Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo.
The most challenging aspect of intravenously-administered drugs currently developed to treat central nervous system (CNS) diseases is their impermeability through the blood-brain barrier (BBB), a specialized vasculature system protecting the brain microenvironment. Focused ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the BBB locally, noninvasively, and reversibly. The objective of this study was to investigate the effect of FUS (center frequency: 1.5 MHz) pulse length (PL), ranging here from 67 μs to 6.7 ms, on the physiology of the FUS-induced BBB opening. Dynamic contrast-enhanced (DCE) and T1-weighted magnetic resonance imaging (MRI) were used to quantify the permeability changes using transfer rate (Ktrans) mapping, the volume of BBB opening (VBBB) and the reversibility timeline of the FUS-induced BBB opening, with the systemic administration of microbubbles at different acoustic pressures, ranging from 0.30 to 0.60 MPa. Permeability and volume of opening were both found to increase with the acoustic pressure and pulse length. At 67-μs PL, the opening pressure threshold was 0.45 MPa, with BBB opening characteristics similar to those induced with 0.60 MPa at the same PL, as well as with 0.67-ms PL/0.30 MPa. On average, these cases had Ktrans = 0.0049 ± 0.0014 min-1 and VBBB = 3.7 ± 4.3 mm(3), and closing occurred within 8 h. The 6.7-ms PL/0.30 MPa induced similar opening with 0.67-ms PL/0.45 MPa, and a closing timeline of 24 to 48 h. On average, Ktrans was 0.0091 ± 0.0029 min-1 and VBBB was 14.13 ± 7.7 mm(3) in these cases. Also, there were no significant differences between the 6.7-ms PL/0.45 MPa, 0.67-ms PL/0.60 MPa and 6.7-ms PL/0.60 MPa cases, yielding on average a Ktrans of 0.0100 ± 0.0023 min-1 and VBBB equal to 20.1 ± 5.7 mm(3). Closing occurred within 48 to 72 h in these cases. Stacked histograms of the Ktrans provided further insight to the nonuniform spatial distribution of permeability changes and revealed a correlation with the closing timeline. These results also suggest a beneficial complementary relationship between the elongation of the PL and the decrease of the peak negative acoustic pressures, and vice versa. Linear regression between Ktrans and VBBB showed a good correlation fit. Also, the time required for closing linearly increased with VBBB. The volume rate of decrease was measured to be 11.4 ± 4.0 mm3 per day, suggesting that the closing timeline could be predicted from the initial volume of opening. Finally, no histological damage was detected in any of the cases 7 d post-FUS, indicating the safety of the methodology and parameters used.


Sex differences in response of the bovine embryo to colony-stimulating factor 2.
We tested whether gene expression of the bovine morula is modified by CSF2 in a sex-dependent manner and if sex determines the effect of CSF2 on competence of embryos to become blastocysts. Embryos were produced in vitro using X- or Y-sorted semen and treated at Day 5 of culture with 10 ng/mL bovine CSF2 or control. In experiment 1, morulae were collected at Day 6 and biological replicates (n = 8) were evaluated for transcript abundance of 90 genes by RT-qPCR using the Fluidigm Delta Gene assay. Expression of more than one-third (33 of 90) of genes examined was affected by sex. The effect of CSF2 on gene expression was modified by sex (P < 0.05) for five genes (DDX3Y/DDX3X-like, NANOG, MYF6, POU5F1 and RIPK3) and tended (P < 0.10) to be modified by sex for five other genes (DAPK1, HOXA5, PPP2R3A, PTEN and TNFSF8). In experiment 2, embryos were treated at Day 5 with control or CSF2 and blastocysts were collected at Day 7 for immunolabeling to determine the number of inner cell mass (ICM) and trophectoderm (TE) cells. CSF2 increased the percent of putative zygotes that became blastocysts for females, but did not affect the development of males. There was no effect of CSF2 or interaction of CSF2 with sex on the total number of blastomeres in blastocysts or in the number of inner cell mass or trophectoderm cells. In conclusion, CSF2 exerted divergent responses on gene expression and development of female and male embryos. These results are evidence of sexually dimorphic responses of the preimplantation embryo to this embryokine.


An augmented computer model of motor unit reorganization in neurogenic diseases of skeletal muscle.
A computer model of denervation and complete reinnervation in skeletal muscle was originally developed for the purpose of furthering an understanding of the underlying mechanisms of motor unit reorganization in neurogenic diseases. We now describe its successor, a computer model for investigating different rates of denervation and reinnervation, as well as incomplete reinnervation. The new model introduces the concept of permanent denervation and features enhanced interactive control over the distribution of motor unit centers and additional measures of dispersion and co-dispersion of muscle fibers. The use of this model for investigating pathophysiologically significant issues in denervating diseases is illustrated with five different sets of parameters. These simulate some of the processes that may be operational in chronic spinal muscular atrophy, amyotrophic lateral sclerosis, and progressive postpolio muscular dystrophy. The enhanced model will allow in-depth analysis of the influence of hypothesized pathophysiological processes on clinical, electrophysiological and pathological outcomes in human disease.


Serum leptin concentration during the terrestrial phase of the Southern elephant seal Mirounga leonina (Carnivora: Phocidae).
This study aimed to verify the serum leptin concentration during the terrestrial phase of the Southern elephant seal (Mirounga leonina) on Elephant Island (South Shetlands, Antarctica). Sera from 25 adult Southern elephant seals were analyzed. Leptin concentration was determined using the 125I radioimmunoassay method. Total protein, triglycerides, and cholesterol concentration were measured by spectrophotometric methods. Seals were grouped by sex and their physiological status (reproducing or molting seals). In reproducing seals, serum concentrations of leptin, total protein, triglycerides, and cholesterol were, respectively, 9.33+/-1.97 ng/ml, 6.87+/-0.09 g/dl, 98.26+/-2.12 mg/dl, and 232.17+/-41.18 mg/dl in males and 5.30+/-1.36 ng/ml, 6.44+/-0.29 g/dl, 109.01+/-3.34 mg/dl, and 219.20+/-26.65 in females (mean+/-1 SD). In molting seals, these values were 2.35+/-1.51 ng/ml, 7.42+/-0.25 mg/dl, 321.10+/-20.01 mg/dl, and 244.66+/-22.24 mg/dl in males and 2.94+/-1.89 ng/ml, 7.88+/-0.46 mg/dl, 197.54 mg/dl, and 224.55+/-16.70 mg/dl in females. In both males and females, there were no significant differences (P>0.05) in total protein and cholesterol concentration between reproducing and molting seals. However, both males and females showed higher leptin concentration (P<0.05) and lower triglyceride concentration (P<0.05) in the reproductive period than in the molt period. In the reproductive period, it was expected that the Southern elephant seal shows an inhibited hunger sensation, mobilizes stored energy, and stimulates the HPG axis. Results from the present study support this hypothesis and suggest that this strategy may be effected by the hormonal stimulation of leptin.


Research and quality improvement: different processes, different evidence.
Two sources commonly used for evidence-based practice include research findings and quality improvement (QI) reports. However, they often are implemented improperly. It is important for nurses to distinguish between research and QI. A tool for making such a distinction is presented.


Differential Changes in the Amount of Protein Complexes in the Chloroplast Membrane during Senescence of Oat and Bean Leaves.
Antibodies against the individual subunits of protein complexes in the chloroplast membranes were used to follow the amounts of these polypeptides during foliar senescence. No change was found in the amount of polypeptides of photosystem I reaction center and the chloroplast coupling factor during senescence of oat (Avena sativa L.) and bean (Phaseolus vulgaris L.) leaves. A significant decrease in the amount of the different components of the cytochrome b(6)-f complex was detected. This change may account for the decrease in the rate of electron transport, which might be the rate limiting step of photosynthesis in senescing leaves.


Human and mouse induced pluripotent stem cells are differentially reprogrammed in response to kinase inhibitors.
Conventional human induced pluripotent stem cells (hiPSCs), reprogrammed from somatic cells by induced expression of Oct4, Sox2, Klf4, and c-Myc, are phenotypically different from mouse embryonic stem cells (ESCs). In mice, culture in N2B27 serum-free 2i media (mitogen-activated protein kinase/extracellular signal-regulated kinase and glycogen synthase kinase 3 inhibitors; PD0325901 and CHIR99021) plus leukemia inhibitory factor (LIF) (2i+LIF medium) enriches for germline competent ESCs. Here, we demonstrate that flat-shaped hiPSC colonies can be reprogrammed into bowl-shaped multi-potent stem cells (2i-hiPSCs) by using 2i+LIF medium. Mechanical dissociation of 2i-hiPSC colonies enables stable maintenance for >20 passages. Importantly, gene expression profiling demonstrated that 2i-hiPSCs more closely resemble primitive neural stem cells (PNSCs). Notably, this 2i-induced phenotype was generated from conventional hiPSCs, but not human ESCs (hESCs), thus correlating with the observation of neuroectodermal SOX1-positive colonies in conventional hiPSCs, but not hESCs in 2i+LIF medium. Thus, 2i-hiPSCs, which are nonteratoma forming PNSCs, may represent a safe source of cells for neural research and regenerative medicine.


Molecular biomarker panels for assessment of selenium status in rats.
Molecular biomarkers are mRNA transcripts that indicate the (nutrient) status of an organism or tissue. Molecular biomarker panels have the potential to readily and more accurately determine nutrient status than individual traditional biomarkers. To study the efficacy of molecular biomarker panels for predicting selenium (Se) status, we examined 30 biomarkers from rats fed graded levels of Se from deficient to eight times the minimum Se requirement, including four liver and four kidney traditional biomarkers, and 13 liver and nine kidney selenoprotein mRNA levels. Multiple regression analysis against liver and kidney Se and glutathione peroxidase-1 (Gpx1) activity, with stepwise single elimination of biomarkers that did not significantly contribute, was used to identify biomarker panels with significant (P < 0.05) regression coefficients. Resulting regression equations were then used to predict Se status, and compared with traditional Se biomarkers panels. Over the full spectrum of Se status from 0 to 0.8 microg Se/g diet, the resulting 4-selenoprotein mRNA biomarker panel predicted liver Se concentration with a correlation of 0.948, which was nominally higher and statistically the same as the correlation of 0.909 for the panel based on Gpx1 activity. The molecular biomarker panels for predicting kidney Se and liver and kidney Gpx1 activity were all comparable to predictions based on traditional biomarkers. These analyses show that molecular biomarker panels can be used to predict accurately two traditional biomarkers of Se status. The resulting analyses also illustrate that additional orthogonal biomarkers reflecting higher Se intakes are needed to better predict supernutritional Se status and further strengthen this approach.


