.
Swine pasivirus 1 (SPaV-1) was first detected in the feces of healthy pigs in France as a new species in family Picornaviridae. We investigated the presence, distribution, and genetic variability of this virus in 7 geographic areas with intensive pig breeding farms in eastern Romania. A total of 564 porcine specimens, including 82 fecal specimens and 482 pools of organs, were collected from healthy pigs in different stages of production from pathogen-free swine farming units. The virus was found in 6 of 7 areas investigated. Of the 564 samples analyzed, 218 were positive for SPaV-1, with the highest prevalence of the virus in organ homogenates (39% positive) followed by feces (37% positive). The highest susceptibility to infection was found in nurseries (50% positive in both the first and second months of feeding). Sequencing analysis of VP0 revealed 3 different Romanian sequences. The phylogenetic investigations suggest that the Romanian sequences cluster with other Pasivirus strains selected from the GenBank database, forming a separate clade from other Picornaviridae genera and defining the described Pasivirus.


Learning among nursing faculty: insights from a participatory action research project about teaching international students.
It is imperative that nursing education addresses the issues arising from globalization. The adjustment challenges faced by international nursing students globally highlight the need to understand how nursing faculty experience and teach nursing classes with a mix of domestic and foreign students. This article reports on a participatory action research (PAR) study to examine and enhance the scholarly teaching of international nursing students. The overarching research question for this PAR was: How did participation in a PAR study contribute to shared learning and professional development of nursing faculty teaching international students? Five major themes were identified across the PAR: creating sharing spaces, recognizing and respecting diversity, developing and acknowledging teaching capabilities, utilizing precious time, and valuing the research. In summary, PAR was a useful approach to engage faculty in research by providing a process and a space to address concerns about the teaching and learning of international students.


Electrophysiologic effects of nitroglycerin during experimental coronary occlusion.
Previous studies have shown that nitroglycerin (TNG) exerts beneficial electrophysiological effects in the setting of acute myocardial ischemia. To investigate the basis for these actions, the effects of TNG during coronary occlusion were studied in 19 anesthetized mongrel dogs. Refractory periods (obtained by extrastimulus method) and conduction times measured from local electrograms were determined in potentially ischemic and nonischemic areas prior to and after varying periods of occlusion of the left anterior descending coronary artery and following administration of TNG (300-400 mug intravenous bolus followed by an infusion titrated to reduce systolic blood pressure by 20 mm Hg). Following 15 minutes of occlusion, refractory periods in the ischemic zones shortened to 83% of control (P less than 0.001) resulting in a difference between refractory periods in the nonischemic and ischemic zones of 17.7%. After TNG administration this difference was decreased to 10.0% (P less than 0.001). However, with periods of occlusion of 60-90 min TNG did not significantly affect the difference of refractory periods. TNG had no significant effects on conduction times in nonischemic or ischemic areas. In six dogs, the effects of coronary occlusion and TNG on ventricular automaticity were examined by induction of complete heart block. The idioventricular rate and ventricular escape intervals after cessation of ventricular overdrive were used as indices of automaticity. Control idioventricular rates (62.5 +/- 3.7 beats/min) remained unchanged following both coronary occlusion (62.0 +/- 3.9) and TNG administration (60.7 +/- 3.2). Similarly, mean control escape intervals (1.84 +/- 0.2 sec) did not change after occlusion (1.78 +/- 0.3 sec) or TNG administration (1.86 +/- 0.2 sec). In conclusion, these observations suggest that 1) TNG enhances the electrical stability of the acutely ischemic myocardium by decreasing the difference of refractory periods between nonischemic and ischemic areas in the immediate period following occlusion, 2) since TNG has no significant effects on ventricular automaticity, its beneficial effects might be limited in suppression of arrhythmias of re-entrant origin.


