Longitudinal study of the associations between change in sedentary behavior and change in adiposity during childhood and adolescence: Gateshead Millennium Study.
Sedentary time (ST) has been reported to have a range of negative health effects in adults, however, the evidence for such effects among children and adolescents is sparse. The primary aim of the study was to examine associations between changes in sedentary behavior (time and fragmentation) and changes in adiposity across childhood and adolescence. Participants were recruited as part of the Gateshead Millennium Study. Measures were taken at age 7 (n=502), 9 (n=506), 12 (n=420) and 15 years (n=306). Participants wore an ActiGraph GT1M and accelerometer epochs were 'sedentary' when recorded counts were ⩽25 counts per 15 s. ST was calculated and fragmentation (SF) was assessed by calculating the number of sedentary bouts per sedentary hour. Associations of changes in ST and SF with changes in adiposity (body mass index (BMI), and fat mass index (FMI)) were examined using bivariate linear spline models. Increasing ST by 1% per year was associated with an increase in BMI of 0.08 kg m-2 per year (95% CI: 0.06-0.10; P<0.001) and FMI of 0.15 kg m-2 per year (0.11-0.19; P<0.001). Change in SF was associated with BMI and FMI (P<0.001). An increase of 1 bout per sedentary hour per year (that is, sedentary time becoming more fragmented) was associated with an increase in BMI of 0.07 kg m-2 per year (0.06-0.09; P<0.001) and an increase in FMI of 0.14 kg m-2 per year (0.10-0.18; P<0.001) over the 8 years period. However, an increase in SF between 9-12 years was associated with a 0.09 kg m-2 per year decrease in BMI (-0.18-0.00; P=0.046) and 0.11 kg m-2 per year decrease in FMI (-0.22-0.00; P=0.049). Increased ST and increased SF from 7-15 years were associated with increased adiposity. This is the first study to show age-specific associations between change in objectively measured sedentary behavior and adiposity after adjustment of moderate-to-vigorous-intensity physical activity in children and adolescents. The study suggests that, targeting sedentary behavior for obesity prevention may be most effective during periods in which we see large increases in ST.


Quantitative NMR (qNMR) spectroscopy based investigation of the absolute content, stability and isomerization of 25-hydroxyvitamin D2/D3 and 24(R),25-dihydroxyvitamin D2 in solution phase.
Vitamin D is an important parameter, in serum/plasma based diagnostic analysis, for the determination of optimal regulation of calcium and phosphate homeostases in the human body, vital for the monitoring/progression of osteomalacia and rickets. Particularly, the quantification of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D in blood is an excellent indicator for the vitamin D status of a patient. For this purpose, LC-MS/MS methods, based on appropriate vitamin D reference standards, are considered to be 'gold standard' for such measurements. We have utilized quantitative NMR spectroscopy to determine the absolute content of these molecules, available as non-certified chemicals, and have determined the stability of these callibrators in borderline polar solvents at room temperature. We have observed significant isomerization of the analytes, which can play a big role in quantification of these analytes by hyphenated LC and GC analytical techniques. Appropriate explanations are given for the observation of new impurities with time in solution phase. The spin system selected for quantitation was determined using relevant 1D and 2D NMR pulse sequences. The advantage of the qNMR approach is that it is based on the quantification of atoms rather than molecular properties (e.g., quantitation by LC/UV, GC, etc.). Since the signals in an NMR spectrum are different nuclear spin-systems dispersed precisely in a magnetic environment, with the intensity being directly proportional to the amount of a particular type of nuclear spin, this technique delivers unparalleled information about the chemical structure and the absolute content.


Role of Potassium Ions in Regulation of Calcium-Activated Chloride Channels.
Using the patch-clamp method in the whole cell configuration, it was shown that external potassium ions play an important role in the regulation of calcium-activated chloride channels (CaCCs). A clear dependence of the conductivity of the СаССs on the external potassium concentration was shown. The effect of external potassium in the range 0-15 mM on the conductivity of chloride channels was significantly greater than the effect it had on other ionic currents (sodium or potassium). There is reason to believe that these changes in the conductivity of CaCCs may contribute to the development of pathophysiological processes such as hypokalemia or hyperkalemia.


Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study.
Chronic migraine (CM) is a debilitating neurological disorder with few treatment options. Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients. In this randomized, controlled multicenter study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active (n = 105) or sham (n = 52) stimulation. The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a ≥50% reduction in mean daily visual analog scale scores) in each group at 12 weeks. There was not a significant difference in the percentage of responders in the Active compared with the Control group (95% lower confidence bound (LCB) of -0.06; p = 0.55). However, there was a significant difference in the percentage of patients that achieved a 30% reduction (p = 0.01). Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability (p = 0.001) and direct reports of pain relief (p = 0.001). The most common adverse event was persistent implant site pain. Although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability. Additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need. Clinical trials.gov (NCT00615342).


Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer.
Screening for activating driver gene alterations at the time of diagnosis is the standard of care for advanced non-small cell lung cancer (NSCLC). Activating RET fusions are identified in approximately 1-2% of NSCLCs and have emerged as a targetable driver alteration. Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy. As with use of TKIs in other oncogene-addicted NSCLCs, development of acquired resistance is pervasive and should be specifically delineated through use of repeat tissue biopsy with genetic profiling at the time of disease progression. If an actionable resistance mechanism emerges for which there is a candidate targeted therapy, combination inhibition should be considered. Alternatively, or in the absence of such findings, platinum doublet chemotherapy or particularly platinum-pemetrexed therapy with or without bevacizumab demonstrates a moderate effect.We would not recommend the routine use of nonselective multi-targeted TKIs such as cabozantinib and vandetanib, which have modest activity but limited tolerability due to predictable off-target effects. Single-agent immunotherapy has minimal activity in RET fusion-positive NSCLC. The role of combination chemotherapy and immunotherapy requires further study but may be considered, particularly in the presence of an activating KRAS alteration. While further development of novel RET-selective TKIs may address common RET-specific resistance mutations, they will not have activity against off-target, RET-independent resistance mechanisms. This again highlights the importance of serial biopsy and next-generation sequencing for the rational choice of sequential therapy in RET fusion-positive NSCLC.


Validation of a clinical prediction rule for severe acute lower intestinal bleeding.
Acute lower intestinal bleeding is a heterogeneous disorder and identification of high-risk patients is challenging. We previously retrospectively identified predictors of severity in patients with acute lower intestinal bleeding. The aim of this study was to prospectively validate a clinical prediction rule for severe acute lower intestinal bleeding. This was a prospective, observational cohort study of consecutive patients admitted to an academic, tertiary care or a community-based teaching hospital for management of acute lower intestinal bleeding. Data were collected on seven previously identified predictors of severe bleeding: heart rate > or = 100/min, systolic blood pressure < or = 115 mmHg, syncope, nontender abdominal exam, rectal bleeding in the first 4 h of evaluation, aspirin use, and >2 comorbid conditions. Severe bleeding was defined as transfusion of > or =2 units of red blood cells, and/or a decrease in hematocrit of > or =20% in the first 24 h, and/or recurrent rectal bleeding after 24 h of stability (accompanied by a further decrease in hematocrit of > or =20%, and/or additional blood transfusions, and/or readmission for acute lower intestinal bleeding within 1 wk of discharge). Patients were stratified into 3 risk groups according to the previously developed prediction rule: low (no risk factors), moderate (1-3 risk factors), and high (>3 risk factors). A total of 275 patients with acute lower intestinal bleeding were identified. The risk of severe bleeding in each risk category was similar in the validation and derivation cohorts (p values >0.05): low risk 6%versus 9%, moderate risk 43%versus 43%, and high risk 79%versus 84%. The area under the receiver operating characteristic curve was 0.754 for the validation cohort and 0.761 for the derivation cohort. The magnitude of the risk score was significantly correlated with major clinical outcomes including surgery, death, blood transfusions, and length of stay. We have developed and prospectively validated a clinical prediction rule for acute severe lower intestinal bleeding. This prediction rule could improve the triage of patients to appropriate levels of care and interventions, and guide a more standardized approach to acute lower intestinal bleeding.


Correlations between left atrial volumes and strains in healthy adults: Detailed analysis from the three-dimensional speckle-tracking echocardiographic MAGYAR-Healthy Study.
Little is known about the relationship between left atrium (LA) volumes and contractility features along the cardiac cycle. The present study aimed to assess, by three-dimensional speckle-tracking echocardiography (3DSTE), correlations between LA volumes, volume-based functional properties, and strains during the cardiac cycle in healthy adults. We included 217 healthy adult volunteers (mean age 33.4 ± 12.7 years, 112 males) who underwent complete two-dimensional Doppler echocardiography with 3DSTE. LA stroke volumes were greater in subjects with the greater maximum LA volume (Vmax ) in reservoir, conduit, and booster pump phases of LA function. While LA emptying fraction in LA reservoir phase was not different between subjects depending in their Vmax value, a significantly lower LA emptying fraction could be detected in LA conduit phase in subjects whose Vmax was >50 mL. In booster pump function, LA emptying fraction was not significantly different whatever the Vmax . Only global and mean segmental peak LA radial strain (RS) and 3D strain (3DS) and the same strains at atrial contraction appeared greater in subjects with greater Vmax , whereas the other strain parameters were not different. In healthy subjects, LA-RS and LA-3DS, objective features of LA contractility, are greater in subjects with greater LA volumes up to a point beyond which this association disappears.