Optimized phase gradient measurements and phase-amplitude interplay in optical coherence elastography.
In compressional optical coherence elastography, phase-variation gradients are used for estimating quasistatic strains created in tissue. Using reference and deformed optical coherence tomography (OCT) scans, one typically compares phases from pixels with the same coordinates in both scans. Usually, this limits the allowable strains to fairly small values <10?4 to 10?3, with the caveat that such weak phase gradients may become corrupted by stronger measurement noises. Here, we extend the OCT phase-resolved elastographic methodology by (1) showing that an order of magnitude greater strains can significantly increase the accuracy of derived phase-gradient differences, while also avoiding error-phone phase-unwrapping procedures and minimizing the influence of decorrelation noise caused by suprapixel displacements, (2) discussing the appearance of artifactual stiff inclusions in resultant OCT elastograms in the vicinity of bright scatterers due to the amplitude-phase interplay in phase-variation measurements, and (3) deriving/evaluating methods of phase-gradient estimation that can outperform conventionally used least-square gradient fitting. We present analytical arguments, numerical simulations, and experimental examples to demonstrate the advantages of the proposed optimized phase-variation methodology.


Are elastic stain and specialty sign out necessary to evaluate pleural invasion in lung cancers?
The seventh edition of American Joint Committee on Cancer (AJCC) staging system assigns lung cancers with visceral pleural invasion in the tumor size of 3 cm or less than 3 cm as T2 and without pleural invasion as T1. However, it may be difficult to distinguish with certainty between PL0 (no pleural invasion) and PL1 (extends through the elastic layer) on routine hematoxylin and eosin (H&E) stain. In this study, 25 cases of peripherally located lung adenocarcinoma were retrieved from the surgical pathology archives at the Asan Medical Center from May through June 2009. One representative H&E-stained slide was selected from each case and circulated to 31 pathology trainees and board-certified pathologists at Asan Medical Center who evaluated presence or absence of pleural invasion on H&E-stained slides. Elastic stain was used to determine the final status of pleural invasion for each case. The concordance rate of all pathologists with elastic stain results was, overall, 60.5%. The concordance rate of 2 lung specialists was 64%, better than the remaining faculty (54.7%). Fellows' and residents' evaluations were slightly more concordant than those of faculty responses (faculty overall, 56.4%; fellows, 62%; residents, 63.6%), but this difference was not statistically significant (P = .228). Our results confirm that pleural invasion status is difficult to discern with certainty on H&E-stained sections alone. Therefore, we recommend the routine use of elastic stain in evaluation of pleural invasion in all peripherally located lung cancers. Furthermore, our study indicates that subspecialty sign out may be preferable in evaluation of pleural invasion status.


[Tissue banks for molecular diagnostics].
The application of modern high throughput-technologies in genome and proteome research permits the identification of molecular, disease-associated mechanisms. Research data are mostly derived from experiments in which cell lines or animal models are used. In order to translate this knowledge into clinical usage it is necessary to examine numerous, well-documented tissues. Tissue collections that are appropriate for such investigations exist, particularly in pathology institutes. These tissues are routinely fixed informalin and embedded in paraffin and in some cases additional tissue pieces are also kept frozen for future diagnostic purposes. The linking of tissues with corresponding clinico-pathological data and the use of the tissue microarray technology will enable rapid selection of new potential biomarkers for all kinds of diseases. By continuing the upgrading of tissue banks and by introducing quality controls, a significant potential for molecular diagnostics will be available in the future. This will contribute enormously to uncover and to establish novel therapeutical possibilities.


Electrostatic stabilization of charged colloidal particles with adsorbed polyelectrolytes of opposite charge.
Repulsive electrostatic double-layer forces are responsible for the stabilization of charged colloidal particles in the presence of adsorbed polyelectrolytes of opposite and high line charge densities. This mechanism is revealed by studies of electrophoretic mobility and colloidal stability performed with dynamic light scattering as a function of the polyelectrolyte dose and the ionic strength for two different types of latex particles and four different types of polyelectrolytes. The dependence of these quantities is very similar for bare charged latex particles and the same particles in the presence of the different oppositely charged polyelectrolytes. Positively charged particles in the presence of anionic polyelectrolytes behave analogously to negatively charged particles in the presence of cationic polyelectrolytes.


Fetal striatal homotransplantation for Huntington's disease: first two case reports.
Based on the successful use of fetal striatal brain grafting in the restoration of striatal function in rat and nonhuman primate models of Huntington's disease, as well as on the evidence for the clinical potential of fetal brain grafting in the treatment of Parkinson's disease, homotopic fetal striatal homotransplantations were performed in two huntingtonians. Case 1 was a 37 year-old female with moderate to severe Huntington's disease of 9 years evolution; case 2 was a 29 year-old male with mild Huntington's disease of 5 years evolution. Using open microsurgery, each patient was implanted to the ventricular wall of the right caudate nucleus with both striata from a 13 week-old and a 12 week-old human fetus, respectively. Since surgery both patients were kept on cyclosporine A. Surgery produced no damaging effect to either patient. The time course of the neurological progression of their disease, spanning 33 months for case 1, and 16 months for case 2, reveal that the disease in both patients has progressed more slowly in relation to their preoperative state. Although presently it is not possible to determine to what extent, surgery has modified the course of their disease, or if it will continue to have an effect on it, these surgeries represent the first step towards the development of brain grafting for Huntington's disease.


Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-gamma.
Interleukin-10 (IL-10) is a cytokine derived from CD4+ T-helper type 2 (T(H2)) cells identified as a suppressor of cytokines from T-helper type 1(T(H1)) cells. Interleukin-12 (IL-12) is produced by B cells, macrophages and dendritic cells, and primarily regulates T(H1) cell differentiation, while suppressing the expansion of T(H2) cell clones. Interferon-gamma (IFN-gamma) is a product of T(H1) cells and exerts inhibitory effects on T(H2) cell differentiation. These cytokines have been implicated in the pathogenesis of asthma and allergies. In this context, IL-12 and IFN-gamma production in asthma have been found to be decreased, and this may reduce their capacity to inhibit IgE synthesis and allergic inflammation. IL-10 is a potent inhibitor of monocyte/macrophage function, suppressing the production of many pro-inflammatory cytokines. A relative underproduction of IL-10 from alveolar macrophages of atopic asthmatics has been reported. Therapeutic modulation of T(H1)/T(H2) imbalance in asthma and allergy by mycobacterial vaccine, specific immunotherapy and cytoline-guanosine dinucleotide motif may lead to increases in IL-12 and IFN-gamma production. Stimulation of IL-10 production by antigen-specific T-cells during immunotherapy may lead to anergy through inhibition of CD28-costimulatory molecule signalling by IL-10s anti-inflammatory effect on basophils, mast cells and eosinophils.


Evaluation of nasal airway resistance during rapid maxillary expansion using acoustic rhinometry.
The purpose of this study was to evaluate nasal airway resistance (NAR) during rapid maxillary expansion (RME) using acoustic rhinometry (AR). The sample comprised 22 children (13 girls and nine boys) with maxillary constriction. The mean age was 12.9 +/- 1.54 years and all patients were found to have normal nasal cavities following anterior rhinoscopic examination. A modified bonded splint type RME appliance was used for expansion. AR was used to measure NAR before (T1), during (T2) and after (T3) expansion, and at the end of retention (T4). Each AR recording was performed, for each patient, with and without the use of a decongestant. Subjective evaluation of reported changes in nasal breathing were also undertaken at T3. The results showed that NAR was significantly reduced with the use of RME, with the main decrease observed during expansion (P < 0.05). The use of a decongestant was not found to have any effect on the results. Subjective evaluation showed that 59 per cent of patients considered that their nasal breathing had improved following RME.


Comparison of Postoperative Changes in Inflammatory Marker Levels Between Transthoracic and Transcatheter Device Closures of Atrial Septal Defects in Children.
To explore the postoperative changes in inflammatory markers in children who underwent device closure of an atrial septal defect (ASD) via a transthoracic or transcatheter approach. The experimental and clinical data were retrospectively collected and analyzed for a total of 53 pediatric patients between September 2018 and December 2018. According to the different treatments, 19 patients who underwent transthoracic device closure were assigned to group A, and the remaining 34 patients who underwent a transcatheter approach were assigned to group B. All patients were successfully occluded without any device-related severe complication. Compared with the preoperative levels, the postoperative levels of most inflammatory cytokines in both groups were significantly increased and reached a peak on the first day after the procedure. The level of postoperative inflammatory cytokines was significantly lower in group B than in group A. In addition, there was no significant difference in procalcitonin before and after the transcatheter approach. Systemic inflammatory reactions occurred after transthoracic or transcatheter device closure of ASDs in pediatric patients. However, these inflammatory reactions were more significant in patients who underwent a transthoracic approach than in patients who underwent a transcatheter approach.


Immunogenicity of oral poliovirus vaccine in Taiwan.
Previous studies have shown that the immune response to trivalent oral poliovirus vaccine (OPV) varies widely from country to country. However, there has been no report on the immunogenicity of this vaccine in Taiwanese children. In this study, 98 children were followed up for 17 months to study the antibody responses following four doses of trivalent OPV. The results showed that, after two doses of vaccine, all children were protected against poliovirus type 1 and 2. All except two children also developed protective antibodies against poliovirus type 3. After three doses, the antibody levels in all subjects were above protective concentrations. The fourth dose, given at 18 months of age, further boosted the antibody titers. These findings show that the OPV currently used in Taiwan is highly immunogenic in Taiwanese children.