Neuroprotective role of Asiatic acid in aluminium chloride induced rat model of Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia, characterized by memory loss, cognitive impairment and personality disorders accompanied by diffuse structural abnormalities in the brain of elderly people. The current investigation explored the neuroprotective potential of asiatic acid (AA), a natural triterpene of Centella asiatica on aluminium chloride (AlCl3) induced rat model of AD. Oral administration of AlCl3 (100 mg/kg b.w.) for 42 days significantly elevated the levels of Al, activity of acetyl cholinesterase and expressions of amyloid precursor protein, amyloid beta1-42, beta and gamma secretases, glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, interleukins -1β, 6, 4, 2, tumor necrosis factor alpha, inducible nitric oxide synthase, nuclear factor- k beta and cyclooxygenase-2 in the hippocampus and cortex compared to the control group. Our observations suggested that AA treatment mitigated AlCl3 induced AD associated pathologies, which might be due to its multiple pharmacological actions. Further studies are necessary in order to explore the link between AlCl3-mediated oxidative stress and associated apoptosis to establish its neuroprotective role in AD.


High frequency ultrasound imaging with optical arrays.
Dynamically focused and steered high frequency ultrasound imaging systems require arrays with fine element spacing, wide bandwidths, and large apertures. However, these characteristics are difficult to achieve at frequencies greater than 30 MHz using conventional array construction methods. Optical schemes offer a solution. Focused laser beams incident on a suitable surface can generate and detect acoustic radiation. Precisely controlling the position and size of the beams defines points of transmission and detection, making it possible for pulse-echo image formation by synthetic aperture methods. An optical detection array was built, relying on a conventional piezoelectric transducer as an ultrasound source. The detection system, with near optimal resolution over a wide depth of field, demonstrates the potential for high frequency array implementation using optical techniques. A possible application is in pathology, where 2-D or 3-D fine resolution pulse-echo imaging can be performed in situ without the need for biopsies.


Hybrid integrated PDMS microfluidics with a silica capillary.
To harness the properties of both PDMS and silica, we have demonstrated hybrid integrated PDMS microfluidic systems with fused silica capillaries. The hybrid integrated PDMS microfluidics and silica capillary (iPSC) modules exhibit a novel architecture and method for leakage free CE sample injection merely requiring a single high voltage source and one pair of electrodes. The use of the iPSC device is based on a modular approach which allows the capillary to be reused extensively whilst replacing the attached fluidic module for different experiments. Integrating fused silica capillaries with PDMS microfluidic modules allows the direct application of a wide variety of well established conventional CE protocols for separations of complex analytes. Furthermore it bears the potential for facile coupling to standard electro-spray ionization mass spectrometry (ESI-MS), letting users focus on the sample analysis rather than the development of new separation protocols. The fabrication of the iPSC module consists of a simple and quick three-step method that submerges a fused silica capillary in PDMS prepolymer. After cross linking the prepolymer and punching the inlets, the iPSC module layer can be mounted onto a microfluidic device for CE separation.


In vitro hepatic differentiation of human mesenchymal stem cells.
This study examined whether mesenchymal stem cells (MSCs), which are stem cells originated from embryonic mesoderm, are able to differentiate into functional hepatocyte-like cells in vitro. MSCs were isolated from human bone marrow and umbilical cord blood, and the surface phenotype and the mesodermal multilineage differentiation potentials of these cells were characterized and tested. To effectively induce hepatic differentiation, we designed a novel 2-step protocol with the use of hepatocyte growth factor and oncostatin M. After 4 weeks of induction, cuboidal morphology, which is characteristic of hepatocytes, was observed, and cells also expressed marker genes specific of liver cells in a time-dependent manner. Differentiated cells further demonstrated in vitro functions characteristic of liver cells, including albumin production, glycogen storage, urea secretion, uptake of low-density lipoprotein, and phenobarbital-inducible cytochrome P450 activity. In conclusion, human MSCs from different sources are able to differentiate into functional hepatocyte-like cells and, hence, may serve as a cell source for tissue engineering and cell therapy of hepatic tissues. Furthermore, the broad differentiation potential of MSCs indicates that a revision of the definition may be required.