Initial radiological signs of dentofacial deformity in juvenile idiopathic arthritis.
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and the temporomandibular joint (TMJ) is often involved. TMJ arthritis in growing individuals can cause deformation of facial skeleton (dentofacial deformity) and TMJ components (TMJ deformity). Treatment outcome hinges on early initiation of anti-inflammatory treatment and orthopaedic treatment with dental splints. The aim of the present study was to characterize the radiological signs of dentofacial deformity in patients with a JIA-induced need for orthopaedic treatment. We retrospectively studied 96 patients with JIA and 20 non-JIA controls to identify the initial radiological signs of JIA-induced dentofacial deformity leading to initiation of orthopaedic treatment. We found that initial radiological signs of dentofacial deformities were subtle and characterized by minor mandibular asymmetry and occlusal plane steepening. Radiological findings of TMJ deformity associated with initial dentofacial deformity were frequent and characterized by condylar articular surface flattening (OR 8.42), condylar subcortical cyst (OR 5.94), condylar surface erosion (OR 5.38) and condylar deviation in form (OR 25.39). Radiological signs of TMJ deformity were also documented in TMJs considered "healthy" during initial clinical and radiological examination. This study presents new knowledge of importance for early diagnosis of dentofacial deformity in JIA. Early diagnosis of dentofacial deformity is important as treatment outcome is greatly influenced by timely initiation.


Somatostatin Receptor Subtype-4 Regulates mRNA Expression of Amyloid-Beta Degrading Enzymes and Microglia Mediators of Phagocytosis in Brains of 3xTg-AD Mice.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR4) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR4 agonist NNC 26-9100 on mRNA expression of key genes associated with AD pathology (microglia mediators of Aβ phagocytosis, amyloid-beta (Aβ)-degrading enzymes, anti-oxidant enzymes and pro-inflammatory cytokines) in 3xTg-AD mice. Mice were administered NNC 26-9100 (0.2 µg, i.c.v.) or vehicle control, with cortical and subcortical brain tissue collected at 6 h and 24 h post-treatment. At 6 h, NNC 26-9100 treatment decreased cortical expression of cluster of differentiation-33 (Cd33) by 25%, while increasing cortical and subcortical macrophage scavenger receptor-1 (Msr1) by 1.8 and 2.0-fold, respectively. The Cd33 downregulation and Msr1 upregulation support a state of microglia associated Aβ phagocytosis. At 24 h, NNC 26-9100 treatment increased the cortical expression of Sstr4 (4.9-fold), Aβ-degrading enzymes neprilysin (9.3-fold) and insulin degrading enzyme (14.8-fold), and the antioxidant catalase (3.6-fold). Similar effects at 24 h were found in subcortical tissue with NNC 26-9100 treatment, but did not reach statistical significance. No changes in pro-inflammatory cytokine expression were found. These data demonstrated NNC 26-9100 facilitates transcriptional changes in brain tissue identified with Aβ phagocytosis and clearance, further supporting SSTR4 as a treatment target for AD.


Single cell epigenomic and transcriptomic analysis uncovers potential transcription factors regulating mitotic/meiotic switch.
In order to reveal the complex mechanism governing the mitotic/meiotic switch in female germ cells at epigenomic and genomic levels, we examined the chromatin accessibility (scATAC-seq) and the transcriptional dynamics (scRNA-seq) in germ cells of mouse embryonic ovary between E11.5 to 13.5 at single-cell resolution. Adopting a strict transcription factors (TFs) screening framework that makes it easier to understand the single-cell chromatin signature and a TF interaction algorithm that integrates the transcript levels, chromatin accessibility, and motif scores, we identified 14 TFs potentially regulating the mitotic/meiotic switch, including TCFL5, E2F1, E2F2, E2F6, E2F8, BATF3, SP1, FOS, FOXN3, VEZF1, GBX2, CEBPG, JUND, and TFDP1. Focusing on TCFL5, we constructed Tcfl5+/- mice which showed significantly reduced fertility and found that decreasing TCFL5 expression in cultured E12.5 ovaries by RNAi impaired meiotic progression from leptotene to zygotene. Bioinformatics analysis of published results of the embryonic germ cell transcriptome and the finding that in these cells central meiotic genes (Stra8, Tcfl5, Sycp3, and E2f2) possess open chromatin status already at the mitotic stage together with other features of TCFL5 (potential capability to interact with core TFs and activate meiotic genes, its progressive activation after preleptotene, binding sites in the promoter region of E2f2 and Sycp3), indicated extensive amplification of transcriptional programs associated to mitotic/meiotic switch with an important contribution of TCFL5. We conclude that the identified TFs, are involved in various stages of the mitotic/meiotic switch in female germ cells, TCFL5 primarily in meiotic progression. Further investigation on these factors might give a significant contribution to unravel the molecular mechanisms of this fundamental process of oogenesis and provide clues about pathologies in women such as primary ovarian insufficiency (POI) due at least in part to meiotic defects.


The effect of particle size reduction on the jaw gape in human mastication.
Eight subjects participated in chewing experiments to examine how the jaw gape in consecutive chewing cycles depends on the dimensions and the volume of the food bolus. Different volumes of chewing-gum and a silicone rubber (Optosil) were used. The initial particle size of Optosil was also varied. With the aid of a sieving procedure, the size distribution of Optosil particles was determined after different numbers of chewing cycles. The maximum size of a chewing-gum bolus along three orthogonal axes was determined after a random number of chewing cycles for all the volumes of chewing-gum offered. The jaw gape was measured by means of an optical motion analysis system and calibrated at the level of the first molars. The maximum jaw gape and the gape at the first fall in mandibular velocity after the onset of jaw-closing were determined for different chewing cycles from the position signal and its time derivative. For each volume of chewing gum offered to the subject, the average of the maximum gapes attained in the subsequent cycles of jaw movement was related to the characteristic height of a bolus of that volume; maximum velocity of closing appeared to occur while the antagonistic teeth were already penetrating the gum bolus. The increase in the maximum jaw gape, the gape at the velocity maximum, and the height of the gum bolus, as a function of the volume of chewing-gum, could be well-described by a power function of the volume. The exponent of the power function for both jaw gapes was only slightly smaller than the exponent obtained for the bolus height.(ABSTRACT TRUNCATED AT 250 WORDS)


Cortical correlates of face and scene inversion: a comparison.
Face recognition is more strongly impaired by stimulus inversion than nonface object recognition. This phenomenon, known as the face inversion effect (FIE), suggests that the visual system contains specialized processing mechanisms that are more engaged by upright faces than by inverted faces or nonface objects. Neuroimaging and neuropsychological studies indicate that environmental scenes may also recruit specialized-purpose processing machinery but a comparable inversion effect for scenes has not been established. Here we demonstrate that both face and scene inversion lead to behavioral penalties during performance of a continuous visual matching task; however, the scene inversion effect was less robust and declined in magnitude over the course of the experiment. Scene inversion led to greater neural response in the functionally defined lateral occipital (LO) object area for inverted versus upright scenes and reduced response in the parahippocampal place area (PPA), while face inversion lead to greater response in LO and the right middle fusiform (MF) object area for inverted versus upright faces but no change in the fusiform face area (FFA). A whole-brain analysis revealed several regions that responded more strongly to either upright versus inverted faces or upright versus inverted scenes, some of which may be involved in post-recognition processing. These results demonstrate that both face and scene inversion cause a shift from specialized processing streams towards generic object-processing mechanisms; however, this shift only leads to a reliable behavioral penalty in the case of face inversion.


Gastrinoma and neurofibromatosis type 2: the first case report and review of the literature.
Gastroenteropancreatic neuroendocrine tumors have occasionally been described in association with neurofibromatosis type 1, whereas an association with neurofibromatosis type 2 has never been reported. This report refers to an Italian 69 year old woman with neurofibromatosis type 2 and a pancreatic gastrinoma. In the past she had encephalic meningiomas, a tongue schwannoma and bilateral acoustic neurinomas. She presented with weight loss and a long-term history of diarrhea, responsive to proton pump inhibitors. Upper gastrointestinal endoscopy revealed peptic ulcer of the duodenal bulb. Blood tests were normal, except for the elevation of plasma gastrin (1031 pg/ml; reference value <108) and chromogranin A (337 U/L; reference value <36). After secretin stimulation testing, the plasma gastrin level rose to 3789 pg/ml. The abdomen magnetic resonance imaging and gallium68-DOTATOC positron emission tomography scan demonstrated the presence of a 1.2 x 2 cm lesion in the pancreatic head and a liver metastatis. Pancreatic endoscopic ultrasound with fine needle aspiration revealed cytomorphologic features suggestive of pancreatic gastrinoma. Brain magnetic resonance showed a pituitary microadenoma. There was no evidence of hyperparathyroidism. The genetic test for multiple endocrine neoplasia type 1 syndrome mutation was negative. This report focuses on the first case of coexistence of gastrinoma with neurofibromatosis type 2. Although the clinical relevance of this association remains to be determined, our case report will surely give cause for due consideration.


Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment.
An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.


Analysis of Drug Effects on iPSC Cardiomyocytes with Machine Learning.
Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an attractive experimental platform to investigate cardiac diseases and therapeutic outcome. In this study, iPSC-CMs were utilized to study their calcium transient signals and drug effects by means of machine learning, a central part of artificial intelligence. Drug effects were assessed in six iPSC-lines carrying different mutations causing catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly malignant inherited arrhythmogenic disorder. The antiarrhythmic effect of dantrolene, an inhibitor of sarcoplasmic calcium release, was studied in iPSC-CMs after adrenaline, an adrenergic agonist, stimulation by machine learning analysis of calcium transient signals. First, beats of transient signals were identified with our peak recognition algorithm previously developed. Then 12 peak variables were computed for every identified peak of a signal and by means of this data signals were classified into different classes corresponding to those affected by adrenaline or, thereafter, affected by a drug, dantrolene. The best classification accuracy was approximately 79% indicating that machine learning methods can be utilized in analysis of iPSC-CM drug effects. In the future, data analysis of iPSC-CM drug effects together with machine learning methods can create a very valuable and efficient platform to individualize medication in addition to drug screening and cardiotoxicity studies.


Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis.
Modifications to the extracellular matrix (ECM) can be either causal or consequential of disease processes including arthritis and cancer. In arthritis, the cartilage ECM is adversely affected by the aberrant behaviours of inflammatory cells, synoviocytes and chondrocytes, which secrete a plethora of cytokines and degradative proteases. In cancer, the ECM and stromal cells are linked to disease severity, and metalloproteinases are implicated in metastasis. There have been some successes in the field of targeted therapies, but efficacy depends upon the type and stage of disease. ECM targets are becoming increasingly attractive for drug delivery, owing to changes in ECM structure and composition in the diseased state, and the long in vivo half-life of its components. This review will highlight various strategies for targeting therapeutics to arthritic joints, including antibody and peptide-mediated drug delivery platforms to aid delivery to the ECM and retention at disease sites. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.


Prolonged ileus with acute spinal cord injury responding to metaclopramide.
This is a case report of an acute C-5 complete quadriplegic with prolonged ileus. The ileus resolved only after the administration of metoclopramide. Metoclopramide is a drug that increases gastrointestinal motility, has few significant side effects, and may be of use in decreasing the ileus associated with acute spinal cord injuries.


Determination of chamaechromone in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetic study.
A rapid, simple and accurate method was developed for the determination of chamaechromone in rat plasma using liquid chromatography tandem mass spectrometry (LC-MS-MS). Rosuvastatin was used as the internal standard. The plasma samples were extracted by liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on Xbridge™ C(18) column (2.1mm×50mm, 3.5μm) with linear gradient elution using water and methanol, both of which were acidified with 0.1% aqueous formic acid. The flow rate was 0.4mL/min and the total run time was 6min. Detection was performed on a triple-quadrupole tandem mass spectrometer using positive ion mode electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The MS/MS ion transitions monitored were m/z 543.3→198.9 and 481.9→258.3 for chamaechromone and rosuvastatin, respectively. Good linearity was observed over the concentration range of 8-6400ng/mL in 0.1mL of rat plasma. The lowest concentration (8ng/mL) in the calibration curve was estimated as LLOQ with both deviation of accuracy and RSD of precision <20% (n=6). Intra-assay and inter-assay variability were less than 11% in plasma. This method was successfully applied to a pharmacokinetic study of chamaechromone in rats after intravenous (5mg/kg) and oral (100mg/kg) administration. Following oral administration the concentration-time curve of chamaechromone exhibited a biphasic absorption profile. The maximum mean concentration in plasma (C(max), 795.9±14.6ng/L) was achieved at 11.3±0.8h (T(max)) and the area under curve (AUC(0-60)) was 6976.7±1026.9ngh/L. After single intravenously administration of chamaechromone, the essential pharmacokinetic parameters C(max), AUC(0-48) were 4300.7±113.6ng/L and 3672.1±225.4ngh/L, respectively. The result showed that the compound was poorly absorbed with an absolute bioavailability being approximately 8.9%.


Risk factor analysis of hypersensitivity reactions to abacavir.
A hypersensitivity reaction to abacavir has been known to occur in approximately 4% of patients treated with the drug. The goal of this study was to determine risk factors associated with the development of hypersensitivity reactions to abacavir. We constructed an analysis population from all protocols conducted by GlaxoSmithKline that involved at least 24 weeks of abacavir exposure with a quality-assured or validated clinical database by June 30, 2000. Demographic, clinical, and laboratory characteristics of patients who developed a hypersensitivity reaction to abacavir were compared with those of patients who did not. Univariate and multivariate logistic regression models were fit to understand the predictive ability of each potential risk factor. Odds ratios (ORs) and 95% Wald CIs were computed. A total of 5332 patients exposed to abacavir were included in this analysis; 197 cases of hypersensitivity reaction were reported (3.7%). In univariate models, several associations were noted, but most subgroups produced rates within the expected range of 3% to 6%. The multivariate model using all demographic data available (Model 1) indicated that the risk of hypersensitivity reaction among black patients (3% hypersensitivity reaction) was lower (OR = 0.59; 95% CI, 0.38-0.91) compared with other ethnic groups. In addition, a lower rate of hypersensitivity reaction was observed in patients who received previous therapy for HIV-1 infection with other antiretroviral agents (3% hypersensitivity reaction) compared with those receiving therapy for the first time (OR = 0.58; 95% CI, 0.44-0.78). The only characteristics identified as prognostic factors for hypersensitivity reaction to abacavir were antiretroviral treatment status (ie, treatment experience) and black race, each resulting in a lower rate compared with the expected incidence.


Linear dichroism and the orientation of reaction centers of Rhodopseudomonas sphaeroides in dried gelatin films.
Aqueous mixtures of reaction centers of Rhodopseudomonas sphaeroides and gelatin were dried to form thin films. Following hydration, these films were stretched as much as two to three times their original length. Polarized absorption spectra showing linear dichroism were obtained for both unstretched and stretched films, with the planes and stretching axes of the films mounted in various geometries relative to the electric vector of the measuring beam. These data were analyzed in terms of the following model: Reaction centers possess an axis of symmetry that is fixed in relation to the reaction center structure. In unstretched films this axis is confined to the film plane and oriented at random within the plane. In stretched films the symmetry axis is aligned with the direction of stretching. In both preparations reaction centers are distributed randomly with respect to rotation about the axis of symmetry. The data are consistent with this model when the analysis acknowledges less than perfect orientation. For perfect orientation in a stretched film the model predicts uniaxial symmetry about the axis of stretching. The approach to this condition was examined with films stretched to different extents. Extrapolation yielded dichroic ratios for the ideal case of perfect orientation, and allowed calculation of the angles between the axis of symmetry and the various optical transition dipoles in the reaction center. This treatment included the two absorption bands of the bacteriochlorophyll 'special pair' (photochemical electron donor) in the Qx region, at 600 and 630 nm, which we were able to resolve in light minus dark difference spectra.


Location of age-related modifications in rat muscle glyceraldehyde-3-phosphate dehydrogenase.
The interactions of rat muscle glyceraldehyde-3-phosphate dehydrogenase purified from young and old animals with NADH and with the fluorescent analogue nicotinamide 1,N6-ethenoadenine dinucleotide were investigated. While the spectra of the circular polarization of fluorescence emitted by the ethenoadenine derivative when bound to the two enzyme preparations were identical large differences were revealed between the corresponding spectra in the case of NADH. From these results it was concluded that age-related modifications occur in the nicotinamide binding sites, but not in the adenine binding sites of this enzyme. The circular polarization of fluorescence of the ethenoadenine derivative was found to depend on the stoichiometry of its complexes with the enzyme while the spectra obtained for NADH were independent of the degree of saturation of the coenzyme binding sites. These observations demonstrate that progressive structural changes occur at the adenine site as a function of coenzyme saturation. These changes may be responsible for the strong negative cooperative in coenzyme binding. The finding that only the nicotinamide binding sites are affected by age explains our previous observation that while the affinity toward coenzyme binding which depends on both adenine and nicotinamide moieties is reduced upon aging the negative cooperativity of binding is not significantly changed, since this latter property depends on the state of the adenine site only.


[Usefulness of polymerase chain reaction for the diagnosis of Bazin erythema induratum].
Erythema induratum of Bazin (BEI), is included in the group of cutaneous granulomatous lobulillar panniculitis. The aethiopathogenic association between EI and tuberculosis can not rely on the clinicohistological features of these panniculitis and M. tuberculosis has never been isolated from BEI lesions. Detection of the mycobacterial DNA by PCR on cutaneous biopsy samples would allow to confirm this association. Fourteen patients with clinical BEI were chosen retrospectively. Seventeen lesional biopsy samples were obtained, stained with the Kinyoun carbolfuchsin acid-fast technique and haematoxylin and eosin and tested by PCR. A fragment of the IS6110 insertion sequence specific of M. tuberculosis was amplified and confirmed by digestion with Sal I restriction endonuclease. The efficiency of the procedure, the presence of inhibitory substances and the preservation of DNA were checked by PCR of the beta-actin gene. M. tuberculosis DNA was detected in 12 of the 17 samples tested (70.5%) which corresponded to 10 of the 14 patients (71.4%). According to beta-actin PCR results, the rate of extracted DNA was inadequate on four of the five negative biopsies. The results of these series suggest the probable involvement of M. tuberculosis on the BEI pathogenesis and give support to the usefulness of the PCR in the diagnosis of this pathology concerning the need of specific treatment.


Wetting characteristics of aqueous rhamnolipids solutions.
The wetting properties of surfactants on solid surfaces form the basis of many industrial and biological processes. The preferential adsorption of the surfactants from aqueous solutions onto solid surfaces alter the adhesion tension of the surface and this behavior may cause partial to complete wetting of the surfaces by the aqueous surfactant solutions. However, different types of surfactants show different wetting characteristics. To study the wetting properties of biologically produced rhamnolipids (RL), advancing contact angles of the aqueous solutions of the RL mixture of R1 and R2 in a ratio of R2/R1=1.1 were measured as a function of surfactant concentration. For a comparison of the wetting performance, sodium dodecyl sulfate (SDS) was chosen as the reference surfactant. A hydrophilic glass surface, a hydrophobic polymer, polyethylene terephthalate (PET), and gold surface were used as the solid surfaces to determine the wetting characteristics of rhamnolipids. At low surfactant concentrations (RL concentration <3x10(-5)M, SDS concentration<3x10(-4)M) contact angle (Theta) varied in a certain range depending on the character of the surfactant interactions with the surface. This was followed by a decrease in contact angle. Parallel to this behavior, at low surfactant concentrations the adhesion tension decreased, then remained constant and an increase at higher surfactant concentrations was obtained on hydrophobic surfaces. On hydrophilic surfaces a steady decrease in adhesion tension was observed with both surfactant solutions.


