Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies.
Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.


Author Correction: Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB.
The authors wish to point out that in Figure 1f, the picture of DAPI in the ATG5 siRNA group is incorrect. During the process of image synthesis, the authors mixed the pictures of DAPI in the control group and ATG5 siRNA group, leading to the duplicate between them of DAPI. Furthermore, the AMPK blot and the AKT blot in Figure 2a were inadvertently duplicated with the third β-actin in Figure 2a and AKT in Figure 4e, respectively. The authors would like to apologize for any inconvenience this may have caused.


Resolving intestinal fibrosis through regenerative medicine.
Crohn's Disease and Ulcerative Colitis, known collectively as Inflammatory Bowel Disease (IBD), are lifelong gastrointestinal disorders that commonly present at a young age and are increasing in incidence and prevalence. Fibrosis is a common and incurable complication of IBD. When fibrotic complications occur, patients often have to undergo disfiguring surgery. Thus, research has focused on regenerative therapies as a means to prevent and treat established fibrosis. Both cell and non-cell therapies (exosomes) have anti-fibrotic and anti-inflammatory properties. This review discusses these emerging therapeutics and their potential to treat intestinal fibrosis.


Psychophysical influences on the validity of anomaloscopic assessments of color vision.
Anomaloscopes are used in clinical and research applications involving the assessment of color vision. Output data include the matching range (MR), the midpoint, and the anomaly quotient (AQ). The latter is commonly used to compare data obtained using different instruments. However, the midpoint and AQ ultimately depend on the MR, for which there is no universal operational definition. In this study, 5 volunteers with normal color vision each completed 510 trials in a rating task with an anomaloscope employing the Moreland equation. The aim was to investigate the nature of the perceptual transition into, and out of, a metameric match. This was found to be less than abrupt, providing ample opportunity for the influence of individual response biases. Consequently, an agreed-upon definition of the MR, associated with an appropriate psychophysical technique, would facilitate the identification and tracking over time of acquired color vision deficits and would improve the validity of interstudy comparisons.


Nuclear receptors in osteoclasts.
Osteoclasts are bone-resorbing cells that play an essential role in the remodeling of bone under physiological conditions and numerous pathological conditions, such as osteoporosis, bone metastasis, and inflammatory bone erosion. Nuclear receptors are crucial to various physiological processes, including metabolism, development and inflammation, and function as transcription factors to activate target genes. Synthetic ligands of nuclear receptors are also available for the treatment of metabolic and inflammatory diseases. However, dysregulated bone phenotypes have been documented in patients who take synthetic nuclear receptor ligands as a therapy. Therefore, the effect of nuclear receptors on bone cells has become an important area of exploration; additionally, the molecular mechanisms underlying the action of nuclear receptors in osteoclasts have not been completely understood. Here, we cover the recent progress in our understanding of the roles of nuclear receptors in osteoclasts.


Photodynamic actions of indocyanine green and trypan blue on human lens epithelial cells in vitro.
The purpose of this study was to evaluate the toxicity and photodynamic activity of indocyanine green (ICG) and trypan blue (TryB) on cultured human lensepithelial cells (LECs). Experimental study. Lens epithelial cell viability was assessed after treatment with ICG and TryB concentrations ranging from 0.025 to 5.0 mg/ml, and exposure to 806 nm diode laser. At ICG concentrations below 0.5 mg/ml, there was > or =75% cell viability; at higher ICG concentrations there was dose-dependent cytotoxicity in addition to loss of cellular viability due to ICG photosensitization. TryB had little cytotoxicity to the LECs: >80% cells were viable irrespective of the dye concentration or laser treatment. These data indicate that ICG may have application as a photosensitizer in the selective eradication of residual LECs after cataract surgery to reduce the incidence of posterior capsule opacification.


Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia.
Alterations in the density or distribution of interstitial white matter neurons are taken as evidence in support of an early developmental component to schizophrenia. However, the existence and nature of interstitial white matter neuron changes in schizophrenia remain inconclusive. Recently, we reported that interstitial white matter neuron density is increased in the superficial white matter of the superior temporal gyrus in schizophrenia, but unchanged in deep white matter. This study extends our investigations to the dorsolateral prefrontal cortex and parahippocampal gyrus. Using the specific neuronal antibody NeuN, interstitial white matter neuron density was found to be increased in schizophrenia in the superficial white matter of the dorsolateral prefrontal cortex, with no significant changes elsewhere. As interstitial white matter neurons are presumed to be remnants of the embryonic cortical subplate, these findings provide additional evidence supportive of an early developmental abnormality in schizophrenia.


Superposition of arteriolar vasomotion waves and regulation of blood flow in skeletal muscle microcirculation.
In skin muscle microcirculation of Syrian hamsters, rhythmic diameter changes were studied along the arteriolar network, under normoxic conditions, at rest. A teflon coated-aluminum chamber was implanted in the dorsum skin of animals. The microcirculation was investigated using intravital microscopy technique. Vessel diameters were determined by a computer-assisted method. Power spectrum analysis of vasomotion recordings was carried out with Fast Fourier Transform and Autoregressive modelling. To determine vasomotion waveform spreading, cross-spectral data (amplitude and phase) were computed, using the modified periodogram method (FFT). The arterioles were classified according to Strahler's method. Order 1 vessels (diameter: 7.50 +/- 1.16 microns) showed the highest frequency, 4-15 cycles per min, and percentage amplitude in the range 60-100%. Order 2 and 3 arterioles had intermediate frequencies, and amplitude in the range 50-100%, and 15-50%, respectively. The largest order 4 vessels (diameter: 28.97 +/- 9.55 microns) had the lowest frequency, 0.3-3 cpm, and amplitude in the range 5-20%. In most networks, cross-correlation analysis revealed two groups of frequency components. Low frequency group was propagated from order 4 and 3 vessels downstream. High frequency components were transmitted upstream from order 1 and 2 arterioles. Therefore, a complex superposition of waveforms resulted from the activity of discrete points along the microvasculature. In conclusion, rhythmic diameter changes of arterioles in skeletal muscle microcirculation regulate blood flow distribution in capillary units and control tissue oxygenation.


Simultaneous determination of chloroquine and metronidazole in human biological fluid by high pressure liquid chromatography.
Chloroquine (CQ) and metronidazole (MZ) were measured in human urine and plasma by HPLC with UV detection. This method was used to analyse plasma levels in 4 African volunteers after an oral dose of 1000 mg CQ and 750 mg MZ, in a European on weekly prophylaxis of 500 mg CQ, and on 50 hospital urine samples. In the Africans peak plasma levels were over 1 microgram/ml and peak time was 1 1/2-2 hr. In the European plasma levels ranged from 0.58 to 0.36 microgram/ml. Over 80% of the urine samples contained CQ, MZ or both. The assay system was found flexible and economical for the therapeutic monitoring of these two important tropical drugs.


Urinary excretion of 5-hydroxyindoleacetic acid--no relationship to the level in cerebrospinal fluid.
Concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were determined in urine and cerebrospinal fluid (CSF) by mass fragmentography. A pronounced day-to-day variation in the urinary excretion of 5-HIAA was found both in psychiatric patients and a healthy control. Lumbar punctures performed twice 3-12 weeks apart in 11 healthy controls resulted in reproducible levels of 5-HIAA in CSF (r = 0.89; P less than 0.001). The mean of three periods of daily 5-HIAA excretion was not correlated to the CSF level measured in 18 psychiatric patients (r = 0.09). Three weeks of chlorimipramine treatment significantly decreased CSF 5-HIAA levels (P less than 0.05), but not the urinary excretion of 5-HIAA. It might be concluded that measurement of urinary 5-HIAA excretion is of little value compared to CSF levels in studies of serotonin in the central nervous system.


New mutation identified in two sisters with adult-onset erythropoietic protoporphyria.
Erythropoietic protoporphyria (EPP; OMIM #177000) is a rare disease that usually presents in infancy or early childhood. The uncommon adult-onset EPP is often associated with acquired somatic mutations of the FECH gene, secondary to blood dyscracias. We investigated two sisters with adult-onset EPP. We found a novel germline mutation in the FECH gene, in trans with the common hypomorphic IVS3-48C allele. The adult presentation and identical genotypes of the two sisters suggests that the late development of the condition is to an extent a function of the mutation. The exact mechanism for this delayed penetrance is not clear, although these atypical cases raise the possibility of other genetic or nongenetic disease-modifying factors.


Effect of extracellular Na on isoproterenol-induced cAMP levels in depolarized uterus.
In the present study, the absence of a quantitative correlation between isoproterenol induced relaxation of uterine strips and tissue cAMP levels was demonstrated by using three depolarizing media: 127 mM KCl (0 NaCl), 47.5 mM KCl (NaCl), and 47.5 mM KCl (80 mM NaCl). While the degree of relaxation by isoproterenol was similar in all three media, isoproterenol (10(-4)M) increased cAMP by 100% in Na+ free depolarizing media, by 337% in Na+ containing depolarizing medium and by 600% in normal non-depolarizing medium. After pretreatment of the tissue with 10(-5) M D-600, 10(-4) M isoproterenol increased cAMP levels by 600% in all three depolarzing media. Studies using 10(-8) M isoproterenol produced qualitatively similar results. cGMP levels did not change significantly in any of the above studies. Na+ appears to be producing its effect on isoproterenol induced increase in cAMP levels indirectly by reducing the increase in intracellular Ca2+ concentration known to occur with depolarization.