Race, intervening variables, and two components of low birth weight.
The low birth weight (LBW) gap between blacks and whites has remained largely unexplained in past research. Most previous research on the topic has focused on LBW as a single entity, and without using a causal framework for analysis. The present study examines the determinants of race differences in the two main components of LBW--preterm birth (PRETERM) and intrauterine growth retardation (IUGR)-within a partially causal framework that includes social and proximate explanatory variables. The data come from the 1988 National Survey of Family Growth. This study asks, first, through what intervening variables do race and other exogenous sociodemographic variables operate to raise the risk of these adverse pregnancy outcomes? Second, what are the determinants of the two components of LBW when all explanatory variables are included in the model? The findings reveal differences in how race (and other exogenous variables) act through downstream variables to affect PRETERM and IUGR, as well as differences in the net determinants of these pregnancy outcomes. The models are better able to account statistically for race differences in IUGR (which is explained by intervening sociodemographic, attitude, and behavior variables) than in PRETERM (which is explained partly by intervening health variables).


Spiroindolones, a potent compound class for the treatment of malaria.
Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.


Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years.
We assessed the effects of sodium valproate and carbamazepine monotherapy on bone mineral density (BMD) in children. BMD at the lumbar vertebrae (L1-L4) and radius-ulna was measured by the dual-energy x-ray absorptiometry (DEXA) method in 19 children (9 girls, 10 boys) with uncomplicated epilepsy and in 57 healthy children (28 girls, 29 boys), between the ages of 6 and 12 years. The study patients had been receiving either sodium valproate (n = 13) or carbamazepine (n = 6) monotherapy for more than 6 months. There were no significant differences between the control and study patients in age, height, weight, physical activity, or of serum concentrations of calcium, phosphate, and transaminases (aspartate aminotransferase, alanine aminotransferase). However, the serum alkaline phosphatase concentration was greater in the patient group as compared with the control group. BMD values were lower in girl patients (L1-L4; 0.497 +/- 0.08 vs 0.566 +/- 0.07 g/cm2, p < 0.05), but not in boys (0.534 +/- 0.06 vs 0.530 +/- 0.08 g/cm2). While BMD reduction was 8% in valproate therapy (midregion of radius-ulna; 0.287 +/- 0.03 vs 0.312 +/- 0.04 g/cm2, p < 0.04), it was reduced only 4.5% in the carbamazepine-treated group (0.298 +/- 0.01 vs 0.312 +/- 0.04 g/cm2, statistically not significant), although the mean durations of monotherapy with valproate (1.8 +/- 0.7 years) and carbamazepine (1.7 +/- 0.8 years) were similar. Thus decreased bone mineralization was observed in children with epilepsy, treated with sodium valproate even though treatment was for a rather short time.


Multi-institutional dosimetric and geometric commissioning of image-guided small animal irradiators.
To compare the dosimetric and geometric properties of a commercial x-ray based image-guided small animal irradiation system, installed at three institutions and to establish a complete and broadly accessible commissioning procedure. The system consists of a 225 kVp x-ray tube with fixed field size collimators ranging from 1 to 44 mm equivalent diameter. The x-ray tube is mounted opposite a flat-panel imaging detector, on a C-arm gantry with 360° coplanar rotation. Each institution performed a full commissioning of their system, including half-value layer, absolute dosimetry, relative dosimetry (profiles, percent depth dose, and relative output factors), and characterization of the system geometry and mechanical flex of the x-ray tube and detector. Dosimetric measurements were made using Farmer-type ionization chambers, small volume air and liquid ionization chambers, and radiochromic film. The results between the three institutions were compared. At 225 kVp, with 0.3 mm Cu added filtration, the first half value layer ranged from 0.9 to 1.0 mm Cu. The dose-rate in-air for a 40 × 40 mm(2) field size, at a source-to-axis distance of 30 cm, ranged from 3.5 to 3.9 Gy/min between the three institutions. For field sizes between 2.5 mm diameter and 40 × 40 mm(2), the differences between percent depth dose curves up to depths of 3.5 cm were between 1% and 4% on average, with the maximum difference being 7%. The profiles agreed very well for fields >5 mm diameter. The relative output factors differed by up to 6% for fields larger than 10 mm diameter, but differed by up to 49% for fields ≤5 mm diameter. The mechanical characteristics of the system (source-to-axis and source-to-detector distances) were consistent between all three institutions. There were substantial differences in the flex of each system. With the exception of the half-value layer, and mechanical properties, there were significant differences between the dosimetric and geometric properties of the three systems. This underscores the need for careful commissioning of each individual system for use in radiobiological experiments.


Economic burden of readmission due to postoperative cerebrospinal fluid leak in Chinese patients.
Aim: This real-world data study investigated the economic burden and associated factors of readmissions for cerebrospinal fluid leakage (CSFL) post-cranial, transsphenoidal, or spinal index surgeries. Methods: Costs of CSFL readmissions and index hospitalizations during 2014-2018 were collected. Readmission cost was measured as absolute cost and as percentage of index hospitalization cost. Factors associated with readmission cost were explored using generalized linear models. Results: Readmission cost averaged US$2407-6106, 35-94% of index hospitalization cost. Pharmacy costs were the leading contributor. Generalized linear models showed transsphenoidal index surgery and surgical treatment for CSFL were associated with higher readmission costs. Conclusion: CSFL readmissions are a significant economic burden in China. Factors associated with higher readmission cost should be monitored.


Capillary networks in tumor angiogenesis: from discrete endothelial cells to phase-field averaged descriptions via isogeometric analysis.
Tumor angiogenesis, the growth of new capillaries from preexisting ones promoted by the starvation and hypoxia of cancerous cell, creates complex biological patterns. These patterns are captured by a hybrid model that involves high-order partial differential equations coupled with mobile, agent-based components. The continuous equations of the model rely on the phase-field method to describe the intricate interfaces between the vasculature and the host tissue. The discrete equations are posed on a cellular scale and treat tip endothelial cells as mobile agents. Here, we put the model into a coherent mathematical and algorithmic framework and introduce a numerical method based on isogeometric analysis that couples the discrete and continuous descriptions of the theory. Using our algorithms, we perform numerical simulations that show the development of the vasculature around a tumor. The new method permitted us to perform a parametric study of the model. Furthermore, we investigate different initial configurations to study the growth of the new capillaries. The simulations illustrate the accuracy and efficiency of our numerical method and provide insight into the dynamics of the governing equations as well as into the underlying physical phenomenon.


A Simulation Study of Coronavirus as an Epidemic Disease Using Agent-Based Modeling.
At the end of 2019, the world faced the novel coronavirus, and with it fear of economic collapse and mass fatalities. Simulation systems can be used to monitor the behavior of the virus. Simulation provides an abstract representation of reality by conveying details and characteristics of reality in a simple application. One of the most important ways to simulate is agent-based modeling. The health information professional plays an important role in developing these models. In this research, we simulate the spread of COVID-19 in a region restricted to a population with specific demographic characteristics and social relationships. This study aims to clarify the effects of preventative techniques that suppress the spread of epidemics, such as quarantines, social distancing, and reduced mass transit.


Dendritic Spines in the Spinal Cord: Live Action Pain.
Dendritic spines are microscopic protrusions on neurons that house the postsynaptic machinery necessary for neurotransmission between neurons. As such, dendritic spine structure is intimately linked with synaptic function. In pathology, dendritic spine behavior and its contribution to disease are not firmly understood. It is well known that dendritic spines are highly dynamic in vivo. In our recent publication, we used an intravital imaging approach, which permitted us to repeatedly visualize the same neurons located in lamina II, a nociceptive processing region of the spinal cord. Using this imaging platform, we analyzed the intravital dynamics of dendritic spine structure before and after nerve injury-induced pain. This effort revealed a time-dependent relationship between the progressive increase in pain outcome, and a switch in the steady-state fluctuations of dendritic spine structure. Collectively, our in vivo study demonstrates how injury that leads to abnormal pain may also contribute to synapse-associated structural remodeling in nociceptive regions of the spinal cord dorsal horn. By combining our live-imaging approach with measures of neuronal activity, such as with the use of calcium or other voltage-sensitive dyes, we expect to gain a more complete picture of the relationship between dendritic spine structure and nociceptive physiology.


Structural control of cytochrome P450-catalyzed ω-hydroxylation.
The regiospecific or preferential ω-hydroxylation of hydrocarbon chains is thermodynamically disfavored because the ease of C-H bond hydroxylation depends on the bond strength, and the primary C-H bond of a terminal methyl group is stronger than the secondary or tertiary C-H bond adjacent to it. The hydroxylation reaction will therefore occur primarily at the adjacent secondary or tertiary C-H bond unless the protein structure specifically enforces primary C-H bond oxidation. Here we review the classes of enzymes that catalyze ω-hydroxylation and our current understanding of the structural features that promote the ω-hydroxylation of unbranched and methyl-branched hydrocarbon chains. The evidence indicates that steric constraints are used to favor reaction at the ω-site rather than at the more reactive (ω-1)-site.


Subharmonic stochastic synchronization and resonance in neuronal systems.
We study the response of a model neuron, driven simultaneously by noise and at least two weak periodic signals. We focus on signals with frequencies components kf(0),(k+1)f(0),...(k+n)f(0) with k>1. The neuron's output is a sequence of pulses spaced at random interpulse intervals. We find an optimum input noise intensity for which the output pulses are spaced approximately 1/f(0), i.e., there is a stochastic resonance (SR) at a frequency missing in the input. Even higher noise intensities uncover additional, but weaker, resonances at frequencies present in the input. This is a different form of SR whereby the most robust resonance is the one enhancing a frequency, which is absent in the input, and which is not possible to recover via any linear processing. This can be important in understanding sensory systems including the neuronal mechanism for perception of complex tones.