Exposure Versus Cognitive Restructuring Techniques in Brief Internet-Based Cognitive Behavioral Treatment for Arabic-Speaking People With Posttraumatic Stress Disorder: Randomized Clinical Trial.
Cognitive behavioral interventions delivered via the internet are demonstrably efficacious treatment options for posttraumatic stress disorder (PTSD) in underserved, Arabic-speaking populations. However, the role of specific treatment components remains unclear, particularly in conflict-affected areas of the Middle East and North Africa. This study aims to evaluate 2 brief internet-based treatments in terms of efficacy, including change in PTSD symptom severity during treatment. Both treatments were developed in line with Interapy, an internet-based, therapist-assisted cognitive behavioral therapy protocol for PTSD and adapted to the specific research question. The first treatment comprised self-confrontation and social sharing (exposure treatment; 6 sessions); the second comprised cognitive restructuring and social sharing (cognitive restructuring treatment; 6 sessions). The 2 treatments were compared with each other and with a waitlist control group. In total, 365 Arabic-speaking participants from the Middle East and North Africa (mean age 25.49, SD 6.68 y) with PTSD were allocated to cognitive restructuring treatment (n=118, 32.3%), exposure treatment (n=122, 33.4%), or a waitlist control group (n=125, 34.2%) between February 2021 and December 2022. PTSD symptom severity, posttraumatic maladaptive cognitions, anxiety, depressive and somatoform symptom severity, and quality of life were assessed via self-report at baseline and after treatment or waiting time. PTSD symptom severity was also measured throughout treatment or waiting time. Treatment satisfaction was assessed after treatment completion. Treatment use and satisfaction were compared between the 2 treatment conditions using appropriate statistical tests (eg, chi-square and Welch tests). Multiple imputation was performed to address missing data and evaluate treatment-associated changes. These changes were analyzed using multigroup change modeling in the completer and intention-to-treat samples. Overall, 200 (N=240, 83.3%) participants started any of the treatments, of whom 123 (61.5%) completed the treatment. Treatment condition was not significantly associated with the proportion of participants who started versus did not start treatment (P=.20) or with treatment completion versus treatment dropout (P=.71). High treatment satisfaction was reported, with no significant differences between the treatment conditions (P=.48). In both treatment conditions, PTSD, anxiety, depressive and somatoform symptom severity, and posttraumatic maladaptive cognitions decreased, and quality of life improved significantly from baseline to the posttreatment time point (P≤.001 in all cases). Compared with the baseline assessment, overall PTSD symptom severity decreased significantly after 4 sessions in both treatment conditions (P<.001). Moreover, both treatment conditions were significantly superior to the waitlist control group regarding overall PTSD symptom severity (P<.001) and most other comorbid mental health symptoms (P<.001 to P=.03). Differences between the 2 conditions in the magnitude of change for all outcome measures were nonsignificant. Internet-based cognitive behavioral treatments for PTSD focusing primarily on either self-confrontation or cognitive restructuring are applicable and efficacious for Arabic-speaking participants. German Clinical Trials Register DRKS00010245; https://drks.de/search/de/trial/DRKS00010245.


Metabolism of 4,4'-methylenebis(2-chloroaniline) by canine liver and kidney slices.
4,4'-Methylenebis(2-chloroaniline) (MBOCA) metabolism in canine liver and kidney slices was investigated using HPLC to separate the metabolites. Liver slices metabolized 5-10% of the 14C-MBOCA in 60 min and produced seven metabolites resolved by HPLC. The major metabolite, representing approximately 80% of the metabolism, was 2-amino-5-[(4-amino-3-chlorophenyl)methyl]-3-chlorophenyl hydrogen sulfate, previously identified as the major urinary metabolite in dogs. An MBOCA-glucoside was identified by mild acid hydrolysis, which released MBOCA and glucose. An O-glucuronide was characterized as labile to beta-glucuronidase, stabile to arylsulfatase, and mild acid. It was formed in increased amounts when 2,6-dichloro-4-nitrophenol (DCNP) was added to the incubation. Two other glucuronide metabolites were labile to mild acid and beta-glucuronidase, stabile to arylsulfatase, and were formed in decreased amounts in the presence of D-(+)-galactosamine (D-gal) and p-nitrophenyl sulfate (PNPS). Renal cortical slices metabolized 3-5% of the 14C-MBOCA in 90 min, producing six metabolites. Based on retention time and lability to hydrolysis, three of these, the MBOCA-glucoside, a glucuronide, and 2-amino-5-[(4-amino-3-chlorophenyl)methyl]-3-chlorophenyl hydrogen sulfate were also found as kidney metabolites. One additional sulfur-containing metabolite was labile to mild acid and arylsulfatase. The major kidney metabolite represented 25-40% of the metabolism and was unaffected by mild acid, beta-glucuronidase, arylsulfatase, DCNP, and D-gal. Covalent binding in liver slices was 20-27 pmol/mg of wet weight/60 min and in kidney was 9-13 pmol/mg of wet weight/90 min.(ABSTRACT TRUNCATED AT 250 WORDS)