Migration and T-lymphocyte effector function.
The development of immunity depends upon the capacity of responding T cells to become mobilized from lymphoid tissues where they are primed to sites of antigen exposure, wherever they occur in the body. Activation-induced alterations in the ability of T cells to migrate signify a fundamental change in biological function. Considerable attention is now focused on identifying mechanisms that regulate the migration and persistence of T cells that disseminate to non-lymphoid compartments as effector cells, and those that are retained in the lymphoid compartment. There are many unanswered questions about the developmental relationships and roles in protective immunity of antigen-experienced T cells that partition in different tissues.


Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma.
Mantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogeneous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently used in patients who are untreated. Over the last several years, several targeted or small-molecule therapies have shown efficacy in the relapsed/refractory setting and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase 2 study of 38 patients with MCL who were untreated and ineligible to receive transplantation, in which the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multicenter, open-label, nonrandomized, single-arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness, or risk factors. Lenalidomide was dosed at 20 mg daily from days 1 to 21 of each 28-day cycle. The dose of venetoclax was determined using the time-to-event continual reassessment method. Rituximab was dosed at 375 mg/m2 weekly, starting on cycle 1, day 1 until cycle 2, day 1. No dose-limiting toxicities were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common adverse events were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86%, respectively. In total, 86% of patients achieved minimal residual disease undetectability via next-generation sequencing. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.clinicaltrials.gov as #NCT03523975.


Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach.
To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.


Exercise for sarcopenia in older people: A systematic review and network meta-analysis.
Sarcopenia is a serious public health concern among older adults worldwide. Exercise is the most common intervention for sarcopenia. This study aimed to compare the effectiveness of different exercise types for older adults with sarcopenia. Randomized controlled trials (RCTs) that examined the effectiveness of exercise interventions on patient-important outcomes for older adults with sarcopenia were eligible. We systematically searched MEDLINE, Embase and Cochrane Central Register of Controlled Trials via Ovid until 3 June 2022. We used frequentist random-effects network meta-analyses to summarize the evidence and applied the Grading of Recommendations, Assessment, Development, and Evaluations framework to rate the certainty of evidence. Our search identified 5988 citations, of which 42 RCTs proved eligible with 3728 participants with sarcopenia (median age: 72.9 years, female: 73.3%) with a median follow-up of 12 weeks. We are interested in patient-important outcomes that include mortality, quality of life, muscle strength and physical function measures. High or moderate certainty evidence suggested that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life compared to usual care (standardized mean difference from 0.68 to 1.11). Moderate certainty evidence showed that resistance and balance exercise plus nutrition (mean difference [MD]: 4.19 kg) was the most effective for improving handgrip strength (minimally important difference [MID]: 5 kg). Resistance and balance exercise with or without nutrition (MD: 0.16 m/s, moderate) were the most effective for improving physical function measured by usual gait speed (MID: 0.1 m/s). Moderate certainty evidence showed that resistance and balance exercise (MD: 1.85 s) was intermediately effective for improving physical function measured by timed up and go test (MID: 2.1 s). High certainty evidence showed that resistance and aerobic, or resistance and balance, or resistance and aerobic exercise plus nutrition (MD from 1.72 to 2.28 s) were intermediately effective for improving physical function measured by the five-repetition chair stand test (MID: 2.3 s). In older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life. Adding nutritional interventions to exercise had a larger effect on handgrip strength than exercise alone while showing a similar effect on other physical function measures.


Improved high-performance liquid chromatographic assay for encainide and its metabolites in human body fluids.
Methods reported previously for the determination of encainide and its metabolites in biological fluids have not been extensively described and evaluated. We report an improved high-performance liquid chromatographic assay for the quantification of these compounds in plasma and urine with complete estimation of the accuracy and reproducibility of the analytical method. The major improvements consist of: (1) the use of ethaverine as an appropriate internal standard; (2) the use of the salting-out technique which improves the extraction recovery for the metabolites of encainide and the sensitivity of the assay; and (3) a shift of the ultraviolet absorption wavelength from 254 to 270 nm to increase the selectivity of the detection.


Febrile ulceronecrotic Mucha-Habermann disease during pregnancy: A case report.
Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe form of 'pityriasis lichenoides et varioliformis acuta', with a progressive and potentially fatal course. To the best of our knowledge, there has been no reported case of FUMDH during pregnancy before. Due to life-threatening nature of the disease and the lack of evidence-based treatment, management of FUMHD in pregnancy is a therapeutic challenge. Additionally, some of the drugs that are effective in the treatment are contraindicated in pregnancy. Herein, we report a 27-year-old woman diagnosed with FUMHD in her 19th week of pregnancy and treated with ceftriaxone and erythromycin.


Chronic renal insufficiency does not induce behavioral and cognitive alteration in rats.
In humans, chronic kidney disease (CKD) is associated with cognitive decline, increase in anxiety, or depression. The underlying mechanisms of these changes remain unclear. The aim of this study was to elucidate whether and how experimentally induced long-term CKD affects cognitive functions in rats. Thirty male Wistar rats underwent 5/6 nephrectomy (5/6 Nx), an established model of CKD, or sham surgery. Development of CKD was monitored using biochemical analyses and confirmed by renal histology. Behavioral tests of anxiety, depression and spatial behavior were performed before, and at 3 and 9 months after the surgery. CKD in 5/6 Nx rats was characterized by significant decrease of renal function, e.g., glomerular filtration rate, and progressive glomerulosclerosis, tubular atrophy, and interstitial fibrosis; and increased plasma uremic toxins. Mortality was higher in 5/6 Nx rats in comparison with controls. Compared to control group, the surviving 5/6 Nx rats presented similar general locomotor activity, depression traits, and spatial abilities (p=0.43, p=0.84, p=0.71, respectively). At 9 months, lower anxiety in the light-dark box test was observed in 5/6 Nx rats if compared with the control group (p=0.02). Despite the development of progressive CKD in 5/6 Nx rats, no expected behavioral changes were observed. Further experimental studies associating behavioral responses to severity of CKD are definitely needed to confirm the solely psychosocial aspect background of CKD-associated cognitive impairment in humans.


Occurrence of cathepsin D isozymes with different specificities in monkey skeletal muscle.
Cathepsin D was highly purified from the skeletal muscle of Japanese monkey (Macaca fuscata fuscata) by a procedure including affinity chromatography on concanavalin A-Sepharose and pepstatin-Sepharose, and then resolved into ten isozymes (A through J) by isoelectric focusing. When examined for specificity toward oxidized insulin B chain, isozyme A was highly specific and cleaved exclusively the Leu15-Tyr16 bond, whereas isozyme F was less specific, cleaving the Leu15-Tyr16 and Glu13-Ala14 bonds, with slower cleavages at several other bonds. These results demonstrate for the first time the occurrence of isozymes with different specificities among cathepsin D isozymes obtained from a single source.


GenDrux: a biomedical literature search system to identify gene expression-based drug sensitivity in breast cancer.
This paper describes the development of a web-based tool, GenDrux, which extracts and presents (over the Internet) information related to the disease-gene-drug nexus. This information is archived from the relevant biomedical literature using automated methods. GenDrux is designed to alleviate the difficulties of manually processing the vast biomedical literature to identify disease-gene-drug relationships. GenDrux will evolve with the literature without additional algorithmic modifications. GenDrux, a pilot system, is developed in the domain of breast cancer and can be accessed at http://www.microarray.uab.edu/drug_gene.pl. GenDrux can be queried based on drug, gene and/or disease name. From over 8,000 relevant abstracts from the biomedical literature related to breast cancer, we have archived a corpus of more than 4,000 articles that depict gene expression-drug activity relationships for breast cancer and related cancers. The archiving process has been automated. The successful development, implementation, and evaluation of this and similar systems when created may provide clinicians with a tool for literature management, clinical decision making, thus setting the platform for personalized therapy in the future.


Induction of cell surface human leukocyte antigen-G expression in pandemic H1N1 2009 and seasonal H1N1 influenza virus-infected patients.
A novel H1N1 virus of swine origin (H1N1v) recently caused a pandemic; however, knowledge of immunologic aspects of the virus infection are limited. Human leukocyte antigen-G (HLA-G) was speculated to play critical roles in viral infection, although its clinical relevance in H1N1 infection remains unknown. In this study, HLA-G expression in peripheral T lymphocytes, monocytes, and CD4(+) CD25(+) FoxP3+ regulatory T (Treg) cells (in 50 H1N1v-infected and 41 seasonal H1N1-infected patients and 27 control subjects) were analyzed by flow cytometry. Plasma-soluble HLA-G (sHLA-G, in 28 H1N1v-infected, 29 seasonal H1N1-infected patients and 85 control subjects) were determined with enzyme-linked immunosorbent assay. The percentage of HLA-G-positive T lymphocytes and monocytes among patients with H1N1v and seasonal H1N1 infections was dramatically increased compared with controls (all p < 0.001). Treg was markedly increased among H1N1v- infected patients compared with normal controls (p = 0.041), but not for the seasonal H1N1-infected patients. Meanwhile, no significant difference was observed for sHLA-G levels between the groups. Together, cell surface HLA-G expression was markedly induced in H1N1v-infected and seasonal H1N1-infected patients, and increased Treg was observed only in H1N1v-infected patients. Given its immune-suppressive property, elevated cell surface HLA-G expression may help to explain the virus escaping from host immune responses.


Expression of epidermal growth factor receptor, transforming growth factor-alpha and Ki-67 in relationship to malignant transformation of pleomorphic adenoma.
Quantitative assessment is more sensitive as a measure of cellular protein content as compared with standard optical density measurements. The data support the hypothesis that increased epidermal growth factor receptor (EGFR) and transforming growth factor (TGF)-alpha expression is associated with early events in malignant transformation of pleomorphic adenoma (PA). In the present study, we attempted to identify EGFR and TGF-alpha expression and Ki-67 index in carcinoma ex-pleomorphic adenoma (Ca ex-PA) and PA. We also compared the presence of EGFR and TGF-alpha and Ki-67 index with clinical data. The tissues were stained with monoclonal antibodies to EGFR, TGF-alpha and Ki-67. The results were analysed using quantitative immunohistochemical analysis. We also analysed the association of patients' prognosis with clinical parameters and the histological classification of the carcinomatous component. As regards the association of patients' prognosis with EGFR staining and Ki-67 index, a significant increase was observed in patients who died or had residual disease compared with patients who were alive without disease. In the immunohistochemical analysis of EGFR and TGF-alpha and Ki67 index, a significant increase was observed in Ca ex-PA, especially with adenocarcinoma, compared with PA and sialadenitis.