A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus.
The insulin receptor purified from skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM) displayed a 25-55% reduction in insulin-stimulated autophosphorylation and tyrosyl-specific phosphotransferase activity relative to controls. This decrease was not explained by alterations of muscle fiber composition, insulin binding affinity or capacity, or the Km values for ATP; the lower kinase activity was entirely attributed to a decrease in the Vmax of the enzyme. Phosphorylation sites in the beta-subunit of the control and diabetic receptor were identified by tryptic digestion and reverse-phase high performance liquid chromatography. Autophosphorylation occurred primarily in two regions of the beta-subunit: the regulatory region containing Tyr-1146, Tyr-1150, and Tyr-1151, and the C terminus containing Tyr-1316 and 1322. Autophosphorylation of the regulatory region at all three tyrosyl residues (tris-phosphorylation) appears to be necessary to activate the receptor kinase (White, M. F., Shoelson, S. E., Stepman, E. W., Keutmann, H. & Kahn, C. R. (1988) J. Biol. Chem. 263, 2969-2980). The receptor from NIDDM patients showed a decreased level of tris-phosphorylation of the regulatory region which was closely associated (r2 = 0.97) with the decreased kinase activity. In contrast, weak associations were found between kinase activity and the bis-phosphorylated forms of the regulatory region (r2 = 0.51) and the C terminus (r2 = 0.35). Therefore, the reduced formation of the tris-phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris-phosphorylation of the regulatory region may cause, in part, the reduced insulin-stimulated kinase activity of the insulin receptor in muscle of NIDDM patients.


Long-term co-exposure DBP and BaP causes imbalance in liver macrophages polarization via activation of Notch signaling regulated by miR-34a-5p in rats.
Humans are often exposed to complex mixtures of environmental pollutants over long periods of time. It is reported that Dibutyl phthalate (DBP) and benzo[a]pyrene (BaP) are typical environmental pollutants, which are associated with liver injury. Nevertheless, little is known about the effects of DBP and BaP combined exposure on liver. In the current study, rats were exposed to DBP alone (50, or 250 mg/kg), BaP alone (1, or 5 mg/kg), or DBP and BaP (50 + 1, or 250 + 5 mg/kg) for ninety days. More serious liver damage, including abnormal liver function, infiltration of inflammatory cells and disturbed secretion of inflammatory factors, were observed in long-term co-exposure to DBP and BaP group relative to those in single exposure group. Our data showed that long-term co-exposure to DBP and BaP induces macrophages to polarize toward M1 and inhibits polarization of M2 macrophages. Long-term co-exposure to DBP and BaP downregulated miR-34a-5p level and upregulated Notch signaling. These results indicated that imbalance in macrophages M1/M2 polarization mediated by activation of Notch signaling due to reduced miR-34a-5p level may contribute to additive effects on disorder of inflammatory factors secretion and subsequent liver injury following long-term DBP and BaP co-exposure.


Atrial appendages and venoatrial connections in hearts from patients with visceral heterotaxy.
Venoatrial connections are important when choosing surgical options for patients with visceral heterotaxy. The precise morphology of the atriums, however, is often obfuscated by the term "visceral heterotaxy." This morphologic study aims to clarify the features of significance to the cardiac surgeon. We investigated 183 hearts from patients known from postmortem inspection to have so-called visceral heterotaxy. The connections of the systemic and pulmonary veins to the atriums, and the detailed morphology of the atriums, were examined in each case. Pectinate muscles extended bilaterally to the crux in 125 hearts determined to have isomeric morphologically right appendages. The other 58 hearts all exhibited bilaterally smooth-walled vestibules, and were diagnosed as having isomeric left appendages. Bilateral superior caval veins were frequent in both groups. The inferior caval vein was right- or left-sided with equal frequency in both groups, but was interrupted only in hearts with isomeric left appendages. The pulmonary veins connected in extraatrial fashion in 48% of cases with isomeric right appendages, whereas, most commonly, pulmonary veins were connected bilaterally to the atriums in those with isomeric left appendages (60%). Both the morphology of the atrial appendages and the venoatrial connections need to be distinguished to establish precise diagnoses in patients with so-called visceral heterotaxy ("splenic syndromes").


Desmoid fibromatosis involving the ureter: A rare presentation with intraoperative challenges.
Following failed retrograde and antegrade ureteric stenting, a 35-year-old male patient underwent an elective boari flap for marked proximal hydroureteronephrosis due to a periureteric mass in the right iliac fossa. Intraoperative vascular surgical assistance was required for control of arterial bleeding due to friable vessel wall. Histopathology demonstrated desmoid fibromatosis.


Crystallization of fragment D from human fibrinogen.
Fragment D from human fibrinogen has been crystallized. The fragment, which is composed of three disulfide-linked chains (alpha' beta' gamma' = 88,000), was generated with either plasmin or mild trypsin digestion. The crystals diffracted out to 3.5 A; the space group is P2(1), unit cell dimensions a = 108 A, b = 48 A, c = 167 A, beta = 106 degrees. Fragment D was also co-crystallized with the ligand GPRP-amide, in which case the space group is consistent with P212121, unit cell dimensions a = 476 A, b = 82 A, c = 432 A.


An examination of the mechanical properties of the annulus fibrosus: the effect of vibration on the intra-lamellar matrix strength.
Vibration has been associated with low back pain and disc herniation; however the mechanism responsible for this association is unclear. It is theorized that herniation propagates through annular layers via clefts that form in the extracellular matrix between collagen fibres (intra-lamellar matrix) within each lamella. The effect of cyclic compressive loading at 5 Hz, applied to porcine functional spine units, on the mechanical properties of excised single annular lamellae was examined. These lamellae were tested under tension applied perpendicular to the collagen fibre orientation, effectively isolating the intra-lamellar matrix. Vibration affected the deformation magnitude at the end of the toe region of the stress-stretch ratio curve; specifically vibrated tissues showed larger toe regions (stretch ratio of 1.50 as compared to 1.31 observed in the control tissues, p=0.027). It is hypothesized that this result may be due to damaged elastin-a protein responsible for minimizing deformation and assisting with returning tissues to normal length following tension.


Tissue carriers for processing fragile bio-materials in immuno-electron microscopy.
The preparation and use of tissue carriers for processing fragile biological materials from postfixation up to embedding in electron microscopy is described. Trimmed small pieces of vibratome sections can be very practical and safely transported in these carriers throughout osmification, dehydration for long times, and infiltration up to embedding in epoxy resins. This small device is especially suited for post-embedding immunogold electron microscopy.


High hydrostatic pressure enables almost 100% refolding of recombinant human ciliary neurotrophic factor from inclusion bodies at high concentration.
Protein refolding from inclusion bodies (IBs) often encounters a problem of low recovery at high protein concentration. In this study, we demonstrated that high hydrostatic pressure (HHP) could simultaneously achieve high refolding concentration and high refolding yield for IBs of recombinant human ciliary neurotrophic factor (rhCNTF), a potential therapeutic for neurodegenerative diseases. The use of dilution refolding obtained 18% recovery at 3 mg/mL, even in the presence of 4 M urea. In contrast, HHP refolding could efficiently increase the recovery up to almost 100% even at 4 mg/mL. It was found that in the dilution, hydrophobic aggregates were the off-path products and their amount increased with the protein concentration. However, HHP could effectively minimize the formation of hydrophobic aggregates, leading to almost complete conversion of the rhCNTF IBs to the correct configuration. The stable operation range of concentration is 0.5-4.0 mg/mL, in which the refolding yield was almost 100%. Compared with the literatures where HHP failed to increase the refolding yield beyond 90%, the reason could be attributed to the structural difference that rhCNTF has no disulfide bond and is a monomeric protein. After purification by one-step of anionic chromatography, the purity of rhCNTF reached 95% with total process recovery of 54.1%. The purified rhCNTF showed similar structure and in vitro bioactivity to the native species. The whole process featured integration of solubilization/refolding, a high refolding yield of 100%, a high concentration of 4 mg/mL, and a simple chromatography to ensure a high productivity.


13-lncRNAs Signature to Improve Diagnostic and Prognostic Prediction of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a common type of cancer with a high mortality rate and is usually detected at the middle or late stage, missing the optimal treatment period. The current study aims to identify potential long non-coding RNA (lncRNAs) biomarkers that contribute to the diagnosis and prognosis of HCC. The differentially expressed lncRNAs (DElncRNAs) in HCC patients were detected from the Cancer Genome Atlas (TCGA) dataset. LncRNAs signature was screened by LASSO regression, univariate, and multivariate Cox regression. The models for predicting diagnosis and prognosis were established, respectively. The prognostic model was evaluated by Kaplan-Meier survival curve receiver operating characteristic (ROC) curve and stratified analysis. The diagnostic model was validated by ROC. The lncRNAs signature was further demonstrated by functional enrichment analysis. We found the 13-lncRNAs signature that had a good performance in predicting prognosis and could help to improve the value of diagnosis. In the training set, testing set, and entire cohort, the low-risk group had longer survival than the high-risk group (median OS: 3124 vs. 649 days, 2456 vs. 770 days and 3124 vs. 755 days). It performed well in 1-, 3-, and 5-year survival prediction. 13-lncRNAs-based risk score, age, and race were good predictors of prognosis. The AUC of diagnosis was 0.9487, 0.9265, and 0.9376, respectively. Meanwhile, the 13-lncRNAs were involved in important pathways, including the cell cycle and multiple metabolic pathways. In our study, the 13-lncRNAs signature may be a potential marker for the prognosis of HCC and improve the diagnosis.


[Mutation analysis of seven patients with Waardenburg syndrome].
To perform genetic analysis for 7 patients with Waardenburg syndrome. Potential mutation of MITF, PAX3, SOX10 and SNAI2 genes was screened by polymerase chain reaction and direct sequencing. Functions of non-synonymous polymorphisms were predicted with PolyPhen2 software. Seven mutations, including c.649-651delAGA (p.R217del), c.72delG (p.G24fs), c.185T>C (p.M62T), c.118C>T (p.Q40X), c.422T>C (p.L141P), c.640C>T (p.R214X) and c.28G>T(p.G43V), were detected in the patients. Among these, four mutations of the PAX3 gene (c.72delG, c.185T>C, c.118C>T and c.128G>T) and one SOX10 gene mutation (c.422T>C) were not reported previously. Three non-synonymous SNPs (c.185T>C, c.128G>T and c.422T>C) were predicted as harmful. Genetic mutations have been detected in all patients with Waardenburg syndrome.


Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors.
Four different classes of new 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50≈25μM) turned out as new lead compound for inhibition of 17β-HSD2.


Biliary pseudocyst. A rare consequence of an iatrogenic lesion of the bile ducts.
A patient with a biliary pseudocyst due to an iatrogenic lesion of the hepatic duct is reported. The pseudocyst caused compression of the bile duct with progressive jaundice. Diagnostic problems and the utility of ERCP and PTC in determining the exact site of the lesion for surgical treatment are reported.


Outcome of hypospadias fistula repair.
Objectives To examine the long-term results of hypospadias fistula repair, the factors involved in recurrence and the outcome in cases where this has occurred. Patients and methods The study comprised 113 children undergoing urethrocutaneous fistula repair between 1984 and 1996. Most of the fistulae were closed in two to three layers, with or without a transpositional skin flap. Tunica vaginalis or a scrotal dartos flap was used in patients with inadequate vascularized tissue adjacent to the fistula. Success rates were calculated for each attempt at fistula repair until the patient was cured. Results The median (range) age at primary fistula repair was 40 (18-169) months and the median follow-up after the most recent repair 7.5 (2.3-17) years. The overall success rate of primary fistula repair was 71%. Fistulae which were >2 mm (11 of 21, 52%) were more likely to recur than were those < or = 2 mm (22 of 92, 24%). Recurrence did not relate to the initial form of hypospadias repair, to the means of skin closure nor, with the exception of multiple lesions, to the location of the fistula. The success rates of subsequent repairs were 70% at the second and 50% at the third, fourth and fifth repairs. One child was cured at the sixth attempt. The use of tunica vaginalis or scrotal dartos as a 'waterproofing' layer was limited to the third or subsequent repairs and was successful in five of six cases. Conclusion A simple layered closure with or with no transpositional skin flap is effective in 71% of repairs. For recurrent fistulae, tissues from an unscarred area (tunica vaginalis or scrotal dartos layer) should be used to cover the fistula.


Genetic injury in hybrid male mice exposed to low doses of 60Co gamma-rays or fission neutrons. III. Frequencies of abnormal sperm and reciprocal translocations measured during and following long-term weekly exposures.
Male B6CF1 mice were exposed to either fission neutrons or 60Co gamma-rays at once-weekly doses approaching occupational levels for periods up to 60 weeks. Both during and after the irradiation sequence, the mice were screened to determine the incidence of abnormal epididymal sperm and of reciprocal chromosome translocations in metaphase spermatocytes. Abnormal sperm frequencies equilibrated with dose/week by 10 weeks and also showed an additive nonlinear seasonal increment. The relative biological effectiveness (RBE) for these damages is 12 +/- 1. After exposures ended, sperm frequencies in gamma-irradiated mice quickly returned to near-normal levels. Neutron-irradiated males showed a significantly elevated level of abnormalities for approximately 30 weeks--a paradoxical finding--as no clear evidence of cumulative injury was seen during exposure. When assayed at 10 and 25 weeks of exposure but not later, translocation frequencies demonstrated an increment, significant in the neutron series, attributed to irradiated spermatocytes. Dose-response analysis with cumulative dose up to the 60-week maximum gave an RBE of 45 +/- 10. Post exposure, the incidence of translocations subsided slightly, but the RBE remained above 30.


Measurement properties of the Western Ontario rotator cuff outcome measure: a preliminary report.
The purpose of this prospective repeated-measures outcomes study was to investigate the construct validity and sensitivity to change of a newly developed outcome measure, the Western Ontario Rotator Cuff Index (WORC) in a population of patients seen at a tertiary shoulder center. A total of 154 subjects (66 women and 88 men; mean age, 48 years [SD, 14.80 years]) agreed to participate in the study. Of these, 50 patients (16 women and 34 men; mean age, 50 years [SD, 14.36 years]) met the criteria for surgery. The Pearson correlation coefficients between the initial scores and the change scores at 6 months postoperatively of the WORC, Constant-Murley shoulder form, and American Shoulder and Elbow Surgeons standardized shoulder assessment form were high (P < .01). The WORC was sensitive to detect change: F = 28.041 and P < .000 at 3 months and F = 66.927 and P < .000 at 6 months postoperatively. The results of this study support the validity of the WORC for use in patients with rotator cuff pathology.


Berberine oleanolic acid complex salt grafted hyaluronic acid/silk fibroin (BOA-g-HA/SF) composite scaffold promotes cartilage tissue regeneration under IL-1β caused stress.
Since inflammatory cytokines cause stress to chondrocytes and the failure of cartilage defects repair with cartilage tissue engineering, it is necessary to develop a scaffold to maintain cartilage regeneration under inflammatory factors caused stress. Following a berberine-oleanolic acid (OA) complex salt (BOA) was grafted to hyaluronic acid (HA) to obtain water soluble BOA-g-HA, it mixed with silk fibroin (SF) to prepared 4 solutions, which contained 30 mg/mL SF and 0.75, 1.5, 2.25, and 3.0 mg/mL BOA-g-HA respectively. They were lyophilized to fabricate BOA-g-HA/SF-1, BOA-g-HA/SF-2, BOA-g-HA/SF-3, and BOA-g-HA/SF-4 composite scaffolds respectively. All prepared scaffolds displayed porous network structure and exhibited promising mechanical properties for tissue engineering applications. Among them, the BOA-g-HA/SF-3 composite scaffold showed the highest influence on maintaining chondrocytic phenotype of chondrocytes under IL-1β induced stress. Following SF, HA/SF, and BOA-g-HA/SF-3 composite scaffolds with seeded chondrocytes were treated with IL-1β induction for 1 week, specimens were incubated with cell culture medium for 3 week or were subcutaneously implanted into nude mice for 4 weeks. The results demonstrated that the BOA-g-HA/SF-3 composite scaffold promotes cartilage tissue regeneration in vitro and in vivo under IL-1β caused stress, suggesting that it can be potential applied for repairing cartilage defects in osteoarthritis patients.


Development and validation of a length- and habitus-based method of total body weight estimation in adults.
Erroneous weight estimation during the management of emergency presentations in adults may contribute to patient harm and poor outcomes. Patients can often not be weighed during emergencies and a weight estimation is required to facilitate weight-based therapies. Many existing methods of weight estimation are either unacceptably inaccurate or very difficult to use during the provision of emergency care. The weight estimation system developed in this study was based on and modified from the PAWPER XL-MAC method, a pediatric weight estimation system that uses recumbent length and mid-arm circumference (MAC) to predict total body weight. This model was validated in the 2015-2018 National Health and Nutrition Examination Survey (NHANES) datasets. The primary outcome measure was to achieve >95% of estimations within 20% of measured weight (P20 > 95%). The modified PAWPER XL-MAC model achieved a P20 of 96.0% and a P10 of 71.3% in the validation dataset (N = 11,520). This accuracy (P20 > 95%) was maintained in both sexes, all ages, all ethnic groups, all lengths and in all habitus-types, except for the subgroup of severely obese individuals. The modified PAWPER XL-MAC model proved to be a very accurate method of weight estimation. It is more accurate than most other published reports of existing methods of weight estimation, except for patients' own estimations. It therefore could have a role in facilitating emergency drug dose calculations, if prospective studies bear out the accuracy found in this study.


Guar gum: a cheap substitute for agar in microbial culture media.
To determine the possibility of using guar gum, a colloidal polysaccharide, as a cheap alternative to agar for gelling microbial culture media. As illustrative examples, 12 fungi and 11 bacteria were cultured on media solidified with either guar gum or agar. All fungi and bacteria exhibited normal growth and differentiation on the media gelled with guar gum. Microscopic examination of the fungi and bacteria grown on agar or guar gum gelled media did not reveal any structural differences. However, growth of most of the fungi was better on guar gum media than agar, and correspondingly, sporulation was also more advanced on the former. Bacterial enumeration studies carried out for Serratia sp. and Pseudomonas sp. by serial dilution and pour-plate method yielded similar counts on both agar and guar gum. Likewise, a selective medium, succinate medium used for growth of Pseudomonas sp. did not support growth of Bacillus sp. when inoculated along with Pseudomonas on both agar or guar gum supplemented medium. Guar gum, a galactomannan, which is 50 times cheaper than Difco-bacto agar, can be used as a gelling agent in place of agar in microbial culture media. As the media gelled with guar gum do not melt at temperature as high as 70 degrees C, these can be used for isolation and maintenance of thermophiles.


Simulation of the critical nitrogen dilution curve in Jiangxi double-cropped rice region based on leaf dry matter weight.
In order to investigate the feasibility of using rice critical nitrogen concentration as a nitrogen nutrition diagnosis index, a two-year positioning field gradient experiment using four rice varieties and four nitrogen levels (0, 75, 150, 225 kg·ha-1 for early rice; 0, 90, 180, 270 kg·ha-1 for late rice) was conducted for early and late rice. The critical dilution curves (Nc%) of the double-cropped rice based on leaf dry matter (LDM) were constructed and verified using the field data. Two critical nitrogen dilution curves and nitrogen nutrition indexes (NNI) of rice LDM were constructed for early rice [Nc% = 2.66LDM-0.79, R2 = 0.88, NNI ranged between 0.29-1.74, and the average normalized root mean square error (n-RMSE = 19.35%)] and late rice [Nc% = 7.46LDM-1.42, R2 = 0.91, NNI was between 0.55-1.53, and the average (n-RMSE = 15.14%)]. The relationship between NNI and relative yield was a quadratic polynomial equation and suggested that the optimum nitrogen application rate for early rice was sightly smaller than 150 kg·ha-1, and that for late rice was about 180 kg·ha-1. The developed critical nitrogen concentration dilution curves, based on leaf dry matter, were able to diagnose nitrogen nutrition in the double-cropped rice region.