Reconstitution of the membrane-bound, ubiquinone-dependent pyruvate oxidase respiratory chain of Escherichia coli with the cytochrome d terminal oxidase.
Pyruvate oxidase is a flavoprotein dehydrogenase located on the inner surface of the Escherichia coli cytoplasmic membrane and coupled to the E. coli aerobic respiratory chain. In this paper, the role of quinones in the pyruvate oxidase system is investigated, and a minimal respiratory chain is described consisting of only two pure proteins plus ubiquinone 8 incorporated in phospholipid vesicles. The enzymes used in this reconstitution are the flavoprotein and the recently purified E. coli cytochrome d terminal oxidase. The catalytic velocity of the reconstituted liposome system is about 30% of that observed when the flavoprotein is reconstituted with E. coli membranes. It is also shown that electron transport from pyruvate to oxygen in the liposome system generates a transmembrane potential of at least 180 mV (negative inside), which is sensitive to the uncouplers carbonyl cyanide p-(tri-chloromethoxy)phenylhydrazone and valinomycin. A trans-membrane potential is also generated by the oxidation of ubiquinol 1 by the terminal oxidase in the absence of the flavoprotein. It is concluded that (1) the flavoprotein can directly reduce ubiquinone 8 within the phospholipid bilayer, (2) menaquinone 8 will not effectively substitute for ubiquinone 8 in this electron-transfer chain, and (3) the cytochrome d terminal oxidase functions as a ubiquinol 8 oxidase and serves as a "coupling site" in the E. coli aerobic respiratory chain. These investigations suggest a relatively simple organization for the E. coli respiratory chain.


Antiretroviral resistance testing for clinical management.
The advent of highly active antiretroviral therapy (HAART) has dramatically changed the management of HIV disease. These powerful regimens of drugs have reduced morbidity and mortality as well as number of hospitalizations among individuals with HIV. Nevertheless, many patients fail to achieve viral suppression. Various factors underlie this problem, but resistance to current medications has been increasingly recognized as an important element. Several methods of assessing antiretroviral resistance in HIV-1 are currently available. Phenotype assays directly assess the level of susceptibility of a virus to specific drugs. Genotype assays determine the presence of viral mutations that may affect viral susceptibility to a particular drug or class of drugs. An increasing amount of data indicates that antiretroviral resistance testing may improve response to therapy and increase the likelihood of achieving viral suppression. In this paper we review the available data regarding the role of antiretroviral resistance testing and compare the two different assays. We also discuss limitations of the current assays, interpretation of the data, and current consensus guidelines. Although many questions remain, antiretroviral resistance testing along with expert opinion can aid in the management of HIV disease.


Improvements to the SMO algorithm for SVM regression.
This paper points out an important source of inefficiency in Smola and Schölkopf's sequential minimal optimization (SMO) algorithm for support vector machine (SVM) regression that is caused by the use of a single threshold value. Using clues from the KKT conditions for the dual problem, two threshold parameters are employed to derive modifications of SMO for regression. These modified algorithms perform significantly faster than the original SMO on the datasets tried.