Public awareness, attitudes and beliefs regarding intellectual disability: a systematic review.
The general public's responses to people with intellectual disabilities influence the likely success or failure of policies aimed at increasing their social inclusion. The present paper provides a review of general population based research into awareness, attitudes and beliefs regarding intellectual disability published in English between 1990 and mid-2011. An electronic search using PsycINFO and Web of Science plus a hand search of the literature was completed. Most of the 75 studies identified consisted of descriptive surveys of attitudes. They tend to conclude that age, educational attainment and prior contact with someone with an intellectual disability predict attitudes, while the effect of gender is inconsistent. Eight studies examined lay knowledge about intellectual disability and beliefs about its causation in a range of cultural contexts. The impact of interventions designed to improve attitudes or awareness was examined by 12 studies. The evidence is limited by the fact that it is mostly based on relatively small unrepresentative samples and cross-sectional designs. It is concluded that overall, high quality research into general population attitudes to intellectual disability is limited. Public knowledge of intellectual disability and causal beliefs are particularly under-researched areas. There is a notable absence of well designed evaluations of efforts to reduce misconceptions about intellectual disability and tackle negative attitudes. Areas for future research are noted, including the need for well designed studies that consider awareness, attitudes and beliefs in relation to stigma theory.


Incompleteness of the Circle of Willis correlates poorly with imaging evidence of small vessel disease. A population-based study in rural Ecuador (the Atahualpa project).
Studies looking for an association between incompleteness of the Circle of Willis (CoW) and small vessel disease (SVD) markers are scarce and conflicting. We aimed to evaluate this association in an unbiased population-based study conducted in Atahualpa (rural Ecuador). Atahualpa residents 60 years of age or more were identified during a door-to-door survey and invited to undergo magnetic resonance imaging for identification of SVD markers, including white matter hyperintensities (WMHs), strokes, and deep microbleeds. Magnetic resonance imaging (MRA) was used for classifying the CoW according to the presence or absence of one A1 segment of the anterior cerebral artery or one or both P1 segments of posterior cerebral arteries. Of 311 eligible persons, 258 were enrolled. Mean age was 70 ± 8 years, 59% were women, and 74% had a poor cardiovascular health (CVH) status. Of these, 172 patients (67%) had WMH, 40 patients (16%) had SVD-related strokes, and 23 patients (9%) had deep microbleeds. MRA revealed a complete CoW in 157 persons (61%). Persons with SVD markers were older than those without markers (P < .0001). A poor CVH status was noted in 79% of persons with at least 1 SVD marker and in 65% of those with no markers (P = .02). Logistic regression models showed no association of incompleteness of the CoW with any marker of SVD-alone or in combination-after adjusting for age, sex, and CVH status. Lack of association between incompleteness of CoW and SVD markers suggest that genetically determined variants in the intracranial vasculature are not responsible for the high prevalence of SVD among native South American populations.


Primary HSV-2 Infection Complicated by Radiculomyelitis in a Young Immunocompetent Female Patient with Inherited Chromosomally Integrated HHV-6: A Case Report.
HSV-1, HSV-2 and VZV are alpha Herpesviruses, neurotropic viruses that are associated with various neurologic complications upon primary infection or reactivation. Cases of myelitis and radiculomyelitis are rare and appropriate etiologic diagnoses can be tricky. Here we describe the case of a young immunocompetent woman who developed painful and extended vesicular genital lesions, with subsequent radiculomyelitis. HSV-1/-2 PCRs in the cerebrospinal fluid were misleadingly negative, whereas HHV-6 PCR was positive. Positive anti-HSV-2 IgM and IgG in serum was consistent with HSV-2 primary infection. On the other hand, the detection of HHV-6 DNA was explained by inherited chromosomally integrated HHV-6. The clinical course was favorable with high-dose IV acyclovir and corticosteroids. HSV-2-related radiculomyelitis is a rare clinical entity, which can be difficult to diagnose. In this case report, the causative virus was not detected in the patient's CSF, whereas HHV-6 DNA, non-pathogenic in this situation, was paradoxically positive. The diagnosis was based on the clinical features typical for HSV-2 primary infection, confirmed by the serology results. The delay between the genital lesions and the appearance of the radiculomyelitis, along with the absence of HSV-2 detection in the CSF, suggests a possible immuno-mediated physiopathological process. As for the HHV-6 DNA detection in the patient's CSF, it was explained by inherited chromosomally integrated HHV-6. This case illustrates how both negative and positive clinical virology results need careful interpretation according to the clinical findings.


Evaluation on subcellular partitioning and biodynamics of pulse copper toxicity in tilapia reveals impacts of a major environmental disturbance.
Fluctuation exposure of trace metal copper (Cu) is ubiquitous in aquatic environments. The purpose of this study was to investigate the impacts of chronically pulsed exposure on biodynamics and subcellular partitioning of Cu in freshwater tilapia (Oreochromis mossambicus). Long-term 28-day pulsed Cu exposure experiments were performed to explore subcellular partitioning and toxicokinetics/toxicodynamics of Cu in tilapia. Subcellular partitioning linking with a metal influx scheme was used to estimate detoxification and elimination rates. A biotic ligand model-based damage assessment model was used to take into account environmental effects and biological mechanisms of Cu toxicity. We demonstrated that the probability causing 50% of susceptibility risk in response to pulse Cu exposure in generic Taiwan aquaculture ponds was ~33% of Cu in adverse physiologically associated, metabolically active pool, implicating no significant susceptibility risk for tilapia. We suggest that our integrated ecotoxicological models linking chronic exposure measurements with subcellular partitioning can facilitate a risk assessment framework that provides a predictive tool for preventive susceptibility reduction strategies for freshwater fish exposed to pulse metal stressors.


Trust in science and scientists among university students, staff, and faculty of a large, diverse university in Los Angeles during the COVID-19 pandemic, the Trojan Pandemic Response Initiative.
Mistrust in science and scientists may adversely influence the rate of COVID-19 vaccination and undermine public health initiatives to reduce virus transmission. Students, staff and faculty responded to an email invitation to complete an electronic survey. Surveys included 21-items from the Trust in Science and Scientists Inventory questionnaire. Responses were coded so higher scores indicated a higher trust in science and scientists, A linear regression model including sex, age group, division, race and ethnicity, political affiliation, and history of COVID-19, was used to determine variables significantly associated with trust in science and scientists scores at the p < 0.05 level. Participants were mostly female (62.1%), Asian (34.7%) and White (39.5%) and students (70.6%). More than half identified their political affiliation as Democrat (65%). In the final regression model, all races and ethnicities had significantly lower mean trust in science and scientists scores than White participants [Black ([Formula: see text]= -0.42, 95% CI: -0.55, -0.43, p < 0.001); Asian ([Formula: see text]= -0.20, 95% CI: -0.24, -0.17, p < 0.001); Latinx ([Formula: see text]= -0.22, 95% CI: -0.27, -0.18, p < 0.001); Other ([Formula: see text]= -0.19, 95% CI: -0.26, -0.11, p < 0.001)]. Compared to those identifying as Democrat, all other political affiliations had significantly lower mean scores. [Republican ([Formula: see text] =-0.49, 95% CI: -0.55, -0.43, p < 0.0001); Independent ([Formula: see text] =-0.29, 95% CI: -0.33, -0.25, p < 0.0001); something else ([Formula: see text] =-0.19, 95% CI: -0.25, -0.12, p < 0.0001)]. Having had COVID-19 ([Formula: see text]= -0.10, 95% CI: -0.15, -0.06, p < 0.001) had significantly lower scores compared to those who did not have COVID-19. Despite the setting of a major research University, trust in science is highly variable. This study identifies characteristics that could be used to target and curate educational campaigns and university policies to address the COVID19 and future pandemics.


ErbB2 and ErbB4 Cbl binding sites can functionally replace the ErbB1 Cbl binding site.
Poor downregulation of ErbB receptors is associated with enhanced downstream signaling and tumorigenesis. It has been suggested that poor downregulation of ErbB-2, -3 and -4 receptors when compared to ErbB1 is due to decreased recruitment of Cbl E3 ligase proteins. However, a highly conserved Cbl binding site is not only present in ErbB1/EGFR (FLQRpY(1045)SSDP), but also in ErbB2 (PLQRpY(1091)SEDP) and ErbB4 (STQRpY(1103)SADP). We therefore replaced the ErbB1 Cbl binding site by that of ErbB2 and ErbB4. Whereas retrovirally infected NIH3T3 cells containing the EGFR Y1045F mutation showed dramatically impaired Cbl recruitment, EGFR ubiquitination and delayed EGFR degradation, replacement of the EGFR Cbl binding site by that of ErbB2 or ErbB4 did not affect Cbl recruitment, receptor-ubiquitination, -degradation, -downregulation or ligand degradation. We conclude that poor downregulation of ErbB2 and ErbB4 receptors is not due to sequence variations in the Cbl binding site of these receptors.


Urinary tract infection complicated by urine retention presenting as pseudocyesis in a schizophrenic patient.
Pseudocyesis is a rare condition wherein a nonpregnant woman shows signs and symptoms of pregnancy, such as abdominal enlargement, breast enlargement, pigmentation, cessation of menses, subjective sensation of fetal movement and labor pains at the expected delivery date. In the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, it is classified as a somatoform disorder, characterized by a false belief of being pregnant that is associated with objective signs of pregnancy. We report the case of a middle-aged female schizophrenic patient who developed pseudocyesis secondary to a urinary tract infection complicated by acute urine retention. The patient accepted that she had pseudocyesis after the causative medical condition resolved.