Extra-Axial Cerebellopontine Angle Medulloblastoma in an Infant.
Medulloblastoma is a common tumor of the posterior fossa, representing 20-25% of all pediatric neoplasms. It commonly occurs in the midline (cerebellar vermis) and rarely at the cerebellopontine angle. Most of them are intra-axial, and an extra-axial location of this tumor is very rare. Extra-axial cerebellopontine angle medulloblastoma is extremely uncommon and has never been reported in an infant. We report an extra-axial cerebellopontine angle medulloblastoma in a 1-year-old child.


Dose-Dependent Suppression of Human Glioblastoma Xenograft Growth by Accelerator-Based Boron Neutron Capture Therapy with Simultaneous Use of Two Boron-Containing Compounds.
(1) Background: Developments in accelerator-based neutron sources moved boron neutron capture therapy (BNCT) to the next phase, where new neutron radiation parameters had to be studied for the treatment of cancers, including brain tumors. We aimed to further improve accelerator-BNCT efficacy by optimizing dosimetry control, beam parameters, and combinations of boronophenylalanine (BPA) and sodium borocaptate (BSH) administration in U87MG xenograft-bearing immunodeficient mice with two different tumor locations. (2) Methods: The study included two sets of experiments. In Experiment #1, BPA only and single or double irradiation in higher doses were used, while, in Experiment #2, BPA and BSH combinations and single or double irradiation with dosage adjustment were analyzed. Mice without treatment or irradiation after BPA or BPA+BSH injection were used as controls. (3) Results: Irradiation parameter adjustment and BPA and BSH combination led to 80-83% tumor-growth inhibition index scores, irradiation:BNCT ratios of 1:2, and increases in animal life expectancy from 9 to 107 days. (4) Conclusions: Adjustments in dosimetry control, calculation of irradiation doses, and combined use of two 10B compounds allowed for BNCT optimization that will be useful in the development of clinical-trial protocols for accelerator-based BNCT.


Mediastinal bronchogenic cyst: demonstration of a fluid-fluid level at MR imaging.
The appearance of mediastinal bronchogenic cysts at cross-sectional imaging is variable. Intracystic hemorrhage, proteinaceous fluid, or suspended calcium may belie the true cystic nature of the lesion at computed tomography or magnetic resonance (MR) imaging. The authors report a case of a fluid-fluid level seen on MR images of a bronchogenic cyst. This appearance, likely due to dependent layering of proteinaceous material, helped preoperatively confirm the true cystic nature of the lesion.


Histone H2A.z is essential for cardiac myocyte hypertrophy but opposed by silent information regulator 2alpha.
In this study we have shown that the histone variant H2A.z is up-regulated during cardiac hypertrophy. Upon its knock-down with RNA interference, hypertrophy and the underlying increase in growth-related genes, protein synthesis, and cell size were down-regulated. During attempts to understand the mode of regulation of H2A.z, we found that overexpression of silent information regulator 2alpha (Sir2alpha) specifically induced down-regulation of H2A.z via NAD-dependent activity. This effect was reversed by the proteasome inhibitor epoxomicin, suggesting a Sir2alpha-mediated ubiquitin/proteasome-dependent mechanism for degradation of H2A.z. An increase in Sir2alpha also resulted in a dose-dependent reduction of the response to hypertrophic stimuli, whereas its inhibition resulted in enhanced hypertrophy and apoptosis. We have shown that Sir2alpha directly deacetylates H2A.z. Mutagenesis proved that lysines 4, 7, 11, and 13 do not play a role in the stability of H2A.z, whereas Lys-15 was indispensable. Meanwhile, Lys-115 and conserved, ubiquitinatable Lys-121 are critical for Sir2alpha-mediated degradation. Fusion of the C terminus of H2A.z (amino acids 115-127) to H2A.x or green fluorescence protein conferred Sir2alpha-inducible degradation to the former protein only. Because H2A.x and H2A.z have conserved N-tails, this implied that both the C and N termini are critical for mediating the effect of Sir2alpha. In short, the results suggest that H2A.z is required for cardiac hypertrophy, where its stability and the extent of cell growth and apoptosis are moderated by Sir2alpha. We also propose that Sir2alpha is involved in deacetylation of H2A.z, which results in ubiquitination of Lys-115 and Lys-121 and its degradation via a ubiquitin/proteasome-dependent pathway.


Higher serum eosinophil cationic protein levels in children with cow's milk allergy.
In the pathogenesis of cow's milk allergy, abnormal immunologically mediated reactions play a basic role. Eosinophil activation also participates in the development of several allergies. The purpose of this study was to characterize the degree of this activation by measuring the serum level of eosinophil cationic protein (sECP) and establishing whether it is a useful parameter in monitoring oral cow's milk allergy. The sECP level of 35 patients with previously confirmed cow's milk allergy (mean age, 16 months) was evaluated using a fluoroimmunoassay before the cow's milk rechallenge test and at 2 hours and 24 hours after cow's milk challenge. Of the 35 children with previously confirmed cow's milk allergy, 10 had positive clinical reactions after the milk rechallenge test, whereas 25 children had no reaction. The median sECP level of all the patients before the challenge test was significantly higher (12.4 microg/L) than that of the control group (4.3 microg/L) (P < 0.05). Two hours after the challenge, the median sECP of all patients (9.4 microg/L) was lower than the starting values. The median sECP levels were higher in children with positive challenge test results at all time points. However, this difference was not statistically significant. The normalization of sECP level may indicate the cessation of the cow's milk allergy. Therefore, the measurement of sECP may be helpful in determining the optimal time in which to repeat the challenge test, when the result will more likely be negative. The significant decrease of the sECP level 2 hours after the beginning of milk challenge test may be explained by the fact that this protein is excreted into the intestinal lumen.


1,2-Bis[(pyridin-2-ylmethyl)sulfanyl]ethane and its dimorphic hydrochloride salt.
Although having been described as a liquid in the literature for 41 years, 1,2-bis[(pyridin-2-ylmethyl)sulfanyl]ethane, C(14)H(16)N(2)S(2), (I), has now been obtained as monoclinic crystals via a new and convenient method of purification. Molecules of (I) are located on crystallographic inversion centres and are held together by C-H···N and C-H···S interactions, resulting in the formation of a three-dimensional network structure. In addition, two polymorphs of the corresponding hydrochloride salt, 2-[({2-[(pyridin-1-ium-2-ylmethyl)sulfanyl]ethyl}sulfanyl)methyl]pyridin-1-ium dichloride, C(14)H(18)N(2)S(2)(2+)·2Cl(-), (II) and (III), have been isolated. Molecules of (II) and (III) have similar conformations and are located on inversion centres. Both polymorphs form three-dimensional networks through N-H···Cl, C-H···Cl and C-H···S interactions. The structure of (III) displays voids of 35 Å(3).


[Analysis of the related risk factors of diabetic peripheral neuropathy].
To explore the risk factors of diabetic peripheral neuropathy (DPN) and the relationship between DPN and diabetic retinopathy (DR). The data of the in-patients with type 2 diabetes mellitus (T2 DM) were retrospectively studied. A total of 200 T2 DM patients were divided into DPN group (n = 136) and non-DPN group (n = 64) according to peripheral neuropathy. The basic clinical data and the incidence rate of DR were compared between two groups. Logistic regression analysis was used to study the risk factors of DPN. The course of disease, the level of BMI, glycosylated hemoglobin (HbA1c), 2 hour postprandial blood glucose (2 hPG), 2 hour glucose C peptide (2 hC-P) and the incidence rate of the DR were significantly different between two groups (P < 0.01). Logistic regression analysis showed that significant differences were observed in T2 DM complicated by DR (P = 0.023), the course of disease (P = 0.008), the level of HbA1c (P = 0.006), BMI (P = 0.000) and 2 hC-P (P = 0.065). Diabetic retinopathy, the course of disease, the level of BMI,HbA1c and 2 hC-P are the risk factors for type 2 diabetic peripheral neuropathy. Diabetic peripheral neuropathy is positive correlated with diabetic retinopathy.


Lipid peroxidation in the brain and liver of rats during acute stress and melatonin treatment.
We studied the effects of acute stress and exogenous melatonin in various doses on the intensity of lipid peroxidation in emotiogenic structures of the brain and liver of rats with different activity in the open field. Stress had no effect on the content of malonic dialdehyde in the hypothalamus, sensorimotor cortex, and liver of active and passive rats receiving physiological saline. The influence of melatonin on malonic dialdehyde content depended on the dose of this substance. The amount of malonic dialdehyde in brain structures (active and passive rats) and liver (active rats) increased after administration of exogenous melatonin in doses of 0.5 and 2 mg/kg, but decreased after treatment with the hormone in a dose of 1 mg/kg. Melatonin in various doses decreased malonic dialdehyde content in the liver of passive rats. The effects of melatonin are partly related to modulation of lipid peroxidation in central and peripheral tissues of the organism.


Rapid, one-step fabrication and loading of nanoscale 1,2-distearoyl-sn-glycero-3-phosphocholine liposomes in a simple, double flow-focusing microfluidic device.
Liposomes are currently well-established as biocompatible delivery vehicles for numerous compounds. However, conventional manufacturing tends to rely on time-consuming processes, costly equipment, unstable reaction parameters, and numerous pre- and post-processing steps. Herein, we demonstrate a microscope-slide-sized alternative: a double flow-focusing microfluidic geometry capable of sub-hour synthesis and controlled loading of tunable liposomes. Using phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine as the bilayer constituent, the effect of varying the dissolved lipid concentration and flow rate ratio on synthesized liposome diameters was investigated and the encapsulation of fluorescent hydrophobic drug model ergost-5,7,9(11),22-tetraen-3β-ol was performed to ascertain the potential of this device as a loading platform.