What does standard rehabilitation practice after total hip replacement in the UK entail? Results of a mixed methods study.
There is evidence of prolonged poor function in patients following total hip replacement (THR). Studies of progressive resistance training (PRT) interventions to improve function are often compared to 'standard' practice which is not well defined. This study aimed to investigate 'standard' rehabilitation care in the UK after total hip replacement (THR) as well as determine whether PRT was part of 'standard' care. After ethical approval, questionnaire item development about rehabilitation practice was guided by a focus group interview (after informed consent) with physiotherapists (n = 4; >5 years post-qualification) who regularly treated THR patients. An online questionnaire investigating the exercises prescribed and rehabilitation practice following THR was developed and sent to physiotherapists working in hospitals in the UK. The survey was performed from January to May 2011. The survey results were analysed (frequency (%) of responses) focusing on the exercises the physiotherapists considered important, as well as their use of PRT in prescribed regimes. 106 responses were obtained from physiotherapists in the UK. The survey respondents considered that the most important muscles to target in all phases of rehabilitation were the hip abductors (62.2%), followed by the quadriceps (16.9%), and other muscles (21%). Exercise type prescribed revealed no consensus, with weight bearing (42%), functional (45%) and Bed-based/Bridging/Postural exercises (13%) favoured. 83.7% were able to define the basis of progressive resistance training (PRT), but only 33% prescribed it. Standard physiotherapy rehabilitation in the UK after THR is variable, and appears to rarely include PRT. This may be a factor in prolonged poor function in some patients after this common operation.


Cushing's syndrome: new variants and association with empty sella syndrome.
In this article we propose a review of the literature on clinical variants of Cushing's syndrome (CS) and personal observations on one of these variants. Clinical variants of CS are: (1) tumors of the intermediate pituitary lobe; (2) hypothalamic Cushing's with pituitary hyperplasia; (3) cyclic CS; (4) primitive nodular adrenal dysplasia; (5) pre-Cushing's syndrome; (6) association of CS and empty sella. The personal observations relate to the association of CS and empty sella. This syndrome consists of: (a) inappropriate cortisol secretion of pituitary origin; this alteration is less pronounced in comparison with other patients affected by Cushing's disease; (b) marked hirsutism; (c) slight hyperprolactinemia or augmented PRL response after metoclopramide; (d) elevated DHEAS levels.


A one-pot metal-free protocol for the synthesis of chalcogenated furans from 1,4-enediones and thiols.
Transition-metal-free synthesis of chalcogenated furans through the sequential thiol-Michael/Paal-Knorr reaction of 1,4-enediones in the presence of a catalytic amount of p-toluenesulfonic acid has been developed. The present one-pot strategy involves the thiol Michael addition to 1,4-enediones in an anti-Markovnikov fashion with the formation of a new C-S bond, followed by intramolecular dehydrative annulation in the presence of cat. TsOH delivering fully substituted furans in good to excellent yields (50-99%). The reaction is compatible with a wide range of substrates and also capable of multi-gram scale synthesis of chalcogenated furans.


Circulating Tumor DNA Is a Variant of Liquid Biopsy with Predictive and Prognostic Clinical Value in Breast Cancer Patients.
This paper introduces the reader to the field of liquid biopsies and cell-free nucleic acids, focusing on circulating tumor DNA (ctDNA) in breast cancer (BC). BC is the most common type of cancer in women, and progress with regard to treatment has been made in recent years. Despite this, there remain a number of unresolved issues in the treatment of BC; in particular, early detection and diagnosis, reliable markers of response to treatment and for the prediction of recurrence and metastasis, especially for unfavorable subtypes, are needed. It is also important to identify biomarkers for the assessment of drug resistance and for disease monitoring. Our work is devoted to ctDNA, which may be such a marker. Here, we describe its main characteristics and potential applications in clinical oncology. This review considers the results of studies devoted to the analysis of the prognostic and predictive roles of various methods for the determination of ctDNA in BC patients. Currently known epigenetic changes in ctDNA with clinical significance are reviewed. The possibility of using ctDNA as a predictive and prognostic marker for monitoring BC and predicting the recurrence and metastasis of cancer is also discussed, which may become an important part of a precision approach to the treatment of BC.