Chronic substance P (NK1) receptor antagonist and conventional antidepressant treatment increases burst firing of monoamine neurones in the locus coeruleus.
The mechanism of action of conventional antidepressants (e.g. imipramine) has been linked to modulation of central monoamine systems. Substance P (NK1) receptor antagonists may have antidepressant and anxiolytic effects in patients with major depressive disorder and high anxiety but, unlike conventional antidepressants, are independent of activity at monoamine reuptake sites, transporters, receptors, or monoamine oxidase. To investigate the possibility that substance P receptor antagonists influence central monoamine systems indirectly, we have compared the effects of chronic administration of imipramine with that of the substance P receptor antagonist L-760735 on the spontaneous firing activity of locus coeruleus neurones. Electrophysiological recordings were made from brain slices prepared from guinea-pigs that had been dosed orally every day for 4 weeks with either L-760735 (3 mg/kg), imipramine (10 mg/kg), or vehicle (water), or naive animals. Chronic, but not acute, treatment with the substance P receptor antagonist L-760735, induced burst firing of neurones in the locus coeruleus. This effect resembles that of the conventional antidepressant imipramine. However, their effects are dissociable since, in contrast to chronic imipramine treatment, chronic L-760735 treatment does not cause functional desensitisation of somatic alpha2 adrenoceptors. The mechanism by which chronic substance P receptor antagonist or conventional antidepressant treatment influences the pattern of firing activity of norepinephrine neurones remains to be elucidated. However, an indirect action in the periphery or distant brain nuclei has been excluded by the use of the in vitro slice preparation, suggesting a local site of action in the locus coeruleus.


Efficacy of cap-assisted endoscopy for the visualization of the major duodenal papilla: a systematic review and meta-analysis.
The current standard of practice is to use a duodenoscope for the evaluation of the major duodenal papilla (MDP). Recently, cap-assisted endoscopy (CAE), which uses a transparent cap at the tip of a standard front-viewing endoscope, has emerged as an alternative. A systematic literature search was performed in several databases from inception to January 2023 to identify studies evaluating the efficacy of CAE for the evaluation of the MDP. Nine studies including 806 patients met our inclusion criteria. The pooled rate of technical success for CAE was 93.2% (95% confidence interval, 85.6-96.9; I2 = 84.6%). A subgroup analysis comparing CAE with a standard endoscope showed higher odds for the evaluation of the MDP with CAE (but not a duodenoscope, which was better than CAE) with an odds ratio of 57.294 (95% confidence interval, 17.767-184.755; I2 = 45.303%). CAE offers a significant advantage with high rates of complete MDP evaluation compared with standard forward-viewing endoscopy. However, CAE is associated with lower rates of success when compared with side-viewing endoscopes.


Walking the walk: migration and other common themes in blood and vascular development.
In this issue of Cell, a study by N. Cho and coworkers provides insight into the role of vascular endothelial growth factor (VEGF) signaling in Drosophila hematopoiesis. Their work suggests that an ancestral function of VEGF was to guide blood cell migration and highlights the conservation of at least one aspect of VEGF signaling during evolution.


What helps confidence in communication - Perspectives of adults with aphasia: "Get maze…not stay out it".
The ultimate aim of speech-language therapy for adults with aphasia is to enhance their life participation. One key factor which may influence an individual's decisions to participate in meaningful life activities is their confidence in communication. The aim of the current study was to explore what helps confidence in communication from the perspective of adults with aphasia. The study, part of a larger investigation, used a qualitative descriptive research approach underpinned by an interpretivist paradigm. Fifteen adult participants who had post-stroke aphasia and lived at home or in long-term care were recruited. Due to COVID-19 restrictions, participants had to be able to complete an online qualitative interview, given conversational support. Maximum variation sampling was used to ensure diversity within the sample. The researchers conducted individual interviews over Zoom based on a topic guide exploring the person's experiences with confidence in communicating and their perceptions about what has helped their confidence in communication since the onset of aphasia. The interviews were video-recorded and transcribed verbatim. The transcripts were analyzed using qualitative content analysis. Categories of what helps confidence in communication included: Attitudes, Advocating for themselves, Having individualized strategies to deal with communication difficulties, Practicing communication, Other people with aphasia (PWA), Factors related to communication partners, Factors related to the communication context, and Other factors. To enhance confidence, speech-language pathologists could help PWA to develop strategies to deal with inevitable communication breakdowns. They could also support PWA to experience communication success in everyday situations and to advocate for themselves.


Near infrared-emitting multimodal nanosystem for in vitro magnetic hyperthermia of hepatocellular carcinoma and dual imaging of in vivo liver fibrosis.
Prolonged usage of traditional nanomaterials in the biological field has posed several short- and long-term toxicity issues. Over the past few years, smart nanomaterials (SNs) with controlled physical, chemical, and biological features have been synthesized in an effort to allay these challenges. The current study seeks to develop theranostic SNs based on iron oxide to enable simultaneous magnetic hyperthermia and magnetic resonance imaging (MRI), for chronic liver damage like liver fibrosis which is a major risk factor for hepatocellular carcinoma. To accomplish this, superparamagnetic iron oxide nanoparticles (SPIONs) were prepared, coated with a biocompatible and naturally occurring polysaccharide, alginate. The resultant material, ASPIONs were evaluated in terms of physicochemical, magnetic and biological properties. A hydrodynamic diameter of 40 nm and a transverse proton relaxation rate of 117.84 mM-1 s-1 pronounces the use of ASPIONs as an efficient MRI contrast agent. In the presence of alternating current of 300 A, ASPIONs could elevate the temperature to 45 °C or more, with the possibility of hyperthermia based therapeutic approach. Magnetic therapeutic and imaging potential of ASPIONs were further evaluated respectively in vitro and in vivo in HepG2 carcinoma cells and animal models of liver fibrosis, respectively. Finally, to introduce dual imaging capability along with magnetic properties, ASPIONs were conjugated with near infrared (NIR) dye Atto 700 and evaluated its optical imaging efficiency in animal model of liver fibrosis. Histological analysis further confirmed the liver targeting efficacy of the developed SNs for Magnetic theranostics and optical imaging as well as proved its short-term safety, in vivo.


Colonic anastomotic stenoses and Memotherm stent fracture: a report of three cases.
Deployment of a Memotherm colonic stent (Bard, Angiomed, Karlsruhe, Germany) across anastomotic strictures, following anterior resection, is described in three patients. Two patients presented with symptoms of colonic obstruction. Two of the patients had previously undergone unsuccessful balloon dilatation of the stricture. In the third, in addition to the anastomotic stricture, there was local tumor recurrence. Initially, stenting provided effective relief of symptoms. However, in all three patients, fracture of the stents occurred at intervals of 3-7 months after insertion. This use and complication of colonic stenting has not been reported previously.


Next Generation Sequencing Revolutionizes Organismal Biology Research in Bats.
The advent of next generation sequencing technologies (NGS) has greatly accelerated our understanding of critical aspects of organismal biology from non-model organisms. Bats form a particularly interesting group in this regard, as genomic data have helped unearth a vast spectrum of idiosyncrasies in bat genomes associated with bat biology, physiology, and evolution. Bats are important bioindicators and are keystone species to many eco-systems. They often live in proximity to humans and are frequently associated with emerging infectious diseases, including the COVID-19 pandemic. Nearly four dozen bat genomes have been published to date, ranging from drafts to chromosomal level assemblies. Genomic investigations in bats have also become critical towards our understanding of disease biology and host-pathogen coevolution. In addition to whole genome sequencing, low coverage genomic data like reduced representation libraries, resequencing data, etc. have contributed significantly towards our understanding of the evolution of natural populations, and their responses to climatic and anthropogenic perturbations. In this review, we discuss how genomic data have enhanced our understanding of physiological adaptations in bats (particularly related to ageing, immunity, diet, etc.), pathogen discovery, and host pathogen co-evolution. In comparison, the application of NGS towards population genomics, conservation, biodiversity assessment, and functional genomics has been appreciably slower. We reviewed the current areas of focus, identifying emerging topical research directions and providing a roadmap for future genomic studies in bats.


Enhancing biosensing with fourfold amplification and self-powering capabilities: MoS2@C hollow nanorods-mediated DNA hexahedral framework architecture for amol-level liver cancer tumor marker detection.
Two-dimensional carbon-coated molybdenum disulfide (MoS2@C) hollow nanorods are combined with nucleic acid signal amplification strategies and DNA hexahedral nanoframework to construct a novel self-powered biosensing platform for ultra-sensitive dual-mode detection of tumor suppressor microRNA-199a. The nanomaterial is applied on carbon cloth and then modified with glucose oxidase or using as bioanode. A large number of double helix DNA chains are produced on bicathode by nucleic acid technologies including 3D DNA walker, hybrid chain reaction and DNA hexahedral nanoframework to adsorb methylene blue, producing high EOCV signal. Methylene blue also is reduced and an increased RGB Blue value is observed. For microRNA-199a detection, the assay shows a extensive linear range of 0.0001-100 pM with a low detection limit of 4.94 amol/L (S/N = 3). The method has been applied to the detection of actual serum samples, providing a novel method for the accurate and sensitive detection of tumor markers.


Unprecedented dipole alignment in α-phase nylon-11 nanowires for high-performance energy-harvesting applications.
Dipole alignment in ferroelectric polymers is routinely exploited for applications in charge-based applications. Here, we present the first experimental realization of ideally ordered dipole alignment in α-phase nylon-11 nanowires. This is an unprecedented discovery as dipole alignment is typically only ever achieved in ferroelectric polymers using an applied electric field, whereas here, we achieve dipole alignment in as-fabricated nanowires of 'non-ferroelectric' α-phase nylon-11, an overlooked polymorph of nylon proposed 30 years ago but never practically realized. We show that the strong hydrogen bonding in α-phase nylon-11 serves to enhance the molecular ordering, resulting in exceptional intensity and thermal stability of surface potential. This discovery has profound implications for the field of triboelectric energy harvesting, as the presence of an enhanced surface potential leads to higher mechanical energy harvesting performance. Our approach therefore paves the way towards achieving robust, high-performance mechanical energy harvesters based on this unusual ordered phase of nylon-11.