Rock mass classification prediction model using heuristic algorithms and support vector machines: a case study of Chambishi copper mine.
The rock mass is one of the key parameters in engineering design. Accurate rock mass classification is also essential to ensure operational safety. Over the past decades, various models have been proposed to evaluate and predict rock mass. Among these models, artificial intelligence (AI) based models are becoming more popular due to their outstanding prediction results and generalization ability for multiinfluential factors. In order to develop an easy-to-use rock mass classification model, support vector machine (SVM) techniques are adopted as the basic prediction tools, and three types of optimization algorithms, i.e., particle swarm optimization (PSO), genetic algorithm (GA) and grey wolf optimization (GWO), are implemented to improve the prediction classification and optimize the hyper-parameters. A database was assembled, consisting of 80 sets of real engineering data, involving four influencing factors. The three combined models are compared in accuracy, precision, recall, F1 value and computational time. The results reveal that among three models, the GWO-SVC-based model shows the best classification performance by training. The accuracy of training and testing sets of GWO-SVC are 90.6250% (58/64) and 93.7500% (15/16), respectively. For Grades I, II, III, IV and V, the precision value is 1, 0.93, 0.90, 0.92, 0.83, the recall value is 1, 1, 0.93, 0.73, 0.83, and the F1 value is 1, 0.96, 0.92, 0.81, 0.83, respectively. Sensitivity analysis is performed to understand the influence of input parameters on rock mass classification. It shows that the sensitive factor in rock mass quality is the RQD. Finally, the GWO-SVC is employed to assess the quality of rocks from the southeastern ore body of the Chambishi copper mine. Overall, the current study demonstrates the potential of using artificial intelligence methods in rock mass assessment, rendering far better results than the previous reports.


Tumour associated vasculature-on-a-chip for the evaluation of microbubble-mediated delivery of targeted liposomes.
The vascular system is the primary route for the delivery of therapeutic drugs throughout the body and is an important barrier at the region of disease interest, such as a solid tumour. The development of complex 3D tumour cultures has progressed significantly in recent years however, the generation of perfusable vascularised tumour models still presents many challenges. This study presents a microfluidic-based vasculature system that can be induced to display properties of tumour-associated blood vessels without direct incorporation of tumour cells. Conditioning healthy endothelial-fibroblast cell vasculature co-cultures with media taken from tumour cell cultures was found to result in the formation of disorganised, tortuous networks which display characteristics consistent with those of tumour-associated vasculature. Integrin αvβ3, a cell adhesion receptor associated with angiogenesis, was found to be upregulated in vasculature co-cultures conditioned with tumour cell media (TCM) - consistent with the reported αvβ3 expression pattern in angiogenic tumour vasculature in vivo. Increased accumulation of liposomes (LSs) conjugated to antibodies against αvβ3 was observed in TCM networks compared to non-conditioned networks, indicating αvβ3 may be a potential target for the delivery of drugs specifically to tumour vasculature. Furthermore, the use of microbubbles (MBs) and ultrasound (US) to further enhance the delivery of LSs to TCM-conditioned vasculature was investigated. Quantification of fluorescent LS accumulation post-perfusion of the vascular network showed 3-fold increased accumulation with the use of MBs and US, suggesting that targeted LS delivery could be further improved with the use of locally administered MBs and US.


Evaluation of salivary VOC profile composition directed towards oral cancer and oral lesion assessment.
Endogenous substances have been analyzed in biological samples in order to be related with metabolic dysfunctions and diseases. The study aimed to investigate profiles of volatile organic compounds (VOCs) from fresh and incubated saliva donated by healthy controls, individuals with oral tissue lesions and with oral cancer, in order to assess case-specific biomarkers of oxidative stress. VOCs were pre-concentrated using headspace-solid phase microextraction and analyzed using gas chromatography-mass spectrometry. Then, VOCs positively modulated by incubation process were subtracted, yielding profiles with selected features. Principal component analysis and hierarchical cluster analysis were used to inspect data distribution, while univariate statistics was applied to indicate potential markers of oral cancer. Machine learning algorithm was implemented, aiming multiclass prediction. The removal of bacterial contribution to VOC profiles allowed the obtaining of more specific case-related patterns. Artificial neural network model included 9 most relevant compounds (1-octen-3-ol, hexanoic acid, E-2-octenal, heptanoic acid, octanoic acid, E-2-nonenal, nonanoic acid, 2,4-decadienal and 9-undecenoic acid). Model performance was assessed using 10-fold cross validation and receiver operating characteristic curves. Obtained overall accuracy was 90%. Oral cancer cases were predicted with 100% of sensitivity and specificity. The selected VOCs were ascribed to lipid oxidation mechanism and presented potential to differentiate oral cancer from other inflammatory conditions. These results highlight the importance of interpretation of saliva composition and the clinical value of salivary VOCs. Elucidated metabolic alterations have the potential to aid the early detection of oral cancer and the monitoring of oral lesions.


bcl-2 gene rearrangement analysis in Japanese B cell lymphoma; novel bcl-2 recombination with immunoglobulin kappa chain gene.
The rearrangement of bcl-2 gene was studied in 56 Japanese B cell lymphoma cases to investigate the contribution of bcl-2 gene to lymphomagenesis in Japan. Ten out of 56 cases showed bcl-2 gene rearrangement; it was detected in only 5 out of 16 follicular lymphoma cases (31%) and in 5 out of 40 diffuse B cell lymphoma cases (13%). The incidence of bcl-2 gene involvement in Japanese follicular lymphomas was lower than those reported in the United States. This might contribute to the lower incidence of follicular lymphoma cases in Japan. Novel recombination between bcl-2 and Ig kappa genes at the 5' region of bcl-2 and J kappa 4 segment was observed in one follicular lymphoma case, suggesting that bcl-2 gene is transcriptionally activated by Ig kappa enhancer. It was also suggested that this case had originated from a more differentiated B cell than most follicular lymphomas with bcl-2-Ig H recombination.


Effects of gonadotropin-releasing hormone on growth hormone secretion and gene expression in common carp pituitary.
Using radioimmuno- and ribonuclease protection assays, we examined the effects of gonadotropin-releasing hormone and its analogs on the growth hormone mRNA level and growth hormone secretion in common carp (Cyprinus carpio) pituitary fragments with static incubation. After a 24 h treatment, sGnRH ([Trp(7),Leu(8)]-LHRH) and sGnRH-A ([D-Arg(6),Pro(9)]-LHRH) (0.1 nM-1 microM) elevated the GH mRNA level and stimulated the GH secretion in a dose-dependent manner, with a higher potency for sGnRH-A. In a time-course experiment, the function of sGnRH and sGnRH-A (10 nM) on GH secretion was observed after 6 h incubation, while no action on the GH mRNA level were noted until 12 h after treatment. Comparing mammalian GnRH, avian GnRH and piscine GnRH, sGnRH and sGnRH-A showed the highest potency in increasing GH mRNA level and GH-release, followed by cGnRH-II ([His(5),Tyr(8)]-LHRH), and finally LHRH and LHRH-A([D-Trp(6), Pro(9)]-LHRH). These findings, taken together, suggest that GnRH not only can influence GH release, but also play a role in the regulation of GH synthesis.


Forehead Lift for Asians.
Asians have anatomic and clinical characteristics to be considered before forehead lift. Because of the anatomic characteristics of Asians, for the better outcomes of blepharoplasty or augmentation rhinoplasty, forehead lift as a combined surgery must be considered beforehand. Forehead lift is frequently indicated in young Asian patients. Endoscopic browlift without visible scar is favored for patients, and it can be done in a modified multiplane fashion for better outcomes in patients with thick and redundant skin. There are rare but severe complications of endoscopic forehead lift, such as motor nerve paresis and diplopia, although they are temporary in most cases.


Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients.
The current study was to investigate the interaction between Helicobacter pylori and human dendritic cells (DCs). Whether impaired DC function can influence the outcome of H. pylori infections. Human monocyte-derived DCs (MDDCs) from five gastric cancer patients and nine healthy controls were stimulated with H. pylori. Maturation markers of MDDC were examined by flow cytometry. IL-10 and TNF-α released by MDDCs and IL-17 produced by T cells were measured by ELISA. Regulatory signaling pathways of IL-10 were examined by ELISA, western blotting, and chromatin immunoprecipitation assay. The results showed that as compared with healthy individuals, the maturation marker CD40 in MDDCs, IL-17A expression from T cells, and IL-10 expression from MDDCs were significantly lower in gastric cancer patients. Blocking DC-SIGN, TLR2, and TLR4 could reverse H. pylori-associated IL-10 production. Activation of the p38 MAPK and NF-kB signaling pathways concomitant with decreased tri-methylated H3K9 and increased acetylated H3 accounted for the effect of H. pylori on IL-10 expression. Furthermore, upregulated IL-10 expression was significantly suppressed in H. pylori-pulsed MDDCs by histone acetyltransferase and methyltransferase inhibitors. Taken together, impaired DC function contributes to the less effective innate and adaptive immune responses against H. pylori seen in gastric cancer patients. H. pylori can regulate IL-10 production through Toll-like and DC-SIGN receptors, activates p-p38 MAPK signaling and the transcription factors NF-kB, and modulates histone modification.


Suppressed proliferation of lymphatic tissue in diabetic and adrenalectomized-diabetic rats.
One week following induction of diabetes in rats by alloxan administration, the thymus and spleen showed marked involution and a highly significant depression of in vivo incorporation of [3H]deoxycytidine into the DNA of these tissues. Adrenalectomy of diabetic rats reduced the decline of lymphatic tissue weight, but uptake of [3H]deoxycytidine into thymic and spleen DNA remained suppressed. These results indicate that in alloxan-induced diabetes, the observed depressed lymphatic tissue weight and cellular proliferation are not simply due to the elevated plasma level of corticosteroids, but are either a result of the insulin deficiency per se or due to other metabolic alterations associated with the diabetic condition.