Identifying characteristics of an effective fracture liaison service: systematic literature review.
Fracture liaison services (FLS) have been demonstrated to improve outcomes following osteoporotic fracture. The aim of this systematic literature review (SLR) was to determine the characteristics of an FLS that lead to improved patient outcomes. We conducted a SLR, including articles published between 2000 and February 2017, using global (Medline, EMBASE, PubMed and Cochrane Library) and local databases. Studies including patients aged ≥ 50 years with osteoporotic fractures enrolled in an FLS were assessed. Information extracted from each article included key person coordinating the FLS (physician, nurse or other healthcare professional), setting (hospital vs community), intensity (single vs multiple), duration (long vs short term), fracture type and gender. A meta-analysis of randomised controlled trials was conducted based on the key person coordinating the FLS. Out of 7236 articles, 57 were considered to be high quality and identified for further analysis. The SLR identified several components which contributed to FLS success, including multidisciplinary involvement, driven by a dedicated case manager, regular assessment and follow-up, multifaceted interventions and patient education. Meta-analytic data confirm the effectiveness of an FLS following an osteoporotic fracture: approximate 27% increase in the likelihood of BMD testing and up to 21% increase in the likelihood of treatment initiation compared with usual care. The balance of evidence indicates that the multifaceted FLS and dedicated coordination are important success factors that contribute to effective FLS interventions which reduce fracture-related morbidity and mortality.


Vitamin D status in apparently healthy adults in Kashmir Valley of Indian subcontinent.
The worldwide prevalence of vitamin D deficiency is reported to be high. To assess the vitamin D status in apparently healthy adults in Kashmir valley by measuring serum 25-hydroxyvitamin D (25 (OH) D). 92 healthy natives (64 men and 28 non-pregnant/non-lactating women, aged 18-40 years), residing in Kashmir for at least last 5 years and not having any suggestion of systemic disease, were selected for this study. The samples were collected throughout the year in both summer and winter months. Vitamin D deficiency was defined as a serum 25 (OH) D concentration of <50 nmol/l and graded as mild (25-50 nmol/l), moderate (12.5-25 nmol/l) and severe (<12.5 nmol/l). Body mass index, total energy intake, and other nutritional parameters were comparable among subjects in different groups. Overall 76 (83%) of the subjects studied had vitamin D deficiency--25%, 33%, and 25% had mild, moderate, and severe deficiency, respectively. 49 of the 64 males and all but 1 of the 28 females were vitamin D deficient. The prevalence of vitamin D deficiency ranged from 69.6% in the employed group to 100% in the household group. Vitamin D deficiency was equally prevalent in subjects from rural and urban areas. Serum calcium and phosphorus values were comparable in subjects with and without vitamin D deficiency, while daily intake and urinary excretion of calcium were significantly lower in the former. Vitamin D deficient subjects had a significantly lower mean weekly exposure to sunlight. In spite of abundant sunlight, healthy individuals in Kashmir valley are vitamin D deficient, particularly women. Serum 25 (OH) D concentrations are significantly related to sun exposure.


New TNM melanoma staging system: linking biology and natural history to clinical outcomes.
The American Joint Committee on Cancer (AJCC) implemented major revisions of the melanoma TNM and stage grouping criteria in the recently published 6th edition of the Staging Manual. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include: 1) melanoma thickness and ulceration but not level of invasion to be used in the T classification, 2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of microscopic vs. macroscopic nodal metastases to be used in the N classification, 3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase (LDH) to be used in the M classification, 4) an upstaging of all patients with Stage I, II, and III disease when a primary melanoma is ulcerated, 5) a merging of satellite metastases around a primary melanoma and in transit metastases into a single staging entity that is grouped into Stage III disease, and 6) a new convention for defining clinical and pathological staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.


New Trends, Advantages and Disadvantages in Anticoagulation and Coating Methods Used in Extracorporeal Life Support Devices.
The use of extracorporeal life support (ECLS) devices has significantly increased in the last decades. Despite medical and technological advancements, a main challenge in the ECLS field remains the complex interaction between the human body, blood, and artificial materials. Indeed, blood exposure to artificial surfaces generates an unbalanced activation of the coagulation cascade, leading to hemorrhagic and thrombotic events. Over time, several anticoagulation and coatings methods have been introduced to address this problem. This narrative review summarizes trends, advantages, and disadvantages of anticoagulation and coating methods used in the ECLS field. Evidence was collected through a PubMed search and reference scanning. A group of experts was convened to openly discuss the retrieved references. Clinical practice in ECLS is still based on the large use of unfractionated heparin and, as an alternative in case of contraindications, nafamostat mesilate, bivalirudin, and argatroban. Other anticoagulation methods are under investigation, but none is about to enter the clinical routine. From an engineering point of view, material modifications have focused on commercially available biomimetic and biopassive surfaces and on the development of endothelialized surfaces. Biocompatible and bio-hybrid materials not requiring combined systemic anticoagulation should be the future goal, but intense efforts are still required to fulfill this purpose.