Forecasting the spread of the third wave of COVID-19 pandemic using time series analysis in Bangladesh.
During the third wave of the coronavirus epidemic in Bangladesh, the death and infection rate due to this devastating virus has increased dramatically. The rapid spread of the virus is one of the reasons for this terrible condition. So, identifying the subsequent cases of coronavirus can be a great tool to reduce the mortality and infection rate. In this article, we used the autoregressive integrated moving average-ARIMA(8,1,7) model to estimate the expected daily number of COVID-19 cases in Bangladesh based on the data from April 20, 2021, to July 4, 2021. The ARIMA model showed the best results among the five executed models over Autoregressive Model (AR), Moving Average (MA), Autoregressive Moving Average (ARMA), and Rolling Forest Origin. The findings of this article were used to anticipate a rise in daily cases for the next month in Bangladesh, which can help governments plan policies to prevent the spread of the virus. The forecasting outcome indicated that this new trend(named delta variant) in Bangladesh would continue increasing and might reach 18327 daily new cases within four weeks if strict rules and regulations are not applied to control the spread of COVID-19.


Toxicity of diatom polyunsaturated aldehydes to marine bacterial isolates reveals their mode of action.
Diatoms produce and release polyunsaturated aldehydes (PUAs) during senescence in culture and at the end of blooms in nature and these compounds play different ecological roles, as infochemicals, allelochemicals and pheromones In order to elucidate the toxic effects of PUAs, we isolated six bacterial strains from the Mediterranean Sea during a diatom bloom and tested their tolerance to PUA in terms of growth and cell membrane properties. Based upon 16S rRNA sequencing, these bacteria were assigned to the genera Pseudomonas, Sufflavibacter, Halomonas, Vibrio, Idiomarina, and Labrenzia. Growth of these strains was reduced by 50% (EC50) at PUA concentrations ranging from 600 to 1700 μM of 2E,4E/Z-heptadienal (HEPTA), 400-800 μM of 2E, 4E/Z-octadienal (OCTA), and 70-400 μM of 2E, 4E/Z-decadienal (DECA). Two of these strains, Vibrio sp. and Halomonas, sp. were also investigated for membrane fatty acid composition in terms of adaptive modifications of their degree of saturation (ratio between saturated and unsaturated fatty acids) by GC-FID. A direct correlation between hydrophobicity and PUA toxicity was observed, and these bacteria were also found to react to PUAs by increasing the degree of saturation of their membranes fatty acids. Tested PUAs were 4-fold more toxic than the well-investigated n-alkanols, most probably due to their additional chemical aldehyde toxicity to disrupting proteins by the formation of Schiff's bases, and therefore, they act as very toxic and effective poison, probably accumulating in cytoplasmic membranes because of their high hydrophobicity.


Identifying the essential influencing factors of landslide susceptibility models based on hybrid-optimized machine learning with different grid resolutions: a case of Sino-Pakistani Karakorum Highway.
This study attempts to explore the essential influencing factors of landslides and explores the effects of different datasets on landslide susceptibility mapping (LSM) at six grid resolutions (i.e., 10 m, 30 m, 300 m, 1000 m, 2000 m, and 3000 m). Firstly, the geospatial dataset of 21 influencing factors was extracted from 1847 historical landslide InSAR (Interferometric Synthetic Aperture Radar) points, which were taken as a sample for the Sino-Pakistani Karakorum Highway. Secondly, Spearman correlation coefficient (SCC), random forest feature selection (RFFS), and their combinations (SCC-RFFS) were selected at different grid resolutions to identify the essential influencing factors from the 21 original factors. A random division into training set (70%) and test set (30%) was performed. Then, the LSM models for the original influencing factors and the selected influencing factors were constructed separately using machine learning models. Finally, the reasonableness of the essential influencing factors was verified by comparing the accuracy of the models under different grid resolutions. The results show that (1) relief degree of land surface (RDLS), SPI, and rainfall have significant effects on landslide occurrence. (2) The primary elements (i.e., RDLS, slop, rainfall) are less affected by the grid resolution, while the secondary elements (TWI) are more affected by the grid resolution. (3) At 30 m, the SCC-RFFS-RF model can get the highest landslide susceptibility model accuracy. The prediction will also provide scientific guidance for the allocation of land resources on a regional and global scale, and minimize the human and economic costs along the highway, while ensuring safe highway operations.


Reconstitution of M13 bacteriophage coat protein. A new strategy to analyze configuration of the protein in the membrane.
The configuration of M13 bacteriophage coat protein in a model membrane was analyzed using protease digestion followed by gel permeation chromatography on Fractogel TSK in formic acid/ethanol. Important information is contained in the chromatographic patterns of the membrane-bound fragments, as well as of the fragments released by the digestion. A new reconstitution was thereby developed which involves adding a small volume of a concentrated solution of cholate-solubilized coat protein to preformed vesicles (with the amount of detergent added being less than that required to solubilize the vesicles), freezing in liquid nitrogen, thawing, followed by dialysis to remove excess detergent. The coat protein is incorporated with high efficiency (95 percent) making subsequent fractionation unnecessary. In addition, the incorporated protein is not aggregated, and is incorporated with most molecules spanning the membrane, oriented in the same manner as in vivo (N-terminus outwards). Two previously described reconstitutions, using sonication or cholate dialysis, are analyzed and found to be less satisfactory.


Inhibition of lipid peroxidation by idebenone in brain mitochondria in the presence of succinate.
Lipid peroxidation in brain mitochondria was induced by NADH in the presence of ADP and FeCl3. A novel quinone compound, idebenone, inhibited this peroxidation and the inhibition was markedly enhanced by succinate, a substrate of mitochondrial respiration. The concentration of succinate required to exert the maximal effect was 1.5 mM. The concentration of idebenone giving 50% inhibition (IC50) was 0.5 and 84 microM in the presence and absence of succinate, respectively, indicating that succinate enhances the inhibition by 170-fold. Moreover, the inhibitory effect of idebenone in the presence of succinate was abolished by adding thenoyltrifluoroacetate (TTFA), an inhibitor of complex II in the mitochondrial respiratory chain. These results indicate that idebenone is changed through complex II to its reduced form, which protects mitochondria against lipid peroxidation.


Increased sensitivity of the microsomal oxidation of ethanol to inhibition by pyrazole and 4-methylpyrazole after chronic ethanol treatment.
Pyrazole and 4-methylpyrazole, inhibitors of the oxidation of ethanol by alcohol dehydrogenase, also inhibit microsomal metabolism of ethanol. The inhibitory effectiveness of these agents was increased in microsomes isolated from rats treated chronically with ethanol as compared to microsomes from pair-fed controls or from rats treated with other cytochrome P-450 inducers such as phenobarbital or 3-methylcholanthrene. Pyrazole and 4-methylpyrazole produced type II binding spectra with all the microsomal preparations. However, there was an increased affinity (lower Ks value) for these agents by the microsomes from the ethanol-fed rats. A correlation between Ks values and inhibitory effectiveness against ethanol oxidation by the various microsomal preparations could be observed. This suggests that an increase in affinity, which may reflect the induction of an alcohol-preferring isozyme of cytochrome P-450, is responsible for the increased inhibitory effectiveness of pyrazole and 4-methylpyrazole towards ethanol oxidation by microsomes after chronic ethanol treatment. One difference between pyrazole and 4-methylpyrazole was the increased affinity and inhibitory effectiveness of the latter but not the former with microsomes from rats treated with 3-methylcholanthrene. This could be due to the ability of 4-methylpyrazole, compared to pyrazole, to interact with and induce several isozymes of cytochrome P-450. Pyrazole and 4-methylpyrazole are often utilized to evaluate ethanol metabolism by alcohol-dehydrogenase-dependent and -independent pathways. However, the sensitivity of microsomal ethanol oxidation to inhibition by these agents, especially after chronic ethanol treatment, would suggest that their use in this regard is complex and could tend to underestimate the contribution of the microsomal pathway towards the metabolic tolerance found after ethanol treatment.


Different intervention strategies toward live poultry markets against avian influenza A (H7N9) virus: Model-based assessment.
Different interventions targeting live poultry markets (LPMs) are applied in China for controlling avian influenza A (H7N9), including LPM closure and "1110" policy (i.e., daily cleaning, weekly disinfection, monthly rest day, zero poultry stock overnight). However, the interventions' effectiveness has not been comprehensively assessed. Based on the available data (including reported cases, domestic poultry volume, and climate) collected in Guangdong Province between October 2013 and June 2017, we developed a new compartmental model that enabled us to infer H7N9 transmission dynamics. The model incorporated the intrinsic interplay among humans and poultry as well as the impacts of absolute humidity and LPM intervention, in which intervention strategies were parameterized and estimated by Markov chain Monte Carlo method. There were 258 confirmed human H7N9 cases in Guangdong during the study period. If without interventions, the number would reach 646 (95%CI, 575-718) cases. Temporal, seasonal and permanent closures of LPMs can substantially reduce transmission risk, which might respectively reduce human infections by 67.2% (95%CI, 64.3%-70.1%), 75.6% (95%CI, 73.8%-77.5%), 86.6% (95%CI, 85.7-87.6%) in total four epidemic seasons, and 81.9% (95%CI, 78.7%-85.2%), 91.5% (95%CI, 89.9%-93.1%), 99.0% (95%CI, 98.7%-99.3%) in the last two epidemic seasons. Moreover, implementing the "1110" policy from 2014 to 2017 would reduce the cases by 34.1% (95%CI, 20.1%-48.0%), suggesting its limited role in preventing H7N9 transmission. Our study quantified the effects of different interventions and execution time toward LPMs for controlling H7N9 transmission. The results highlighted the importance of closing LPMs during epidemic period, and supported permanent closure as a long-term plan.