The 2020 elephant die-off in Botswana.
The cause of deaths of 350 elephants in 2020 in a relatively small unprotected area of northern Botswana is unknown, and may never be known. Media speculations about it ignore ecological realities. Worse, they make conjectures that can be detrimental to wildlife and sometimes discredit conservation incentives. A broader understanding of the ecological and conservation issues speaks to elephant management across the Kavango-Zambezi Transfrontier Conservation Area that extends across Botswana, Namibia, Angola, Zambia, and Zimbabwe. Our communication addresses these. Malicious poisoning and poaching are unlikely to have played a role. Other species were unaffected, and elephant carcases had their tusks intact. Restriction of freshwater supplies that force elephants to use pans as a water source possibly polluted by blue-green algae blooms is a possible cause, but as yet not supported by evidence. No other species were involved. A contagious disease is the more probable one. Fences and a deep channel of water confine these elephants' dispersal. These factors explain the elephants' relatively high population growth rate despite a spell of increased poaching during 2014-2018. While the deaths represent only ~2% of the area's elephants, the additive effects of poaching and stress induced by people protecting their crops cause alarm. Confinement and relatively high densities probably explain why the die-off occurred only here. It suggests a re-alignment or removal of fences that restrict elephant movements and limits year-round access to freshwater.


Population--a key component of planning education for developing countries.
During the next 20 years, much of the developing world will undergo significant demographic changes, such as population growth and urbanization. The effects of these changes can already be seen in many areas of Latin America, East Asia, and especially Africa. This article suggests how to redesign population studies to provide planners with a framework for understanding the complex interrelationships between demographic factors and development. The commentary which follows provides an example of how the author and her colleagues are implementing such a program at the Department of City and Regional Planning at the University of North Carolina at Chapel Hill.


Development of the human cochlea.
This paper summarizes the most recent findings dealing with the anatomical development of the human cochlea, and especially with ultrastructural data from both scanning and transmission electron microscopic studies. It also briefly reviews physiological findings and attempts to specify the timing of the main developmental events, i.e. the onset of function, the acquisition of adult properties, and the sensitive periods.


Developmental activation of the capability to undergo checkpoint-induced apoptosis in the early zebrafish embryo.
In this study, we demonstrate the developmental activation, in the zebrafish embryo, of a surveillance mechanism which triggers apoptosis to remove damaged cells. We determine the time course of activation of this mechanism by exposing embryos to camptothecin, an agent which specifically inhibits topoisomerase I within the DNA replication complex and which, as a consequence of this inhibition, also produces strand breaks in the genomic DNA. In response to an early (pre-gastrula) treatment with camptothecin, apoptosis is induced at a time corresponding approximately to mid-gastrula stage in controls. This apoptotic response to a block of DNA replication can also be induced by early (pre-MBT) treatment with the DNA synthesis inhibitors hydroxyurea and aphidicolin. After camptothecin treatment, a high proportion of cells in two of the embryo's three mitotic domains (the enveloping and deep cell layers), but not in the remaining domain (the yolk syncytial layer), undergoes apoptosis in a cell-autonomous fashion. The first step in this response is an arrest of the proliferation of all deep- and enveloping-layer cells. These cells continue to increase in nuclear volume and to synthesize DNA. Eventually they become apoptotic, by a stereotypic pathway which involves cell membrane blebbing, "margination" and fragmentation of nuclei, and cleavage of the genomic DNA to produce a nucleosomal ladder. Fragmentation of nuclei can be blocked by the caspase-1,4,5 inhibitor Ac-YVAD-CHO, but not by the caspase-2,3,7[, 1] inhibitor Ac-DEVD-CHO. This suggests a functional requirement for caspase-4 or caspase-5 in the apoptotic response to camptothecin. Recently, Xenopus has been shown to display a developmental activation of the capability for stress- or damaged-induced apoptosis at early gastrula stage. En masse, our experiments suggest that the apoptotic responses in zebrafish and Xenopus are fundamentally similar. Thus, as for mammals, embryos of the lower vertebrates exhibit the activation of surveillance mechanisms, early in development, to produce the selective apoptosis of damaged cells.


Development of an HTS-Compatible Assay for Discovery of Melanoma-Related Microphthalmia Transcription Factor Disruptors Using AlphaScreen Technology.
Microphthalmia transcription factor (MITF) is a master transcription factor expressed in melanocytes, essential for melanocyte survival, differentiation, and pigment formation, and is a key oncogenic factor in melanoma initiation, migration, and treatment resistance. Although identified as an important therapeutic target for melanoma, clinical inhibitors directly targeting the MITF protein are not available. Based on the functional state of MITF, we have designed an MITF dimerization-based AlphaScreen (MIDAS) assay that sensitively and specifically mirrors the dimerization of MITF in vitro. This assay is further exploited for identification of the MITF dimer disruptor for high-throughput screening. A pilot screen against a library of 1280 pharmacologically active compounds indicates that the MIDAS assay performance exhibits exceptional results with a Z' factor of 0.81 and a signal-to-background (S/B) ratio of 3.92 while identifying initial hit compounds that yield an ability to disrupt MITF-DNA interaction. The results presented demonstrate that the MIDAS assay is ready to screen large chemical libraries in order to discover novel modulators of MITF for potential melanoma treatment.


Quality of life among children with sickle cell disease receiving chronic transfusion therapy.
Sickle cell disease (SCD) is a genetic disorder that is most prevalent among those of African American and Mediterranean descent. Hemoglobin SS is the most severe form of SCD and carries an increased risk for stroke. Although the initial treatment for stroke is an exchange transfusion, the use of routine, chronic transfusion therapy (CTT) has been shown to help prevent this neurological injury. The treatment plan is rigorous and time consuming, both of which impact one's quality of life (QoL). The purpose of this study was to explore QoL, from the child's perspective, as it is affected by CTT Semistructured interviews were performed on 10 children undergoing CIT: Five themes emerged from the data: (a) pain, (b) school issues, (c) disease knowledge, (d) transfusion therapy, and (e) having a stroke. Data from this study reveal that CTT does have an impact on QoL. This information is important to share with those making CTT treatment decisions.


Polymorphic variations in peripherin-RDS gene in the Spanish population.
The authors report a study of polymorphisms in the peripherin-RDS gene in 21 Spanish families affected with Autosomal Dominant Retinitis Pigmentosa and 56 unrelated normal individuals. We found 3 variants in first exon and nine variants in the third exon in an SSCP analysis, all corresponding to different previously described polymorphisms.


Prevalence and characteristics of cutaneous allodynia in probable migraine.
Cutaneous allodynia (CA) is a pain in response to non-nociceptive stimulation and a marker of central sensitisation. Probable migraine (PM) is a migraine subtype that fulfils all but one criterion of migraine. Headache intensity and the disability of individuals with PM are similar or lower than individuals with migraine. This study compared CA prevalence and characteristics of PM and migraine using a nationally representative sample in Korea. The Allodynia Symptom Checklist-12 (ASC-12) was used to assess CA (ASC-12 score ≥ 3). PM and migraine prevalence were 11.6% and 5.0%, respectively. CA prevalence did not significantly differ between PM and migraine (14.5% vs. 16.0%, p = 0.701). Participants with PM with CA reported a higher monthly headache frequency (3.3 ± 4.3 vs. 1.8 ± 3.6, p = 0.044), more severe headache intensity (Visuals Analogue Scale, 6.0 [4.0-7.0] vs. 5.0 [3.0-6.0], p = 0.002), and higher impact of headache (Headache Impact Test-6, 56.3 ± 7.2 vs. 48.3 ± 8.0, p < 0.001) than those without CA. Multiple regression analyses revealed that headache frequency and intensity, anxiety, and depression were significant factors for CA in participants with PM. In conclusion, CA prevalence among participants with PM and migraine were comparable. Anxiety, depression, and headache frequency and intensity were significant factors for CA in participants with PM.


Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations.
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif-/- and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.


[Acetabulum surgery. Development, current status and prospects].
The indication for operative treatment of displaced acetabular fractures is widely accepted. The radiologic diagnostics consist of the a.p. pelvic view and the oblique ala and obturator views. With the X-rays and the additional CT images the fracture is classified according to Letournel or to the AO Classification into an A, B or C-type fracture. The appropriate surgical approach is chosen depending on the classification and the site of the main dislocation. Extended or combined approaches are only indicated for complex or older fracture patterns. Osteosynthesis is performed either with small fragment cortical screws in lag screw technique or with reconstruction plates. In about 80% of the cases an anatomical reduction of the joint is possible as prerequisite for good functional results. First clinical trials with computer- and/or CT-assisted procedures are promising. In future computer- and robotics-based procedures will gain increased importance with reduced patient morbidity and improved reconstruction of the joint surface.


Development of temporal and distance parameters of gait in normal children.
Temporal and distance parameters of 33 normal children were obtained from instrumented gait analysis prospectively over five consecutive years. The parameters were normalised to minimise the confounding effects of increasing height and leg length. Rank correlations were performed on normalised speed, normalised stride length, normalised cadence and normalised walk ratio across consecutive pairs of years to examine the ranking of these parameters for an individual child over time. Consistent trends of increasing rank correlation were observed in normalised stride length and normalised walk ratio suggesting that individual children were continuing to adjust these gait parameters towards their own characteristic position within the normal range. Consistent trends were not observed in the rank correlations for normalised speed and normalised cadence. These findings support the concept that individual children predominantly adjusted their cadence to effect changes in speed, while the development of stride length was dictated by other factors specific to the individual child. Rank correlation coefficients for walk ratio between consecutive years increased from the ages of 7-11 years of age and hence walk ratio appears be a feature of gait that matures beyond the age of 7 years. This accords with the proposal that it is an invariant parameter for an individual.


Antioxidant oligomeric proanthocyanidins from sea buckthorn (Hippophae rhamnoides) Pomace.
After flavonol glycosides, monomeric flavan-3-ols, and dimeric and trimeric proanthocyanidins were fractionated from an extract of sea buckthorn (Hippophae rhamnoides) pomace by Sephadex LH-20 gel chromatography, oligomeric proanthocyanidins were eluted. The oligomeric fraction accounted for 84% of the total proanthocyanidins and 75% of the total antioxidant activity of the sea buckthorn pomace extract. To elucidate the structure of the oligomeric fraction, it was depolymerized by acid catalysis in the presence of phloroglucinol. The structure of the resulting flavan-3-ol monomers and flavan-3-ol-phloroglucinol adducts was determined by electrospray ionization mass spectrometry (ESI-MS) and (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy. Quantitative high-performance liquid chromatography investigations demonstrated (+)-gallocatechin as the predominating subunit in the oligomeric fraction. This observation was confirmed by ESI-MS, matrix-assisted laser desorption/ionization mass spectrometry, and (13)C NMR spectroscopy. The results showed that the majority of the flavan-3-ol subunits possessed a 2,3-trans configuration. The oligomers consisted mainly of prodelphinidin subunits whereas procyanidins were present in smaller amounts, indicating a very uncommon composition of the sea buckthorn proanthocyanidins. The mean degree of polymerization of the oligomeric proanthocyanidins was between 6 and 9.