RNA-polymerase III-driven expression cassettes in human gene therapy.
tRNAs, U6 small nuclear RNA and adenovirus virus associated RNAs are transcribed by RNA polymerase III. These RNAs are expressed in high levels and possess increased stability due to their small, compact size. Promoters expressing these RNAs have therefore been used to express a variety of interfering RNAs, including ribozymes, antisense RNAs and sense or decoy RNAs. Intracellular expression and activity of RNA polymerase III-driven interfering RNAs have been demonstrated in several studies. This review will summarize the design and application of RNA polymerase III-driven expression cassettes in human gene therapy using retroviral vectors as the primary method of gene delivery.


The Effect of Dexmedetomidine on Postoperative Opioid Consumption and Pain After Major Spine Surgery.
Adult deformity correction spine surgery can be associated with significant perioperative pain because of inflammatory, muscular, neuropathic, and postsurgical pain. α-2 Agonists have intrinsic antinociceptive and antihyperalgesic properties that can potentially reduce both postoperative opioid consumption and pain. We hypothesized that intraoperative dexmedetomidine would reduce postoperative opioid consumption and improve pain scores in deformity correction spine surgery. Patients undergoing >3 levels of thoracic and/or lumbar spine surgery were enrolled in this prospective randomized double-blind study to receive either dexmedetomidine (1 μg/kg load followed by a continuous infusion of 0.5 μg/kg/h) or saline. Both groups received a single dose of 0.2 mg/kg (ideal body weight) of methadone at the start of surgery. Intraoperative fentanyl was administered based on the clinical and hemodynamic signs suggestive of increased nociception. Postoperative analgesia was provided with a hydromorphone patient-controlled analgesia pump. Opioid consumption and pain scores were recorded at 24, 48, and 72 hours after surgery. One hundred forty-two participants were enrolled with 131 completing the study. There was no significant difference in demographics (age, sex, weight, and ASA physical status), percentage of participants with preoperative opioid use, and daily median opioid consumption between the groups. The study was terminated early after interim analysis. Intraoperative opioid use was reduced in the dexmedetomidine arm (placebo versus dexmedetomidine, median [25%-75% interquartile range]: 7 [3-15] vs 3.5 [0-11] mg morphine equivalents, P = 0.04) but not at 24 hours: 49 (30-78) vs 61 (34-77) mg morphine equivalents, P = 0.65, or 48 hours: 41 (28-68) vs 40 (23-64) mg morphine equivalents, P = 0.60, or 72 hours: 29 (15-59) vs 30 (14-46) mg morphine equivalents, P = 0.58. The Wilcoxon-Mann-Whitney odds are 1.11 with 97.06% confidence interval (0.71-1.76) for opioid consumption. No difference in pain score, as measured by the 11-point visual analog scale, was seen at 24 hours (placebo versus dexmedetomidine, median [25%-75% interquartile range]: 7 [5-7] vs 6 [4-7], P = 0.12) and 48 hours (5 [3-7] vs 5 [3-6], P = 0.65). There was an increased incidence of bradycardia (placebo: 37% vs dexmedetomidine: 59% P = 0.02) and phenylephrine use in the dexmedetomidine group (placebo: 59% versus dexmedetomidine: 78%, P = 0.03). Intraoperative dexmedetomidine does not reduce postoperative opioid consumption or improve pain scores after multilevel deformity correction spine surgery.


EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells.
Multiple myeloma (MM) is a hematologic malignancy characterized by a clonal expansion of plasma cells (PCs) in the bone marrow (BM). Since MM has so far remained incurable, further insights into its pathogenesis and the concomitant identification of new therapeutic targets are urgently needed. The tyrosine kinase receptor EphA3 is known to be involved in various cellular processes including cell viability, cell movement and cell-cell interactions. Recently, EphA3 has emerged as a potential therapeutic target in several hematologic and solid tumors. Here, we aimed to uncover the role of EphA3 in MM. EphA3 mRNA and protein expression in primary MM bone marrow plasma cells (BMPCs), in MM-derived cell lines and in healthy controls (HCs) was assessed using qRT-PCR, Western blotting and flow cytometry. The effects of siRNA-mediated EphA3 silencing and anti EphA3 antibody (EphA3mAb) treatment on MM PC trafficking and viability were evaluated using in vitro assays. The effects of EphA3mAb treatment were also assessed in two MM-derived mouse xenograft models. We found that EphA3 was overexpressed in primary MM BMPCs and MM-derived cell lines compared to HCs. We also found that siRNA-mediated EphA3 silencing and EphA3mAb treatment significantly inhibited the ability of MM PCs to adhere to fibronectin and stromal cells and to invade in vitro, without affecting cell proliferation and viability. Gene expression profiling showed that EphA3 silencing resulted in expression modulation of several molecules that regulate adhesion, migration and invasion processes. Importantly, we found that EphA3mAb treatment significantly inhibited in vivo tumor growth and angiogenesis in two MM-derived mouse xenograft models. Our findings suggest that EphA3 plays an important role in the pathogenesis of MM and provide support for the notion that its targeting may represent a novel therapeutic opportunity for MM.


An Immuno-Clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B.
We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.


Anoikis Patterns in Cervical Cancer: Identification of Subgroups and Construction of a Novel Risk Model for Predicting Prognosis and Immune Response.
Cervical cancer has high morbidity and intratumor heterogeneity. Anoikis, a form of programmed cell death preventing detached cancer cells from readhering, may serve as a potential prognostic signature for cervical cancer. This study aimed to assess the predictive performance of anoikis patterns in cervical cancer prognosis. Differentially expressed anoikis-related genes (DEARGs) were identified between normal and cancer samples using data from the Gene Expression Omnibus database with the elucidation of mutation status and bio-function. Novel anoikis molecular subtypes were defined in The Cancer Genome Atlas (TCGA) cohort with consensus clustering analysis. A multigene prognostic signature was constructed through least absolute shrinkage and selection operator (LASSO) Cox analysis with internal and external validation. The nomogram-based survival probability of cervical cancer over 3 and 5 years was predicted and assessed with calibration, receiver operating characteristic, decision curve analysis, and Kaplan-Meier curves. Additionally, mutation, function, and immune analysis were conducted among different risk groups. We identified 77 DEARGs between normal and cervical cancer tissues and explored their mutation status and functions. The TCGA cohort could be categorized into two subtypes based on these genes. Furthermore, seven prognostic signature genes were constructed, and the nomogram involving DEARGs and clinicopathological characteristics showed satisfactory predictive performance. Functional analysis indicated that immune-related genes were enriched, and immune status, as well as sensitivity of chemotherapies and targeting drugs, were correlated with the risk model. Anoikis patterns play important roles in tumor immunity and can be used to predict the prognosis of cervical cancers.


Alterations of the emotional processing system may underlie preserved rapid reaction time in tinnitus.
Although alterations of the limbic system have been linked to tinnitus persistence, the neural networks underlying such alteration are unclear. The present study investigated the effect of tinnitus on emotional processing in middle-aged adults using functional magnetic resonance imaging and stimuli from the International Affective Digital Sounds database. There were three groups of participants: bilateral hearing loss with tinnitus (TIN), age- and gender-matched controls with bilateral hearing loss without tinnitus (HL) and matched normal hearing controls without tinnitus (NH). In the scanner, subjects rated sounds as pleasant, unpleasant, or neutral. The TIN and NH groups, but not the HL group, responded faster to affective sounds compared to neutral sounds. The TIN group had elevated response in bilateral parahippocampus and right insula compared to the NH group, and left parahippocampus compared to HL controls for pleasant relative to neutral sounds. A region-of-interest analysis detected increased activation for NH controls in the right amygdala when responding to affective stimuli, but failed to find a similar heightened response in the TIN and HL groups. All three groups showed increased response in auditory cortices for the affective relative to neutral sounds comparisons. Our results suggest that the emotional processing network is altered in tinnitus to rely on the parahippocampus and insula, rather than the amygdala, and this alteration may maintain a select advantage for the rapid processing of affective stimuli despite the hearing loss. The complex interaction of tinnitus and the limbic system should be accounted for in development of new tinnitus management strategies.