Advances in Diabetes Pharmacotherapy: An Update for the Emergency Provider.
Diabetes mellitus is a disease that affects millions of Americans, and its prevalence is only anticipated to increase in coming years. It is estimated that diabetes-related visits account for 1% of all emergency department (ED) encounters. In recent years, there have been several new categories of medications approved for the treatment of diabetes, including new insulins, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, an amylin analogue, and sodium-glucose cotransporter-2 inhibitors. This review presents recently approved agents to treat diabetes, with a focus on basic mechanism, place in therapy, and toxicities the ED provider may encounter. Many of these new therapies have been incorporated as first- and second-line agents for the management of diabetes. Recently approved diabetes medications often have different mechanisms of action and adverse effect and overdose profiles compared to traditional agents, such as sulfonylureas and metformin. Emergency providers will encounter patients taking these newly approved medications, as well as treat those presenting with adverse effects and overdoses from them. As such, emergency providers must have a basic understanding of these new therapies so that they can optimally care for diabetic patients.


Electroretinographic abnormalities in Alport syndrome with a novel COL4A5 truncated variant (p.Try20GlyfsTer19).
Alport syndrome comprises a heterogeneous group of inherited kidney diseases that are associated with ocular complications. In this study, we aimed to detail the clinical characteristics of a patient with X-linked Alport syndrome. We performed next-generation sequencing (NGS) with hybridization capture to identify the disease-causing variant of Alport syndrome and a comprehensive ophthalmic examination, including full-field electroretinography (FF-ERG). Genetic testing using NGS with hybridization capture revealed a novel hemizygous variant [c.51_52delGA (p.Trp20GlyfsTer19)] in exon 1 of COL4A5. The patient underwent cataract surgery in both eyes because of decreased visual acuity and photophobia. The best-corrected visual acuity improved from 0.9 and 0.7 in the right and left eyes, respectively, to 1.5 in both eyes. Anterior-segment optical coherence tomography (OCT) revealed anterior and posterior lenticonus. Fundus photographs showed central and peripheral fleck retinopathy. Wide-field fundus autofluorescence (AF) imaging showed mottled hyper- and hypo-AF in the peripheral retina, which was consistent with peripheral fleck retinopathy. Furthermore, OCT revealed thinning of the inner retinal layers, especially at the temporal macular, but the outer retinal layers were preserved. Ganglion cell analysis showed no progression for 5 years. FF-ERG was performed at 41 (phakia) and 46 (pseudophakia) years of age. The amplitudes of dark-adapted (DA) and light-adapted (LA) responses showed selective b-wave abnormalities. The b/a-wave ratios of DA 3.0 were 1.22 and 1.16 in the right and left eyes, respectively. The amplitudes of DA 3.0 oscillatory potentials (OP) were reduced. Five years later, the amplitudes of DA and LA responses revealed no remarkable changes, except for an OP wave of DA 3.0, which was substantially reduced. Our findings revealed electroretinographic abnormalities in a patient with Alport syndrome, which predominantly indicated impairment of the inner retina. Notably, little short-term progression was observed.


[One-stage surgery for Stanford type-A aortic dissection, annulo-aortic ectasia, and chronic constrictive pericarditis--a case report].
A case is reported of a rare combination of chronic constrictive pericarditis and aortic dissection. A 23-year-old male was diagnosed with constrictive pericarditis and annulo-aortic ectasia concomitant with type-A dissection. A pericardiectomy was performed under cardiopulmonary bypass, and an aortic segment, from the root to the arch, was totally replaced by a composite graft using selective cerebral perfusion. Both procedures were performed in one stage. An aged clot was found in the pericardial cavity. Sustained rupture of the aortic dissection into the pericardial cavity is considered to be a possible explanation for the development of constrictive pericarditis. The postoperative course was uneventful and the patient was discharged 34 days after the operation.


Effects of antibiotics on UV-stimulated tube growth of Pinus silvestris pollen.
Studies were made to investigate the effects of different antibiotics on unirradiated pollen and on pollen with enhanced tube growth, stimulated by low doses of UV-light. The antibiotics mitomycin, chloramphenicol, tetracyclin, penicillin, nystatin and carbony-cyanid phenylhydrazon were not able to suppress tube growth stimulation of pine pollen. The data obtained are discussed in view of the stimulation mechanism of low doses of UVP-light.


Canine visceral leishmaniasis and its emergence in the United States.
Leishmaniasis is an important zoonotic disease that accounts for approximately 57,000 deaths among people each year. Dogs are reservoirs for the disease, and dog ownership is a risk factor in endemic areas. This article discusses insect vectors for this disease, as well as diagnosis and treatment for dogs.


Determining Stability in Posterior Wall Acetabular Fractures.
To determine if the radiographic parameters of femoral head coverage by the intact posterior wall, acetabular version, and location of the fracture or a history of dislocation were determinates of hip stability in patients with posterior wall acetabular fractures. Retrospective review. Level I trauma hospital. One hundred eighty-five consecutive patients with isolated unilateral posterior wall (OTA 62-A1) acetabular fractures. Patients underwent dynamic stress fluoroscopic examination under general anesthesia to determine hip stability. A number of radiographic measurements were performed, and an examination under anesthesia served as a standard to compare stable versus unstable hips. Examination under anesthesia (EUA) determined 116 hips to be stable and 22 hips as unstable. Moed and Keith method of wall size measurements and cranial exit point of fracture was statistically different between stable and unstable hips. Twenty-three percent of the unstable hips had wall sizes less than 20%. Average cranial exit point of fracture from dome was 5.0 mm in the unstable group and 9.5 mm in the stable group, and fractures that extend into the dome demonstrate a statistically significant increase in hip instability. Determination of hip stability can be challenging in patients with posterior wall acetabular fractures. Our data suggest that the location of the exit point of the fracture in relation to the dome of the acetabulum is a radiographic marker that can be used to aid physician in determining stability, and wall sizes less than 20% is not a reliable indicator of stability. Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.


der(1)t(1;9): a specific chromosome abnormality in polycythemia vera? Cytogenetic and in situ hybridization studies.
Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one patient this was found as the sole abnormality. The other patient originally presented with trisomy 9 but later developed an extra der(1) during the further course of the disease with disapperance of the extra chromosome 9. In situ hybridization studies on this latter patient proved that the centromere of chromosome 1 was involved in the formation of the derivative chromosome.


Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.
Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained β cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory β cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.


Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media. I. The value of different otoscopic findings.
To determine the value of different pneumotoscopic findings in diagnosing the middle ear effusion (MEE) of acute (AOM) and non-acute otitis media, 11,804 ear-related visits of 2,911 unselected children at ages 0.5-2.5 years were analysed. About half of these were examined by an otolaryngologist in one, and half by a pediatrician in another, urban area. Myringotomy was always performed when MEE was suspected, and it confirmed the presence of MEE in 85% (otolaryngologist) and 82% (pediatrician) of altogether 5,462 acute and in 69% (both doctors) of 1,092 non-acute cases suspected. Redness of the tympanic membrane (TM) was found in only 18% and 27% of the visits with AOM, and it predicted MEE with only 60% and 51% probability, if seen in acute visits. Cloudiness of the TM was noticed in 81% and 67% of the visits with AOM; its specificity and the other calculated variables were good in regard to the diagnosing of MEE, especially in acute cases in both groups. Distinctly impaired mobility of the TM was of about the same diagnostic value, but its position reliably indicated MEE only when bulging. In AOM the colour or mobility of the TM was normal very rarely, but the position was normal in a third of the cases. Thus, although there were differences in the incidences of different otoscopic findings in the two study groups, the diagnostic value of certain pneumatic otoscopic findings, especially cloudiness and distinct hypomobility of the TM, seemed to be good in both groups.


Eating disorders and substance use. An examination of behavioral associations.
The association between the eating disorders of anorexia nervosa (AN) and bulimia nervosa (BN) and substance use disorder (SUD) has been widely investigated, however, our understanding of the relationship between the disorders remains unclear. Explanatory models have tended to focus on behaviors, yet, little is currently known about the patterns of association among disordered eating and substance use behaviors. In this exploratory study, a behavioral approach was used to investigate the cooccurrence of seven disordered eating and three substance use behaviors in women meeting current DSM-III-R criteria for AN (n=12), subthreshold AN (n=14), BN (n=29), and subthreshold BN (n=24). Results suggest that disordered eating behaviors are differentially associated with substance use behaviors. The most robust finding was that diuretic use positively predicted the current level of alcohol use regardless of diagnostic group. The findings for marijuana and tobacco use were less consistent. Results suggest that rather than being pervasive in all eating disordered women, higher levels of alcohol use may be found in those women who use diuretics.


Impaired Neutralizing Antibody Response to COVID-19 mRNA Vaccines in Cancer Patients.
There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin's lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT 50 ) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT 50 levels, with 50-60% of them below the detection limit; (3) mean NT 50 levels in patients with CLL and NHL was ∼2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT 50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies.


Ghrelin is a suppressor of testicular damage following experimentally induced cryptorchidism in the rat.
Cryptorchidism is associated with increased level of reactive oxygen species and lipid peroxidation. This study was undertaken to examine the possible ghrelin ability in attenuation of testicular damage in response to elevated temperature. Thirty male rats were subdivided into sham-operated, cryptorchidism-saline and cryptorchidism-ghrelin group. Bilateral cryptorchidism was induced in groups 2 and 3, surgically. The animals in group 3 were given ghrelin for 7 days and all testes were taken for biochemical and photomicrograph analysis. Glutathione peroxidase activity and glutathione content significantly promoted on day 7 in the cryptorchid rats treated by ghrelin. Catalase activity was higher in the ghrelin-exposed animals than the cryptorchidism-saline group on both experimental days. Although superoxide dismutase activity was elevated by ghrelin treatment on both days, it did not differ significantly. By contrast, significant reduction was observed in thiobarbituric acid reactive substances concentrations following ghrelin administration on day 7. Moreover, ghrelin could improve histopathological scores of the testes, and diminished formation of giant cells and tubular vacuolization. These findings indicate for the first time the novel evidence of ghrelin antioxidant properties in attenuation of rat testicular injury following experimentally induced cryptorchidism.