Ductus arteriosus blood flow during first 48 hours of life.
A volumetric Doppler technique was used to measure net ductus arteriosus shunt during the first 48 hours of life in 30 infants of less than 33 weeks' gestation, and in 10 full term infants. In the full term infants a left to right shunt of 62 ml/kg/minute (95% confidence limits 43-82) shortly after birth decreased rapidly over the first 12 hours and was not measurable by 48 hours. The preterm infants had smaller left to right shunts shortly after birth--49 ml/kg/minute (95% confidence limits 38-59). There was no obvious subsequent change in the mean shunt, although by 48 hours there was greater variation in the size of the shunt. The respiratory distress syndrome did not affect the size of the ductal shunt, but the shorter the gestation period the larger the shunt by 48 hours. A ductal flow of greater than 70 ml/kg/minute at 48 hours of age predicted the subsequent development of a ductal murmur with 75% sensitivity and 100% specificity.


Coverage of dorsal-ulnar hand wounds with a reverse second dorsal metacarpal artery flap.
This article introduces the use of a modified reverse dorsal hand flap harvested from the radial portion of the dorsal hand and wrist and the distal portion of the dorsal forearm for reconstruction of a large defect involving the third to fifth metacarpophalangeal (MCP) joints and the proximal phalanges. From May 2005 to August 2008, a modified reverse dorsal hand flap was transferred in 12 hands in 12 patients (9 male and 3 female). The mean age at flap transfer was 34.2 years (range: 23 to 50 years) old. All flaps survived. At final follow-up (mean, 28 months; range: 25 to 32 months), the mean active range of motion arcs of the third, fourth, and fifth MCP joints were 85 degrees (range: 65 to 97 degrees), 84 degrees (range: 60 to 90 degrees), and 83 degrees (range: 58 to 94 degrees), respectively. Our technique is useful and reliable for coverage of a large defect involving the third to fifth MCP joints and the proximal phalanges.


[Effectiveness of health education interventions targeting taeniasis and cysticercosis among primary school students in disease-elimination pilot areas of Henan Province].
To compare the changes of knowledge, attitude and practice (KAP) related to taeniasis and cysticercosis among primary school students before and after health education interventions in disease-elimination pilot areas of Henan Province, so as to evaluate the effectiveness of health education interventions. A primary school was selected from each of Dushu, Bowang and Yangji townships, Fangcheng County, Henan Province from 2017 to 2019; then, 2 to 3 classes were randomly selected from grade 4 to 6 in each primary school, and finally, all students in these classes were enrolled as study subjects. A thematic health education lecture pertaining to taeniasis and cysticercosis was given once each year by means of "health education in class". The KAP towards taeniasis and cysticercosis was investigated among primary school students using selffilled structured questionnaires, and the changes of awareness of taeniasis and cysticercosis control knowledge and percentage of healthy behaviors formation were compared in primary school students among years and following various frequencies of health education interventions. More than 10 thousand person-time primary school students received health education interventions during the period from 2017 to 2019, and a total of 1 223 person-time primary school students were investigated during the 3-year study period, including 633 person-time men and 590 person-time women and 88.55% of primary school students at ages of 10 to 12 years. The proportion of households raising pigs and using dry toiliets decreased from 5.30% (24/453) and 18.10% (82/453) in 2017 to 3.60% (13/361) and 11.08% (40/361) in 2019, respectively. The awareness rate of taeniasis and cysticercosis control knowledge increased significantly from 0.22% (1/453) in 2017 to 62.59% (256/409) in 2018 and 76.73% (277/361) in 2019 (χ2 = 567.60, P < 0.001), and the awareness rate was 85.25% (104/122) among primary school students attending the thematic special health education courses for successive three times. The awareness rates of taeniasis and cysticercosis control knowledge were 0.44% (1/225), 58.00% (116/200) and 71.63% (149/208) among male students and 0 (0/338), 66.99% (140/209) and 83.66% (128/153) among female students from 2017 to 2019, and there was a significant difference in the awareness of taeniasis and cysticercosis control knowledge between male and female students in 2019 (χ2 = 7.14, P = 0.01). On-site teaching by doctors was the students' favorite way to receive health education interventions (70.07%, 857/1 223), followed by watching health education videos (58.63%, 717/1 223) and seeing parasite specimens (48.9%, 598/1 223). The proportion of students' families who used cutting boards for raw and cooked food separately increased from 7.28% (33/453) in 2017 to 47.37% (171/361) in 2019, was 67.21% (82/122) among students attending the health education courses for successive three times. The proportion of students who frequently washed their hands before meals and after using toilet increased from 71.96% (324/453) in 2017 to 89.47% (319/361) in 2019 and was 95.90% (117/122) among students attending the health education courses for successive three times. In addition, the percentage of students washing hands frequently in families using dry toilets was significantly lower in those who did not use dry toilets (χ2 = 9.21, P = 0.002), and the proportion of students with a habit of eating raw or undercooked meat decreased significantly from 35.76% (162/453) in 2017 to 6.65% (24/361) in 2019 (χ2 = 69.11, P < 0.01). The thematic health education activity of "health education in class" contributes greatly to the increase in the awareness of taeniasis and cysticercosis control knowledge and the rate of healthy behaviors formation among primary school students in diseaseelimination pilot areas of Henan Province.


[Expression of CXCR7 in Acute Monocytic Leukemia and Its Effects on THP-1 Cell Functions].
To study the expression of stromal cell derived factor-1α (SDF-1α) receptor CXCR7 in acute monocytic leukemia (AML-M5), and its effects on proliferation, apoptosis, invasion of acute monocytic leukemia cell line THP-1. CXCR7 protein and mRNA expression levels in THP-1 cells and peripheral blood mononuclear cells (PBMNC) from the newly diagnosed AML-M5 patients and normal individuals were detected by flow cytometry, Western blot and RT-PCR respectively. CCK8, Annexin V/PI double staining and Transwell assay were used to observe the effects of CXCR7 on the proliferation, apoptosis, and invasion of THP-1 cells in vitro. The expression of CXCR7 on immature cell surface of the newly diagnosed AML-M5 patients was significantly higher than that in the control group (P<0.05). CXCR7 was also highly expressed on THP-1 cells surface. The CXCR7 protein and mRNA levels in THP-1 cells and PBMNC of AML-M5 patients were significantly higher than those in the control group (P<0.05). The THP-1 cell proliferation activity was higher in SDF-1α-treated group, but this activity could be inhibited by CXCR7 antibody (P<0.01). CXCR7 antibody did not affect THP-1 cell apoptosis (P>0.05). CXCR7 antibody could inhibit SDF-1α -induced THP-1 cell invasiveness (P<0.01). CXCR7 highly expresses in AML-M5 patients and THP-1 cells, and involves in cell proliferation and invasion. The blocking CXCR7 expression can reduce the risk of AML-M5 cell infiltration.


Multiscale Modeling of Bio-Nano Interactions of Zero-Valent Silver Nanoparticles.
Understanding the specifics of interaction between the protein and nanomaterial is crucial for designing efficient, safe, and selective nanoplatforms, such as biosensor or nanocarrier systems. Routing experimental screening for the most suitable complementary pair of biomolecule and nanomaterial used in such nanoplatforms might be a resource-intensive task. While a range of computational tools are available for prescreening libraries of proteins for their interactions with small molecular ligands, choices for high-throughput screening of protein libraries for binding affinities to new and existing nanomaterials are very limited. In the current work, we present the results of the systematic computational study of interaction of various biomolecules with pristine zero-valent noble metal nanoparticles, namely, AgNPs, by using the UnitedAtom multiscale approach. A set of blood plasma and dietary proteins for which the interaction with AgNPs was described experimentally were examined computationally to evaluate the performance of the UnitedAtom method. A set of interfacial descriptors (log PNM, adsorption affinities, and adsorption affinity ranking), which can characterize the relative hydrophobicity/hydrophilicity/lipophilicity of the nanosized silver and its ability to form bio(eco)corona, was evaluated for future use in nano-QSAR/QSPR studies.


Challenging the Hegemony of the Symptom: Reclaiming Context in PTSD and Moral Injury.
Although post-traumatic stress disorder (PTSD) is now constituted by a set of characteristic symptoms, its roots lie in Post-Vietnam Syndrome, a label generated by a Vietnam-era advocacy movement that focused not on symptoms but on war's traumatic context. When Post-Vietnam Syndrome was subsumed into the abstract, individualistic, symptom-centered language of DSM-III and rendered as PTSD, it not only lost this focus on context but also neglected the experiences of veterans who suffer from things done or witnessed, not primarily from what was done to them, in war. This agent-related trauma has been rediscovered in contemporary work on moral injury, but moral injury too is increasingly subjected to the hegemony of the symptom. Focusing on symptoms, however, unhelpfully pathologizes and individualizes trauma, neglects traumatic context, and legitimates problematic therapeutic approaches. Trauma researchers and clinicians should decenter the language of symptoms and focus instead on context and on alternative accounts of trauma.