Survival after avalanche-induced cardiac arrest.
Criteria to prolong resuscitation after cardiac arrest (CA) induced by complete avalanche burial are critical since profound hypothermia could be involved. We sought parameters associated with survival in a cohort of victims of complete avalanche burial. Retrospective observational study of patients suffering CA on-scene after avalanche burial in the Northern French Alps between 1994 and 2013. Criteria associated with survival at discharge from the intensive care unit (ICU) were collected on scene and upon admission to Level-1 trauma center. Neurological outcome was assessed at 3 months using cerebral performance category score. Forty-eight patients were studied. They were buried for a median time of 43 min (25-76 min; 25-75th percentiles) and had a pre-hospital body core temperature of 28.0°C (26.0-30.7). Eighteen patients (37.5%) had pre-hospital return of spontaneous circulation and 30 had refractory CA. Rewarming of 21 patients (43.7%) was performed using extracorporeal life support. Eight patients (16.7%) survived and were discharged from the ICU, three (6.3%) had favorable neurological outcome at 3 months. Pre-hospital parameters associated with survival were the presence of an air pocket and rescue collapse. On admission, survivors had lower serum potassium concentrations than non-survivors: 3.2 mmol/L (2.7-4.0) versus 5.6 mmol/L (4.2-8.0), respectively (P<0.01). They also had normal values for prothrombin and activated partial thromboplastin compared to non-survivors. Our findings indicate that survival after avalanche burial and on-scene CA is rarely associated with favorable neurological outcome. Among criteria associated with survival, normal blood coagulation on admission warrants further investigation.


Leveraging quality improvement to achieve equity in health care.
INEQUALITY IN QUALITY: Disparities in health care and quality for racial, ethnic, linguistic, and other disadvantaged groups are widespread and persistent. Health care organizations are engaged in efforts to improve quality in general but often make little attempt to address disparities. Most QI interventions are broadly targeted to the general population-a "one-size-fits-all" approach. These standard QI efforts may preferentially improve quality for more advantaged patients and maintain or even worsen existing disparities. Culturally competent QI interventions place specific emphasis on addressing the unique needs of minority groups and the root causes of disparities. QI interventions can reduce disparities in at least three ways: (1) In some cases, standard QI interventions can improve quality more for those with the lowest quality, but this is unreliable; (2) group-targeted QI interventions can reduce disparities by preferentially targeting disparity groups; and (3) culturally competent QI interventions, by tailoring care to cultural and linguistic barriers that cause disparities, can improve care for everyone but especially for disparity groups. A culturally competent approach to QI should (1) identify disparities and use disparities data to guide and monitor interventions, (2) address barriers unique to specific disparity groups, and (3) address barriers common to many disparity group. To achieve equity in health care, hospitals and other health care organizations should move toward culturally competent QI and disparities-targeted QI interventions to achieve equity in health care, a key pillar of quality.


Differential heat shock response of primary human cell cultures and established cell lines.
The influence of hyperthermia on the cellular growth and protein synthesis pattern from primary human brain tumour cells and skin fibroblasts was compared with established and experimentally transformed tumour cell lines. Primary cell cultures did not show any visible morphological changes after 42 degrees C treatment, whereas in immortalized cell lines usually 90% of the cells were found in suspension. Enhanced expression of the major heat shock protein (hsp 70) was found in all heat-treated cells. In contrast to the primary cell cultures, established and transformed cell lines synthesized a protein with an apparent molecular mass of 70 kDa and an isoelectric pH of 7.0 as early as 3 h after the initial hyperthermal treatment.


Thermal conductivity of a single Bi₀.₅Sb₁.₅Te₃ single-crystalline nanowire.
Single-crystalline Bi₀.₅Sb₁.₅Te₃ nanowires were fabricated by a template-assisted pulsed electrodeposition technique; the thermal conductivity of a single Bi₀.₅Sb₁.₅Te₃ nanowire of different diameters was characterized through a self-heating 3 ω method. The temperature-dependent resistance measurements prove the semiconductor behavior of the nanowires. The extremely low thermal conductivity of the nanowires was found compared with the corresponding bulk, and the Umklapp peaks shift to a higher temperature as the decreasing nanowire's diameter decreases, which qualitatively agrees with the theoretical calculations based on the Callaway model. The boundary scattering plays an important role in the reduction of the thermal conductivity and in the shift of the Umklapp peak of the Bi₀.₅Sb₁.₅Te₃ nanowires.


High-dose chemotherapy followed by autologous and allogeneic peripheral blood stem cell transplantation for recurrent disseminated trilateral retinoblastoma.
Trilateral retinoblastoma (TRb) is an intracranial neurogenic tumor associated with unilateral or bilateral retinoblastoma and has very poor prognosis. Patients typically die from leptomeningeal tumor dissemination. A 3-year-old girl who had been diagnosed with TRb had a disseminated relapse after a tumorectomy, cerebrospinal irradiation, and conventional chemotherapy. The disseminated tumor disappeared after the first autologous peripheral blood stem cell transplantation (PBSCT) with high-dose melphalan and thiotepa. During the second complete remission, a second autologous PBSCT with high-dose busulfan and melphalan was performed. Seven months after the first PBSCT, the second relapse occurred, and we subsequently performed an allogeneic PBSCT with myeloablative chemotherapy consisting of melphalan, thiotepa, and cyclophosphamide. The patient showed clinical improvement after the allogeneic PBSCT. Although high-dose chemotherapies have a curative effect for some patients with TRb, the prognoses of disseminated tumors are still poor. Further examination of the high-dose chemotherapy is necessary for the time, the conditioning drugs, and the hematopoietic stem cell sources.


Computer program for the reservoir model of metabolic crossroads.
A program containing 344 sentences, written in BASIC and adapted to run in personal computers (PC) has been developed to simulate the reservoir model of metabolic crossroads. The program draws the holes of the reservoir with shapes reflecting the Vmax, Km (S0.5) and cooperativity coefficients (n) of the enzymes and calculates both the actual velocities and the percentage of contribution of every enzyme to the overall removal of their common substrate.


Leukotriene B4 loaded in microspheres regulate the expression of genes related to odontoblastic differentiation and biomineralization by dental pulp stem cells.
Leukotriene B4 (LTB4) is a potent lipid mediator that stimulate the immune response. Because dental pulp inflammation and dentin repair are intrinsically related responses, the aim of this research was to investigate the potential of LTB4 in inducing differentiation of dental pulp stem cells. Microspheres (MS) loaded with LTB4 were prepared using an oil emulsion solvent extraction evaporation process and sterility, characterization, efficiency of LTB4 encapsulation and in vitro LTB4 release assay were investigated. Mouse dental pulp stem cells (OD-21) were stimulated with soluble LTB4 or MS loaded with LTB4 (0.01 and 0.1 μM). Cytotoxicity and cell viability was determined by lactate dehydrogenase and methylthiazol tetrazolium assays. Gene expression were measured by quantitative reverse transcription polymerase chain reaction after 3, 6, 24, 48 and 72 h. Mineralized nodule formation was assessed after 28 days of OD-21 cell stimulation with LTB4 in mineralized media or not. Groups were compared using one-way ANOVA test followed by Dunnett's post-test (α = 0.05). Treatment with LTB4 or MS loaded with LTB4 (0.01 and 0.1 µm-μM) were not cytotoxic to OD-21 cells. Treatment with LTB4 modulated the expression of the Ibsp (integrin binding sialoprotein) and Runx2 (runt-related transcription factor 2) genes differently depending on the experimental period analyzed. Interestingly LTB4 loaded in microspheres (0.1 μM) allowed long term dental pulp cell differentiation and biomineralization. LTB4, soluble or loaded in MS, were not cytotoxic and modulated the expression of the Ibsp and Runx2 genes in cultured OD-21 cells. When LTB4 was incorporated into MS, odontoblast differentiation and mineralization was induced in long term culture.


Transcriptional and post-transcriptional mechanisms of glucocorticoid antiproliferative effects.
Glucocorticoids (GCs) are used as immunosuppressive and anti-inflammatory agents in treating organ transplantation rejection, autoimmune diseases, (hematological) cancers, and inflammatory disorders. GCs exert their effects through a multitude of mechanisms, the most significant of which is inhibition of cytokine production, and for some cytokines their effects on target cells. Paradoxically, GCs also upregulate the expression of (pro-inflammatory) high-affinity cytokine receptors on target cells in the face of lost ligand (cytokine) stimulation. GC inhibition of cytokine expression occurs at both transcriptional and post-transcriptional levels. GCs acted transcriptionally by binding their cytosolic receptor (GR), thereby facilitating its nuclear translocation and subsequent binding to the promoter region of cytokine genes on sites compatible with GC response element (GRE) motifs, which in turn directly or indirectly regulated gene expression. In addition to direct DNA binding, GCs acted post-transcriptionally by: (1) antagonism of nuclear factors required for efficient gene expression either directly or through induction of the expression of specific transcription factor antagonists, (2) altered Th lineage development by favouring the generation of (anti-inflammatory) Th2 cells and suppressing the induction or the activity of established (pro-inflammatory) Th1 cells, and (3) stimulating the expression of transforming growth factor (TGF)-beta, an immunosuppressive cytokine which inhibited cytokine production. However, these mechanisms are not mutually exclusive, since GCs may utilize more than one mechanism in exerting their anti-proliferative effect.