Diversity of free-living amoebae in soils and their associated human opportunistic bacteria.
Free-living amoebae (FLA) are ubiquitous protozoa found worldwide in the environment. They feed by phagocytosis on various microorganisms. However, some bacteria, i.e., amoebae-resistant bacteria (ARB) or bacterial endocytobionts, can resist phagocytosis and even multiply inside FLA. This study investigated the diversity of culturable FLA in various soils from agricultural and mining sites and their bacterial endocytobionts. FLA were cultured on non-nutrient agar with alive Escherichia coli and identified by PCR and sequencing. Amoebae were lysed and bacterial endocytobionts were cultured on TSA 1/10 and Drigalski medium. Bacterial isolates were identified by PCR and 16S rDNA sequencing and characterized for their antibiotic resistance properties. To measure bacterial virulence, the amoebal model Dictyostelium discoideum was used. The analysis of FLA diversity showed that Tetramitus was the most prevalent genus in agricultural soil from Burkina Faso (73%) and garden soil from Vietnam (42%) while Naegleria and Acanthamoeba were dominant genera in mining soil from Vietnam (55%) and French alpine soil (77%). Some genera were only present in one out of the four soils analyzed. The bacterial endocytobiont included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Human opportunistic pathogens identified as Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia were found associated with amoebae including Micriamoeba, Tetramitus, Willaertia, or Acanthamoeba. Some of these bacteria showed various antibiotic resistance phenotypes and were virulent. Our study confirms that the occurrence of these opportunistic bacteria with FLA in soils may be important for the survival, multiplication, and spread of pathogens in the environment.


The effects of high and low fluoride diets on the frequencies of sister chromatid exchanges.
A recent report suggests that fluoride has mutagenic activity in mice. To examine the potential clastogenic effect of ingested fluoride, we examined the frequencies of baseline SCE and mitomycin C induced SCE as well as baseline chromsomal aberrations and cell-cycle kinetics in mice raised on high and low fluoride diets. The lack of significant differences in any of these parameters between the two groups of animals indicates that dietary fluoride is not clastogenic and supports the continued use of water fluoridation.


Metallothionein immunoreactivity in the liver and kidney of copper injected rats.
Adult male rats were injected intraperitoneally with copper sulphate in physiological saline (3 mg copper/kg body wt). Metallothionein-I (MT-I) levels in liver, kidney, plasma and red blood cells were measured by radioimmunoassay (RIA), prior to the injection and after 7, 16 and 24 h. Copper and zinc levels in liver and kidneys were also monitored. Concentrations of MT-I in liver and kidneys showed a rapid increase and remained elevated for 24 h. Copper concentrations also increased in both tissues but zinc levels remained constant in the kidney and rose only slightly in the liver. MT-I levels increased gradually in plasma but decreased in the red blood cells. Immunochemistry of liver and kidney, using the direct peroxidase technique with antiserum to rat MT-I, revealed an increase in staining in both tissues after copper administration, consistent with the RIA results. The change in distribution of immunoreactive material with time after copper injection indicates a role for MT in the sequestration and excretion of copper in acutely loaded animals.


The effects of a worksite health promotion program on the wives of fire fighters.
One method of increasing the cost-effectiveness of worksite health promotion programs is to develop programs that also have an impact on risk factors of family members and friends of the employees. In this study, 41 wives of fire fighters were interviewed concerning changes the fire fighters and they had made in their health habits--exercise, weight, and consumption of fats, fruits/vegetables, and cereal/whole grain breads--in the previous year. Thirty-two were wives of fire fighters who had received a worksite health promotion program and nine were wives of fire fighters who had not yet received the program. Findings of our exploratory study strongly suggest that wives of fire fighters who received information were more aware of the program (93% vs 56%), had greater exposure to the written diet plan (72% vs 11%) and guide to high fat foods (72% vs 0%) than controls. Furthermore, the intervention led to changes in the fire fighters' health habits that were reported by the wives. No significant changes in the wives' health habits occurred as a result of the intervention, although the changes were in the predicted direction in every category; changes by the wives were, however, related to changes by fire fighters. Involvement of the fire fighters in the preparation of meals and sharing of information from the intervention program by the participant with the wife, were related to change in health habits of the wives.(ABSTRACT TRUNCATED AT 250 WORDS)


The genetic and molecular basis of epilepsy.
In the past decade, studies of large families in which epilepsy has been inherited in an autosomal dominant fashion have revealed several mutated genes, most of which encode ion channel subunits. Despite these exciting findings, only a few families with similar phenotypes have mutations in these known genes. More frustrating has been the genetic research into idiopathic epilepsies with complex inheritance. Although these forms are more common than those with Mendelian inheritance, their unknown mode of inheritance, phenotypic heterogeneity and the uncertainty of the genetic overlap among syndrome subtypes have hampered gene mapping. New techniques of molecular analysis could help the dissection of genes for epilepsies with complex inheritance. Hopefully, in the near future, successful genetic studies will make possible the discovery of new and more-targeted anti-epileptic drugs.


Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice.
Insulin and glucose together have been previously shown to regulate hepatic sterol regulatory element-binding protein (SREBP)-1c expression. We sought to explore the nutritional regulation of lipogenesis through SREBP-1c induction in a setting where effects of sugars versus insulin could be distinguished. To do so, mice were insulin depleted by streptozotocin (STZ) administration and subjected to a fasting-refeeding protocol with glucose, fructose, or sucrose. Unexpectedly, the insulin-depleted mice exhibited a marked induction of SREBP-1c on all sugars, and this increase in SREBP-1c was even more dramatic than in the non-STZ-administered controls. The time course of changes in SREBP-1 induction varied depending on the type of sugars in both control and STZ-administered mice. Glucose refeeding gave a peak of SREBP-1c induction, whereas fructose refeeding caused slow and gradual increments, and sucrose refeeding fell between these two responses. Expression of various lipogenic enzymes were also gradually increased over time, irrespective of the types of sugars, with greater intensities in STZ-administered than in nontreated mice. In contrast, induction of hepatic glucokinase and suppression of phoshoenolpyruvate carboxykinase were insulin dependent in an early refed state. These data clearly demonstrate that nutritional regulation of SREBP-1c and lipogenic genes may be completely independent of insulin as long as sufficient carbohydrates are available.


Carotid artery free-floating thrombus caused by paradoxical embolization from greater saphenous vein ascending thrombophlebitis.
Stroke of unknown origin in young patients is seen to be closely correlated with patent foramen ovale (PFO) than stroke in patients with established stroke mechanisms. We report a case of a young woman without cardiovascular risk factors who was admitted to our emergency department with listlessness and altered mental status. The clinical examination revealed right lower limb swelling. Magnetic resonance imaging and contrast-enhanced computed tomographic scans revealed a free floating thrombus of the left internal carotid artery (ICA) with a large bilateral frontal ischemic lesion. The diagnosis of a medium-sized PFO with moderate right-to-left contrast shunting was made after transesophageal echocardiography. No other cardiac sources for embolization were detected, while an ascending thrombophlebitis of the right greater saphenous vein was detected by venous Doppler ultrasonography. These findings support the diagnosis of ICA free-floating thrombus caused by paradoxical embolization (via the PFO) of clot from the greater saphenous vein. The patient underwent emergency saphenofemoral disconnection with femoral vein thrombectomy and subsequently carotid artery thrombectomy under general anesthesia. No carotid atheromatous wall lesions were detected at surgical exploration; no immunologic pathology, hypercoagulable status, or malignancy were recorded. No hemorrhagic cerebral complications were observed in the postoperative period, and the patient had an improvement of her neurologic status (a reduction of the National Institutes of Health Stroke Scale score from 7 to 3). Her recovery was uneventful. The patient was transferred for rehabilitation on postoperative day 5 with oral anticoagulation. Six-month ultrasound follow-up revealed deep and superficial venous system and carotid artery patency. The patient was asymptomatic and anticoagulation was discontinued. Paradoxical cerebral embolization through a PFO is a rare phenomenon that, in our patient, appeared to have resulted in stroke caused by a free-floating thrombus in the ICA. Accurate evaluation of carotid and lower limb veins by duplex scan is mandatory in cases of stroke of unknown origin, and urgent surgical repair can be useful in order to improve the clinical outcome.


Biomarkers of DNA Damage Response Enable Flow Cytometry-Based Diagnostic to Identify Inborn DNA Repair Defects in Primary Immunodeficiencies.
DNA damage is a constant event in every cell caused by exogenous factors such as ultraviolet and ionizing radiation (UVR/IR) and intercalating drugs, or endogenous metabolic and replicative stress. Proteins of the DNA damage response (DDR) network sense DNA lesions and induce cell cycle arrest, DNA repair, and apoptosis. Genetic defects of DDR or DNA repair proteins can be associated with immunodeficiency, bone marrow failure syndromes, and cancer susceptibility. Although various diagnostic tools are available to evaluate DNA damage, their quality to identify DNA repair deficiencies differs enormously and depends on affected pathways. In this study, we investigated the DDR biomarkers γH2AX (Ser139), p-ATM (Ser1981), and p-CHK2 (Thr68) using flow cytometry on peripheral blood cells obtained from patients with combined immunodeficiencies due to non-homologous end-joining (NHEJ) defects and ataxia telangiectasia (AT) in response to low-dose IR. Significantly reduced induction of all three markers was observed in AT patients compared to controls. However, delayed downregulation of γH2AX was found in patients with NHEJ defects. In contrast to previous reports of DDR in cellular models, these biomarkers were not sensitive enough to identify ARTEMIS deficiency with sufficient reliability. In summary, DDR biomarkers are suitable for diagnosing NHEJ defects and AT, which can be useful in neonates with abnormal TREC levels (T cell receptor excision circles) identified by newborn screening. We conclude that DDR biomarkers have benefits and some limitations depending on the underlying DNA repair deficiency.