Expression of a murine gonadotropin-releasing hormone receptor-luciferase fusion gene in transgenic mice is diminished by immunoneutralization of gonadotropin-releasing hormone.
A line of transgenic mice harboring a fusion gene consisting of 1900 bp of proximal 5'-flanking region from the murine GnRH receptor gene linked to the complementary DNA encoding luciferase was established to determine whether this promoter can direct tissue-specific expression in vivo and serve as a model for identifying the molecular mechanisms underlying hormonal regulation of this gene. Of 10 tissues screened, luciferase was detected predominantly in pituitary gland, but also in brain and testis. To assess hormonal regulation, luciferase activity was measured in intact males and ovariectomized females treated with an anti-GnRH serum alone, and in combination with testosterone or 17beta-estradiol. No effect of steroid treatment on transgene expression was detected. However, immunoneutralization of GnRH resulted in decreased serum LH concentrations and suppressed pituitary expression of luciferase. Furthermore, the effects of GnRH antiserum could be prevented by the administration of a noncross-reactive GnRH agonist. Thus, 1900 bp of 5'-flanking DNA from the murine GnRH receptor gene are sufficient to target luciferase expression in transgenic mice to established sites of GnRH receptor gene expression. Furthermore, we suggest that GnRH regulation of GnRH receptor gene expression is mediated by regulatory elements residing within 1900 bp of the 5'-flanking region.


Modifying the diffusion layer of soluble salts of poorly soluble basic drugs to improve dissolution performance.
The dissolution mechanism of soluble salts of poorly soluble bases can be complex because both the dissolution of the salt and precipitation of the free base can occur depending on the experimental conditions and properties of the molecule. The dissolution of three soluble salts of poorly soluble bases is described in this paper. Two of these compounds precipitate as free base under normal stomach pH conditions (pH from 2-4) during dissolution. This free base precipitation is a result of formation of free base on the surface of the dissolving salt. Diffusion Layer modulated (DLM) solids are defined and presented that can effectively counteract this precipitation mechanism. These DLM materials employ excipients in order to modify the pH or solubility conditions at the surface of the dissolving salt to minimize precipitation of the free base that can occur. Rotating disk dissolution data is presented which shows how these formulated solids can act to improve the dissolution profile for these materials.


Quantitative determination of ragaglitazar in rat plasma by HPLC: validation and application in pharmacokinetic study.
A specific, accurate, precise and reproducible high-performance liquid chromatography (HPLC) method was developed for the estimation of ragaglitazar [(-) DRF 2725, NNC 61-0029], a novel anti-diabetic agent, in rat plasma. The assay procedure involved simple liquid/liquid extraction of ragaglitazar and internal standard (IS, troglitazone) from plasma into ethyl acetate. The organic layer was separated and evaporated under a gentle stream of nitrogen at 40 degrees C. The residue was reconstituted in the mobile phase and injected onto a Kromasil KR 100 - 5C(18) column (4.6 x 250 mm, 5 micro m). Mobile phase consisting of 0.01 M potassium dihydorgen ortho phosphate (pH 3.2) and acetonitrile (30:70, v/v) was used at a flow rate of 1.0 mL/min. The eluate was monitored using an UV detector set at 240 nm. Ratio of peak area of analyte to IS was used for quantification of plasma samples. Nominal retention times of IS and ragaglitazar were 6.9 and 12.2 min, respectively. The standard curve for ragaglitazar was linear (r(2) > 0.999) in the concentration range 0.2-100 micro g/mL. Absolute recovery was >87% from rat plasma for both analyte and IS. The lower limit of quantification (LLOQ) of ragaglitazar was 0.2 micro g/mL. The inter- and intra-day precision in the measurement of quality control (QC) samples, 0.2, 1.0, 5.0 and 50 micro g/mL, were in the range 1.32-3.70% relative standard deviation (RSD) and 1.19-9.39% RSD, respectively. Accuracy in the measurement of QC samples was in the range 94.28-107.45%. Analyte and IS were stable in the battery of stability studies, viz. benchtop, autosampler and freeze/thaw cycles. Stability of ragaglitazar was established for 1 month at -20 degrees C. The application of the assay to a pharmacokinetic study in rats is described.


Structural diversity of calcium binding sites.
Calcium Binding Proteins (CBPs) play a major role in many biological processes. The three dimensional (3D) structure of several CBPs has been resolved by means of X-ray crystallography and nuclear magnetic resonance. We consulted several databases to compile a collection of CBPs of known 3D structure. The analysis of these data shows, the CBP structures are distributed over many different functional families and fold types. The binding site itself is less frequently formed by a continuous sequence segment. In the majority of the cases Ca(2+) ion coordination is spread over different secondary structure elements with considerable distance on the amino acid sequence. The sidechain of amino acids Asp and Glu are the major interaction partner for the ion. Less frequently it is the side chain of Asn, Gln, Ser and Thr. Often main chain oxygen contributes to the Ca(2+) coordination. In addition, water molecules are frequently involved.


Placebos that harm: sham surgery controls in clinical trials.
Recent debates over the use of sham surgery as a control for studies of fetal tissue transplantation for Parkinson's disease have focused primarily on rival interpretations of the US federal regulations governing human-subjects research. Using the core ethical and methodological considerations that underwrite the equipoise requirement, we find strong prima facie reasons against using sham surgery as a control in studies of cellular-based therapies for Parkinson's disease and more broadly in clinical research. Additionally, we believe that these reasons can be generalized to apply to the use of other placebo controls that carry significant risks of positive harms in and of themselves. As a result, our arguments are centrally relevant to the emerging drive to subject therapies with a surgical component to the same rigorous standards of evaluation as those governing the approval of new pharmaceuticals.


Assessment of hyperacute rejection in a rat-to-primate cardiac xenograft model.
We studied a rat-to-cynomolgous monkey model for xenotransplantation of vascularized organs and found that a rat heart was rejected in 5.5 +/- 1.4 min (n = 10). This hyperacute rejection (HAR) was consistent with kinetic experiments in vitro that showed damage to rat endothelial cells (ECs) after 3 min of incubation with primate serum. Histopathology and ultrastructural analysis of rejected hearts showed marked EC damage and early adherence of platelets and polymorphonuclear leukocytes to the endothelium. Immunohistochemical analysis revealed deposition along endothelial surfaces of IgG, IgM, and complement (C) components of the classical but not the alternative pathway, suggesting that, as in the pig-to-primate model, HAR is mediated by the binding of recipient xenogeneic natural antibodies and C activation. The effect of C depletion on xenograft survival was evaluated in two recipients that were treated with cobra venom factor (CVF). CVF caused complete C inactivation, demonstrated by lack of serum hemolytic activity and C-dependent EC cytotoxicity at engraftment and until the animals died. The rat cardiac transplants survived for at least 9 hr and 77 hr. Histology showed massive interstitial hemorrhage, edema, and cellular infiltration with scanty fibrin deposits. These results in CVF-treated recipient monkeys indicate that C activation mediates the development of HAR in this rat-to-primate model. We suggest that the model may be of interest as an alternative to the more expensive and time-consuming pig-to-primate model for testing the efficacy of transgenic modification of donor organs to prolong xenograft survival and for studying mechanisms of discordant xenograft rejection.


Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases.
The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.


HLA class II induction by interferon-gamma in K562 variant cell line: inhibition by serum lipid.
The induction of class II antigen (Ag) by interferon-gamma (IFN-gamma) in variants of the K562 cell line has been examined in this study. Following incubation of K562A cells with IFN-gamma, surface expression of HLA-DR molecules was demonstrated by indirect immunofluorescence, confirmed by immunoblotting, and HLA-DR3 Ag specificity identified. HLA-DP and HLA-DRW52 Ag were co-expressed, but no HLA-DQ expression occurred. A variant of this line, designated K1A, spontaneously developed resistance to IFN-gamma induction of class II Ag, but continued to express class I Ag. In a third K562 variant, designated K562B, no class II gene products could be induced. Northern blot analysis indicated that mRNA levels correlated with surface class I and II Ag expression in all of the K562 cell lines. Resistance to IFN-gamma inducible class II Ag expression in K1A cells did not involve changes in IFN-gamma receptor affinity or number but was shown to be due to an inhibitory effect of serum lipid. These results indicate that cells derived from a common parental line may differ in susceptibility to a regulatory mechanism affecting IFN-gamma inducible class II Ag expression.


Mechanism of Nanoformulated Graphene Oxide-Mediated Human Neutrophil Activation.
Understanding the molecular mechanisms of graphene oxide (GO)-based biomaterials is important for logical biomedical applications. Previous studies have revealed biointeractions between GO and immune effector cells, but the effects on neutrophils, crucial cells in the immune system, have not been thoroughly discussed. In this study, GO nanoformulations were synthesized with different functional groups, including GO, GO-carboxylated (GO-COOH), and PEGylated GO (GO-PEG), with different surface features, which were elucidated using imaging methods and surface-sensitive quantitative spectroscopic techniques, including atomic force microscopy (AFM), transmission electron microscopy (TEM), and X-ray photoemission spectroscopy (XPS). The GO-based nanoformulations elicited reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation in human neutrophils. Nanoformulated GO stimulates NET development via the formation of ROS. An endocytosis study revealed that nanoformulated GO facilitated internalization by neutrophils via macropinocytosis and actin-dependent phagocytosis. Importantly, calcium mobilization and phosphorylation proteins such as mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38) and AKT were involved in the activation of neutrophils. These findings offer the first verification that nanoformulated GO exhibits direct effects on human neutrophils.


Complete Genome Sequence of Stenotrophomonas maltophilia Siphophage Summit.
Stenotrophomonas maltophilia is an opportunistic pathogen exhibiting resistance to multiple antimicrobials. This study reports the complete genome of an S. maltophilia siphophage, Summit. Its genome of 95,728 bp has 148 protein-coding genes and 5 tRNAs, including 1 predicted suppressor tRNA. Possible target genes for the suppressor tRNA are not identified.


Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents.
The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI.