Optic disc shape, corneal astigmatism, and amblyopia.
The cornea and the optic disc form the anteroposterior opening of the sclera. This study evaluated whether an abnormal shape of the optic disc is associated with an abnormal configuration of the cornea measured as corneal astigmatism. The study design was a cross-sectional one. The study included 882 subjects (430 women, 452 men) with a mean age of 45.9 +/- 13.6 years (mean +/- standard deviation; range, 8-87 years) and a mean refractive error of -1.09 +/- 2.76 diopters (range, -21.0 diopters to +7.0 diopters). Corneal astigmatism was determined by keratometry, and the optic disc was analyzed morphometrically by planimetric evaluation of optic disc photographs. Corneal astigmatism, ratio of minimal-to-maximal disc diameter, and optic disc form factor were measured. The amount of corneal astigmatism was significantly (P < 0.001) correlated with an increasingly elongated optic disc shape. Corneal astigmatism was significantly (P < 0.01) higher in eyes with tilted discs. It was significantly (P = 0.006) smaller in eyes with an almost circular disc shape. Amblyopia was significantly (P < 0.05) associated with an elongated optic disc shape and high corneal astigmatism. The axis of corneal astigmatism was correlated with the orientation of the longest disc diameter. The optic disc was significantly (P < 0.05; chi-square test) more often horizontally oval in eyes with a steeper horizontal corneal meridian than in eyes with a steeper vertical corneal meridian. Correspondingly, the disc was significantly (P < 0.05) more often vertically oval in eyes with a steeper vertical corneal meridian than in eyes with a steeper horizontal corneal meridian. An abnormal optic disc shape is significantly correlated with corneal astigmatism. Especially in young children, if an abnormal optic disc shape is found on routine ophthalmoscopy, refractometry should be performed to rule out corneal astigmatism and to prevent amblyopia. The direction of the longest optic disc diameter can indicate the axis of corneal astigmatism.


Epidemiology of restricting back pain in community-living older persons.
To estimate the incidence of back pain leading to restricted activity (restricting back pain) in community-living older persons and to characterize its descriptive epidemiology. Prospective cohort study. Greater New Haven, Connecticut. Five hundred fifty nondisabled, community-living men and women aged 70 and older who did not report restricting back pain at baseline. Participants were interviewed monthly for over 10 years to ascertain the cumulative incidence, time to first episode, incidence rates (first and repeat episodes), and duration of restricting back pain. Cumulative incidence (proportions) was estimated using the Kaplan-Meier method, and incidence rates (per 1,000 person-months) were estimated using a Poisson regression model. During the more than 10 years of follow-up (median 107 months), the cumulative incidence of restricting back pain was 77.3% for men and 81.7% for women. The median time to the first episode was significantly shorter in women (25 months) than men (49 months) (P=.01). The incidence rates of restricting back pain per 1,000 person-months were 32.9 overall-24.4 for men and 37.5 for women (P<.001). There were no differences according to baseline age group. Of the 1,528 total episodes of restricting back pain, the median duration was 1.0 month, and only 6.4% lasted for 3 or more consecutive months. Restricting back pain in older persons is common, short-lived, and frequently episodic. The burden of restricting back pain is greater in older women than older men.


Dynamics of sleep spindles and coupling to slow oscillations following motor learning in adult mice.
Sleep spindles have been implicated in motor learning in human subjects, but their occurrence, timing in relation to cortical slow oscillations, and relationship to offline gains in motor learning have not been examined in animal models. In this study, we recorded EEG over bilateral primary motor cortex in conjunction with EMG for 24 h following a period of either baseline handling or following rotarod motor learning to monitor sleep. We measured several biophysical properties of sleep spindles and their temporal coupling with cortical slow oscillations (SO, <1 Hz) and cortical delta waves (1-4 Hz). Following motor learning, we found an increase in spindles during an early period of NREM sleep (1-4 h) without changes to biophysical properties such as spindle power, peak frequency and coherence. In this same period of early NREM sleep, both SO and delta power increased after motor learning. Notably, a vast majority of spindles were associated with minimal SO power, but in the subset that were associated with significant SO power (>1 z-score above the population mean), spindle-associated SO power was greater in spindles following motor learning compared to baseline sleep. Also, we did not observe a group-level preferred phase in spindle-SO or spindle-delta coupling. While SO power alone was not predictive of motor performance in early NREM sleep, both spindle density and the difference in the magnitude of the mean resultant vector length of the phase angle for SO-associated spindles, a measure of its coupling precision, were positively correlated with offline change in motor performance. These findings support a role for sleep spindles and their coupling to slow oscillations in motor learning and establish a model in which spindle timing and the brain circuits that support offline plasticity can be mechanistically explored.


Microbiome analysis reveals Microcystis blooms endogenously seeded from benthos within wastewater maturation ponds.
Cyanobacterial blooms are prevalent to wastewater treatment facilities owing to the stable, eutrophic conditions. Cyanobacterial proliferations can disrupt operational procedures through the blocking of filtration apparatus or altering the wastewater treatment plant (WWTP) microbiome, reducing treatment efficiency. Conventional wastewater treatment often results in the lysis of cyanobacterial cells and the release of intracellular toxins which pose a health risk to end users. This research identifies a potential seeding source of recurrent toxigenic cyanobacterial blooms within wastewater treatment facilities. Our results demonstrate the capacity of Microcystis to transition between the sediments and surface waters (SWs) of wastewater treatment ponds enabling water utilities to develop adequate monitoring and management strategies. Further, we developed a novel model to demonstrate benthic recruitment of toxigenic Microcystis under laboratory conditions facilitating future research into the genetic mechanisms behind bloom development.


Neural correlates of recognition and naming of famous persons and landmarks: A special role for the left anterior temporal lobe.
The anterior temporal lobes (ATLs) have been shown to be crucial for recognition and naming of unique entities such as persons and places. In this chapter, we review previous research that identified the neural underpinnings of these processes, and discuss the convergence zone theory of conceptual knowledge and proper name retrieval. Lesion-deficit and neuroimaging studies have found that the temporal poles are essential for recognition and naming of unique persons and places. Research has shown laterality, in that the right anterior temporal pole is specialized for recognition and the left for naming. Here, we analyzed recognition and naming of persons and landmarks in a large neurologic sample (N=244) using the Iowa Famous Faces and Famous Landmarks tests. For both categories, education had a significant effect on recognition and naming performances, but age and gender did not. Lesion-symptom maps revealed lower naming scores for both Faces and Landmarks associated with lesions to the anterior and mesial left temporal lobe. Lower recognition scores were also linked to left temporal lobe damage, possibly due to the method we used for measuring recognition (verbally based). Overall, the results demonstrate the importance of the temporal lobes for recognition and naming of unique persons and places.


The association of squamous cell carcinomas of the nasopharynx with Epstein-Barr virus shows geographical variation reminiscent of Burkitt's lymphoma.
Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but occurs with high incidence in certain regions, such as South-East Asia. Two major histological types of NPC are recognized, non-keratinizing carcinoma and squamous cell carcinoma. Non-keratinizing NPCs, which include undifferentiated NPC, are invariably associated with Epstein-Barr virus (EBV) infection, regardless of the geographical or ethnic origin of the patients. By contrast, conflicting results have been published concerning a possible association of squamous cell NPC with the virus. To address this question, squamous cell NPCs have been collated from an area where NPC is endemic, Hong Kong, and from two regions where NPC occurs with a lower incidence, Chengdu, PR China, and Birmingham, United Kingdom. In situ hybridization for the detection of the small EBV-encoded nuclear RNAs (EBERs) demonstrated that all 22 cases from Hong Kong were EBV-positive. By contrast, EBV was detectable in 7 of 19 cases from central China, and in 3 of 7 cases from the U.K. Expression of the virus-encoded latent membrane protein 1 (LMP1) was detected in 3 of 32 EBV-positive squamous cell NPCs. These results indicate that the association of squamous cell NPCs with EBV shows geographical variability in a manner which is reminiscent of the situation encountered in Burkitt's lymphoma. This suggests that squamous cell NPCs are a pathogenetically heterogeneous group of tumours distinct from non-keratinizing NPCs.


Lateralization for the expression and perception of facial emotion as a function of age.
In order to test the hypothesis of right hemisphere changes with age, this study examined lateralization for facial emotion in young, middle-aged, and older women (N = 90). For expression, subjects were photographed while posing positive and negative emotions. Composite photographs were created and rated for intensity. For perception, subjects were required to make intensity judgements about emotional chimeric faces. Overall, subjects demonstrated significant left-sided facial asymmetry for expression and significant left hemispace biases for perception. The findings for facial expression were not influenced by emotional valence or resting face asymmetries. There were no changes in lateralization as a function of age for either expression or perception. Taken together, these findings lend support to the notion that the right hemisphere mediates emotional processing across the adult life span.


Pan-cancer analysis reveals IGFL2 as a potential target for cancer prognosis and immunotherapy.
Insulin-like growth factor like family member 2 (IGFL2) is a gene in the IGFL family, located on chromosome 19, whose role in cancer is unclear, and the aim of this study was to investigate the relevance of IGFL2 expression, prognosis, immunity, and mutation in pan-cancer. Obtaining information from The Cancer Genome Atlas and The Genotype-Tissue Expression Project (GTEx) databases for expression analysis and combining with The Gene Expression Profile Interaction Analysis database for prognostic aspects. Analysis of immune cell infiltration by TIMER and CIBERSORT algorithms. Calculation of correlation of immune-related genes with IGFL2 expression and tumor mutational burden and microsatellite instability. Mutations and DNA methylation were analyzed using the cBioPortal database and the UALCAN database, and functional enrichment was performed using Gene set enrichment analysis (GSEA). IGFL2 expression is significantly elevated in tumor tissue and high expression has a worse prognosis in most cancers. In immune correlation analysis, it was associated with most immune cells and immune-related genes. In most cancers, IGFL2 methylation is lower and the group with mutations in IGFL2 has a worse prognosis than the normal group. The GSEA analysis showed that IGFL2 was significantly enriched in signaling and metabolism. IGFL2 may be involved in the development of many types of cancer, influencing the course of cancer with different biological functions. It may also be a biomarker for tumor immunotherapy.