Progeria caused by a rare LMNA mutation p.S143F associated with mild myopathy and atrial fibrillation.
We present a 6-year-old girl with premature aging associated with mild myopathy, displaying muscle weakness, joint contractures and hyporeflexia. Genetic analysis revealed rare heterozygous point mutation in lamin A/C gene, g.428C>T. Cardiological evaluation showed atrial fibrillation, but we did not find signs of coronary heart disease, which is life-threatening cardiovascular complication in progeria. Electron microscopy of the muscle revealed abnormalities in nuclear architecture, i.e. blebbing, thick lamina and peripheral distribution of heterochromatin. As some diagnostic criteria characteristic for classic progeria are not fulfilled, this case could be regarded as atypical progeria associated with myopathy and atrial fibrillation. To our knowledge, this is the second case of such association described in the literature.


Application of single cell force spectroscopy (SCFS) to the assessment of cell adhesion to peptide-decorated surfaces.
The adhesion forces of cells to peptide-coated functionalized materials were assessed through the Single Cell Force Spectroscopy (SCFS) technique in order to develop a methodology that allows the fast selection of peptide motifs that favor the interaction between cells and the biomaterial. Borosilicate glasses were functionalized using the activated vapor silanization process (AVS) and subsequently decorated with an RGD- containing peptide using the EDC/NHS crosslinking chemistry. It is shown that the RGD-coated glass induces larger attachment forces on mesenchymal stem cell cultures (MSCs), compared to the bare glass substrates. These higher forces correlate well with the enhanced adhesion of the MSCs observed on RGD-coated substrates through conventional adhesion cell cultures and inverse centrifugation tests. The methodology based on the SCFS technique presented in this work constitutes a fast procedure for the screening of new peptides or their combinations to select candidates that may enhance the response of the organism to the implant of the functionalized biomaterials.


Advanced magnetic resonance imaging of articular cartilage.
MRI is one of the most accurate imaging methods available to diagnose disorders of articular cartilage. Conventional two-dimensional and three-dimensional approaches show changes in cartilage morphology. Newer and substantially faster three-dimensional imaging methods show great promise to improve MRI of cartilage. These methods may allow acquisition of fluid-sensitive isotropic data that can be reformatted into arbitrary planes for improved detection and visualization of pathology. Unique MRI contrast mechanisms also allow clinicians to probe cartilage physiology and detect early changes in cartilage macromolecules.


The role of small airway function parameters in preschool asthmatic children.
Small airways are the major sites of inflammation and airway remodeling in all severities of asthma patients. However, whether small airway function parameters could reflect the airway dysfunction feature in preschool asthmatic children remain unclear. We aim to investigate the role of small airway function parameters in evaluating airway dysfunction, airflow limitation and airway hyperresponsiveness (AHR). Eight hundred and fifty-one preschool children diagnosed with asthma were enrolled retrospectively to investigate the characteristics of small airway function parameters. Curve estimation analysis was applied to clarify the correlation between small and large airway dysfunction. Spearman's correlation and receiver-operating characteristic (ROC) curves were employed to evaluate the relationship between small airway dysfunction (SAD) and AHR. The prevalence of SAD was 19.5% (166 of 851) in this cross-sectional cohort study. Small airway function parameters (FEF25-75%, FEF50%, FEF75%) showed strong correlations with FEV1% (r = 0.670, 0.658, 0.609, p<0.001, respectively), FEV1/FVC% (r = 0.812, 0.751, 0.871, p<0.001, respectively) and PEF% (r = 0.626, 0.635, 0.530, p<0.01, respectively). Moreover, small airway function parameters and large airway function parameters (FEV1%, FEV1/FVC%, PEF%) were curve-associated rather than linear-related (p<0.001). FEF25-75%, FEF50%, FEF75% and FEV1% demonstrated a positive correlation with PC20 (r = 0.282, 0.291, 0.251, 0.224, p<0.001, respectively). Interestingly, FEF25-75% and FEF50% exhibited a higher correlation coefficient with PC20 than FEV1% (0.282 vs. 0.224, p = 0.031 and 0.291 vs. 0.224, p = 0.014, respectively). ROC curve analysis for predicting moderate to severe AHR showed that the area under the curve (AUC) was 0.796, 0.783, 0.738, and 0.802 for FEF25-75%, FEF50%, FEF75%, and the combination of FEF25-75% and FEF75%, respectively. When Compared to children with normal lung function, patients with SAD were slightly older, more likely to have a family history of asthma and airflow obstruction with lower FEV1% and FEV1/FVC%, lower PEF% and more severe AHR with lower PC20 ( all p<0.05). Small airway dysfunction is highly correlated with large airway function impairment, severe airflow obstruction and AHR in preschool asthmatic children. Small airway function parameters should be utilized in the management of preschool asthma.


Taurine and GABA release from mouse cerebral cortex slices: effects of structural analogues and drugs.
The effects of structural analogues, excitatory amino acids and certain drugs on spontaneous and potassium-stimulated exogenous taurine and GABA release were investigated in mouse cerebral cortex slices using a superfusion system. Spontaneous efflux of both amino acids was rather slow but could be enhanced by their uptake inhibitors. Taurine efflux was facilitated by exogenous taurine, hypotaurine, beta-alanine and GABA, whereas GABA, nipecotic acid and homotaurine effectively enhanced GABA release. The stimulatory potency of the analogues closely corresponded to their ability to inhibit taurine and GABA uptake, respectively, indicating that these efflux processes could be mediated by the carriers operating outwards. Glutamate induced GABA release, whereas taurine efflux was potentiated by aspartate, glutamate, cysteate, homocysteate and kainate. The centrally acting drugs, including GABA agonists and antagonists, as well as the proposed taurine antagonist TAG (6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide), had no marked effects on spontaneous taurine and GABA release. Potassium ions stimulated dose-dependently both taurine and GABA release from the slices, the responses of taurine being strikingly slow but sustained. Exogenous GABA and nipecotic acid accelerated the potassium-stimulated GABA release, whereas picrotoxin and bicuculline were ineffective. The potassium-stimulated taurine release was unaltered or suppressed by exogenous taurine and analogues, differing in this respect from GABA release. The apparent magnitude of the depolarization-induced GABA release is thus influenced by the function of membrane transport sites, but the same conclusion cannot be drawn with regard to taurine. Haloperidol and imipramine were able to affect the evoked release of both taurine and GABA.


Engineering highly efficient Li+ responsive nanochannels via host-guest interaction and photochemistry regulation.
Artificial nanochannels have seen great progress in energy storage, molecular filters, nanofluidic diodes, and biosensors. Precisely recognizing and transporting molecules or ions underpin the basis of artificial nanochannels. Here, we report highly efficient Li+ responsive nanochannels by design of functionalized porous anodic aluminum oxide (AAO) membranes. The 12-crown-4 unit was tethered to the synthesized spiropyran molecule, creating a smart Li+ responsive element, photochromic crowned spiropyran (CE-SP). The crown unit can specifically bind with Li+ while exempting the harassment of other metallic cations; and importantly, the spiropyran moiety possesses reversible photochemistry response, adding the flexibility to regulate ion transport behaviors. Upon the ultraviolet light stimulus, hydrophobic CE-SP molecules transform to positively charged crowned merocyanine (CE-MC), which can further convert to oxygen-negative ions in weak alkaline environment, thereby forming O--Li+ interaction. Such structural evolutions enable to deftly tune the surface charge and wettability of the nanochannels, and thus ingeniously manipulate Li+ recognition profiled by ionic current signal. Moreover, electrically-driven release of the captured Li+ can be realized in an amiable condition, showing controllable capture-to-release ability. Finite element simulation unveils the fundamental mechanisms of ion transport pertaining to Li+ recognition events in the nanoconfinement. This work thus paves a way to construct high-performance Li+-selective nanodevice, and holds promise for Li+-related electrochemistry energy research.


Estradiol induced alterations of the immune system--I. Enhancement of IgM production.
Estrogens have been postulated as natural modulators of the immune system. In this study we have evaluated the effect of estradiol on in vivo immunoglobulin production in male rats. Administration of either a 75 microgram/kg or 750 microgram/kg dose of estradiol resulted in a dose-related increase of anti-sheep red blood cell antibody titers during a primary antibody response. These same animals when dosed with estradiol during a secondary antibody response showed an earlier appearance of the peak antibody titer in estradiol-treated rats as compared to controls. Rats dosed with estradiol only during the secondary antibody response period also showed a dose-related increase in Ab titer over control values but no shift in the time of appearance of the peak titer. Treatment of sera with 2-mercaptoethanol to evaluate IgG titers showed that 2-mercaptoethanol treatment both reduced the titer to control values and eliminated the estradiol-induced shift in the appearance of the peak antibody titer in rats given estradiol during the primary and secondary antibody response periods. Sera from animals dosed with estradiol during the secondary antibody response period only also showed titers reduced to control levels after 2-mercaptoethanol treatment of the sera. Estradiol-treated rats also had an increase in antibody titers to polysaccharide from Type III pneumococci, a T-cell independent antigen. While total antibody responses were increased following estradiol, there were no differences in the number of antibody-producing cells between control and estradiol-treated animals. The results of these studies suggest that estradiol exerts a direct effect on B cells resulting in increased synthesis of IgM antibodies. We cannot rule out, however, some modulation through regulatory T-cells.


Spontaneous alternans in Brugada ST-segment morphology within minutes.
Brugada syndrome is an inherited, life-threatening, cardiac channelopathy where the electrocardiogram (ECG) characteristically depicts a classic pattern of complete or incomplete right bundle-branch block with ST-segment elevation in the right precordial leads V(1) to V(3). These, almost inalienable, ECG patterns may be dynamic, where changes may resolve to baseline or one particular type may evolve into another. Such alternans has been described with fever, electrolyte imbalances, atrial pacing, glucose and/or insulin administration, psychotropic drugs, beta-adrenergic blocker use, class IA and IC antiarrhythmic provocation testing, such as with ajmaline, procainamide, or flecainide, and even large meals, that is, "full stomach sign." However, spontaneous alternans between the different types of Brugada ECG patterns (types) have not been reported within minutes, in the absence of previously described precipitating factors. We present a novel case where classic, type 2, Brugada-like ECG pattern evolved spontaneously to type 1 before returning to type 2 within minutes of presentation.