[Phase II trial as 2nd line chemotherapy with 5 fluorouracil and cisplatin (5FU-CDDP) for advanced breast cancer].
Thirty patients with advanced breast cancer, previously treated with anthracycline and 5 fluorouracil in bolus administration, were evaluated with a chemotherapy regimen generally used in head and neck cancer. Treatment schedule consisted of: cisplatin 100 mg/m2 on d 1 and 5 fluorouracil 1000 mg/m2 continuous infusion on d 2-3-4-5 every 21 d. With all measurable lesions and 27 evaluable patients, the response rate was 29% (95% confidence interval: 12-47%), with 5 complete responses (3 soft tissue - 2 lung) and 3 partial responses (1 lung - 2 liver). The median duration of response is 4.5 months (range 2-11 months). The 30 patients (93 courses) are evaluable for toxicity. Hematologic toxicity was mild: anemia 68% grade 0, neutropenia 68% grade 0 and thrombocytopenia 83% grade 0. Nausea and vomiting were severe 83% grade 3 + 4 at d 1. Others side effects were mild including 5/91 mucositis grade 2 + 3, peripheral neuropathy 1/31 grade 2 and 2/91 reversible rise in serum creatinine greater than 1.5 mg/dl.


ZEB1 promotes colorectal cancer cell invasion and disease progression by enhanced LOXL2 transcription.
Disease progression after curative surgery is still the main challenge for colorectal cancer (CRC). Identifying biomarkers and precise mechanisms in CRC disease progression is necessary for therapeutic improvement. As a transcription factor, ZEB1 promotes malignancy, but the precise mechanism by which ZEB1-dependent transcriptional regulation remains largely undefined. In this study, the transcriptional regulation of lysyl oxidase-like 2 (LOXL2) by ZEB1 in CRC was investigated. Our data show that ZEB1 enhanced LOXL2 transcription through direct binding to its promoter. The gain of function assays of ZEB1 showed increased cell proliferation, migration, and invasion. The inhibition of LOXL2 impaired the invasion and migratory ability of CRC cells, but had no effect on cell proliferation in vitro and in vivo. Immunohistochemical staining of tumor tissues indicated that elevated ZEB1/LOXL2 expression was significantly associated with lymph node metastasis and TNM stage. More importantly, elevated ZEB1/LOXL2 expression was an independent prognostic factor in CRC patients. These findings provide a molecular basis for the promotion of an invasive cancer phenotype by ZEB1-LOXL2 overexpression. Our results identify ZEB1/LOXL2 as a prognostic biomarker and potential therapeutic target against progression of CRC.


Macrophage activity in organ cultures of the avian cochlea: demonstration of a resident population and recruitment to sites of hair cell lesions.
The factors that regulate the repair and regeneration of the sensory hair cells of the inner ear are not understood. Previous studies of hair cell injury in the lateral line sensory organs of amphibians and the cochleae of mammals have demonstrated that macrophages and other leukocytes are recruited to sites of hair cell lesions. The present study examined the distribution and activity of macrophages in organ cultures of the avian cochlea, a system whose regenerative abilities have been widely studied. Cochleae were removed from chicks and placed in organ culture, and precise hair cell lesions were created using a laser microbeam. Macrophages in the cultures were identified using histochemical, immunocytochemical, and morphologic criteria. It was found that (a) cultured cochleae contained a resident population of macrophages, and (b) increased numbers of macrophages were recruited to the sites of hair cell lesions. Furthermore, the latency of macrophage recruitment to lesions is consistent with a suggested role for macrophages in the initiation of hair cell regeneration.


Local synaptic signaling enhances the stochastic transport of motor-driven cargo in neurons.
The tug-of-war model of motor-driven cargo transport is formulated as an intermittent trapping process. An immobile trap, representing the cellular machinery that sequesters a motor-driven cargo for eventual use, is located somewhere within a microtubule track. A particle representing a motor-driven cargo that moves randomly with a forward bias is introduced at the beginning of the track. The particle switches randomly between a fast moving phase and a slow moving phase. When in the slow moving phase, the particle can be captured by the trap. To account for the possibility that the particle avoids the trap, an absorbing boundary is placed at the end of the track. Two local signaling mechanisms--intended to improve the chances of capturing the target--are considered by allowing the trap to affect the tug-of-war parameters within a small region around itself. The first is based on a localized adenosine triphosphate (ATP) concentration gradient surrounding a synapse, and the second is based on a concentration of tau--a microtubule-associated protein involved in Alzheimer's disease--coating the microtubule near the synapse. It is shown that both mechanisms can lead to dramatic improvements in the capture probability, with a minimal increase in the mean capture time. The analysis also shows that tau can cause a cargo to undergo random oscillations, which could explain some experimental observations.


LIFT: a feasible option for primary and recurrent fistulas.
The development of a surgical solution for anal fistulas with minimal recurrence and morbidity remains a challenge. Ligation of the intersphincteric fistula tract (LIFT), however, is a sphincter sparing technique that provides complete resolution of the transsphincteric fistula as well as minimizing recurrence and fecal incontinence. Our goal is to evaluate the efficacy of fistula tract ligation for primary and recurrent fistulas. A retrospective single-center case study was conducted from data between 2015 and 2019 in a large district hospital in Antwerp, Belgium. Patients who underwent LIFT were included. Demographic patient data as well as primary outcome during the follow-up period were collected. A systematic literature review and analysis was conducted with terms [ANAL FISTULA] [TREATMENT] [LIFT] [LIGATION OF INTERSPHINCTERIC FISTULA]. Primary healing and recurrence associated with surgical modifications were investigated. 4 out of 25 patients presented with early failure (84% primary success rate) after a median follow-up period of 7 months. The median time until recurrence was 105 days. The success rate after a redo ligation was 100%. Twenty-eight studies were included for review and divided into three groups depending on the technical variation of the used technique. The success rate was 74.2% for the LIFT group, 72.9% in the LIFT + group, and 77.5% in the mLIFT group p = .92. LIFT is a feasible treatment option for primary and recurrent fistulas, with excellent success rates where fistula characteristics rather than chosen technique dictate the surgical outcome.


Graves' disease in the Inuit population of Greenland. Presentation of five cases observed during a two month period.
Thyroid hormones are important for metabolic regulation. A number of studies have dealt with the effect of arctic living on thyroid hormone secretion and metabolism in healthy animals and humans. Little is however known of the effect of arctic living on the occurrence of thyroid diseases. In a study from Upernavik, Greenland no cases of hyperthyroidism were observed over the 25 years period from 1950 to 1974. We present five cases of hyperthyroidism due to Graves' disease observed during a two month period in Nuuk Greenland. The discrepancy could be due to improved diagnostic methods and activity or to a real increase in incidence. Systematic studies of thyroid disorders in Greenland are warranted.


Percutaneous Laser Photocoagulation of Osteoid Osteomas.
Osteoid osteoma is a painful benign bone tumor. The curative treatment of this tumor consists of complete surgical or percutaneous excision of the nidus with immediate and dramatic relief of symptoms. Interstitial laser photocoagulation (ILP) is a low-invasive percutaneous technique of thermal destruction (coagulation) of deep-seated tumors elsewhere in the body, using low-power laser energy. The aim of ILP is the local destruction of osteoid osteoma without bone weakening. Twenty-two patients with osteoid osteoma were treated with percutaneous ILP of the nidus under computed tomography guidance. The laser energy was provided by a high-power semiconductor diode laser (805 nm) with a 400-&mgr;m optical fiber. Complete pain relief was obtained in 21 patients. Percutaneous ILP of osteoid osteoma seems to be a promising, simple, precise, and minimally invasive technique as an alternative to traditional surgical and percutaneous ablations.


Oxidative stress in the hippocampus during experimental seizures can be ameliorated with the antioxidant ascorbic acid.
Ascorbic acid has many nonenzymatic actions and is a powerful water-soluble antioxidant. It protects low density lipoproteins from oxidation and reduces harmful oxidants in the central nervous system. Pilocarpine-induced seizures have been suggested to be mediated by increases in oxidative stress. Current studies have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures. The objective of the present study was to evaluate the neuroprotective effects of ascorbic acid (AA) in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), ascorbic acid (500 mg/kg, i.p., AA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of ascorbic acid (500 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of ascorbic acid (AA plus pilocarpine group). After the treatments all groups were observed for 6h. The enzyme activities as well as the lipid peroxidation and nitrite concentrations were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of ascorbic acid were also evaluated on the same parameters. In pilocarpine group there was a significant increase in lipid peroxidation and nitrite level. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the lipid peroxidation level and nitrite content as well as increased the superoxide dismutase and catalase activities in hippocampus of adult rats after seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, proving that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences, and also imply that a strong protective effect could be achieved using ascorbic acid.


Eating behaviours in youths: A comparison between female and male athletes and non-athletes.
This study compared the different factors associated with eating behaviors among young female and male athletes and non-athletes. A total of 580 female and male athletes and 362 female and male non-athletes between 10 and 19 years old participated. We used the subscales of the Eating Attitudes Test (EAT-26) to evaluate the factors associated with unhealthy eating behaviors. We found higher scores for females on the diet subscale compared with males, regardless of athletic group (P < 0.05). Non-athlete youths scored higher on this subscale compared with male athletes (P < 0.05). Our findings indicate higher scores for female athletes with regard to the bulimia and preoccupation with food subscale compared with other the groups (P < 0.05). Moreover, we observed that non-athlete males were more likely to engage in binge eating compared with athletes of the same sex (P < 0.05). Finally, females had higher scores on the oral self subscale than males, regardless of athletic group (P < 0.05). We concluded that the factors associated with eating behaviors differ with regard to sex and group.


Extraction of Knowledge from the Topographic Attentive Mapping Network and its Application in Skill Analysis of Table Tennis.
The Topographic Attentive Mapping (TAM) network is a biologically-inspired classifier that bears similarities to the human visual system. In case of wrong classification during training, an attentional top-down signal modulates synaptic weights in intermediate layers to reduce the difference between the desired output and the classifier's output. When used in a TAM network, the proposed pruning algorithm improves classification accuracy and allows extracting knowledge as represented by the network structure. In this paper, sport technique evaluation of motion analysis modelled by the TAM network was discussed. The trajectory pattern of forehand strokes of table tennis players was analyzed with nine sensor markers attached to the right upper arm of players. With the TAM network, input attributes and technique rules were extracted in order to classify the skill level of players of table tennis from the sensor data. In addition, differences between the elite player, middle level player and beginner were clarified; furthermore, we discussed how to improve skills specific to table tennis from the view of data analysis.