13-Benzyl-4,11-dihy-droxy-1,8-diphen-yl-2,9-di-thia-13-aza-dispiro-[220.127.116.11]tetra-decan-6-one.
In the title compound, C30H31NO3S2, the piperidine ring adopts a distorted chair conformation. The thio-phene rings have twisted conformations about the C-C bonds. The mean plane of the piperidine ring makes a near orthogonal conformation with the toluene ring. Two of the phenyl rings in the structure are positionally disordered over two sets of sites with occupancies of 0.56 (2)/0.44 (2) and 0.672 (16)/0.328 (16). A region of disordered electron density was corrected for using the SQUEEZE [Spek (2015 ▸). Acta Cryst. C71, 9-18] routine in PLATON. The given chemical formula and other crystal data do not take into account the unknown solvent mol-ecule. In the crystal, O-H⋯O hydrogen bonds are observed along with intra-molecular S⋯H, O⋯H, C⋯H and H⋯H contacts.


Supervised pattern recognition for the prediction of contrast-enhancement appearance in brain tumors from multivariate magnetic resonance imaging and spectroscopy.
The purpose of this study was to develop a pattern classification algorithm for use in predicting the location of new contrast-enhancement in brain tumor patients using data obtained via multivariate magnetic resonance (MR) imaging from a prior scan. We also explore the use of feature selection or weighting in improving the accuracy of the pattern classifier. Contrast-enhanced MR images, perfusion images, diffusion images, and proton spectroscopic imaging data were obtained from 26 patients with glioblastoma multiforme brain tumors, divided into a design set and an unseen test set for verification of results. A k-NN algorithm was implemented to classify unknown data based on a set of training data with ground truth derived from post-treatment contrast-enhanced images; the quality of the k-NN results was evaluated using a leave-one-out cross-validation method. A genetic algorithm was implemented to select optimal features and feature weights for the k-NN algorithm. The binary representation of the weights was varied from 1 to 4 bits. Each individual parameter was thresholded as a simple classification technique, and the results compared with the k-NN. The feature selection k-NN was able to achieve a sensitivity of 0.78+/-0.18 and specificity of 0.79+/-0.06 on the holdout test data using only 7 of the 38 original features. Similar results were obtained with non-binary weights, but using a larger number of features. Overfitting was also observed in the higher bit representations. The best single-variable classifier, based on a choline-to-NAA abnormality index computed from spectroscopic data, achieved a sensitivity of 0.79+/-0.20 and specificity of 0.71+/-0.11. The k-NN results had lower variation across patients than the single-variable classifiers. We have demonstrated that the optimized k-NN rule could be used for quantitative analysis of multivariate images, and be applied to a specific clinical research question. Selecting features was found to be useful in improving the accuracy of feature weighting algorithms and improving the comprehensibility of the results. We believe that in addition to lending insight into parameter relevance, such algorithms may be useful in aiding radiological interpretation of complex multimodality datasets.


Yellow phosphorus-induced Brugada phenocopy.
Metallic phosphides (of aluminum and phosphide) and yellow phosphorus are commonly used rodenticide compounds in developing countries. Toxicity of yellow phosphorus mostly pertains to the liver, kidney, heart, pancreas and the brain. Cardiotoxicity with associated Brugada ECG pattern has been reported only in poisoning with metallic phosphides. Brugada phenocopy and hepatic dysfunction were observed in a 29-year-old male following yellow phosphorus consumption. He had both type 1 (day1) and type 2 (day2) Brugada patterns in the electrocardiogram, which resolved spontaneously by the third day without hemodynamic compromise. Toxins such as aluminum and zinc phosphide have been reported to induce Brugada ECG patterns due to the generation of phosphine. We report the first case of yellow phosphorus-related Brugada phenocopy, without hemodynamic compromise or malignant arrhythmia.


Life expectancy and health expenditure evolution in Eastern Europe-DiD and DEA analysis.
Exploration of long-term health expenditure and longevity trends across three major sub-regions of Eastern Europe since 1989. 24 countries were classified as EU 2004, CIS, or SEE. European Health for All Database (HFA-DB) 1989-2012 data were processed using difference-in-difference (DiD) and data envelopment analysis (DEA). The strongest expenditure growth was recorded in EU 2004 followed by SEE and the CIS. A surprisingly similar longevity increase was present in SEE and EU 2004. In 1989, countries that joined EU in 2004 were relatively inefficient in the number of life-years gained yet had a lower life expectancy than the SEE region and was only slightly higher than the CIS region (DEA). By 2012 the revenue spent was roughly linear to additional life-year expectancies. EU 2004 members were the best performers in terms of balanced longevity increase followed by health expenditure growth. The SEE economies' longevity gains were lagging slightly behind at a far lower cost. An extrapolated CIS expenditure to longevity increase ratio has the fastest-growing long-term promise.


[Isolation of surface antigens of influenza virus A/Hong Kong 1/68 (H3N2) by density gradient fractionation with a new carboxypolypeptidase (author's transl)].
Isolation of pure neuraminidase and hemagglutinin from influenza virus A/Hong Kong 1/68 (H3N2) can be achieved using the coupled action of a new carboxypolypeptidase from Streptomyces fradiae and sodium dodecyl sulfate (SDS). Biochemical, physical and physico-chemical studies showed that the two molecules are in pure form and of glycoproteic nature.


Cyclic nucleotide phosphodiesterase activity in muscle of patients with carcinoma.
Cyclic nucleotide phosphodiesterase activity has been measured in muscle biopsies taken from healthy controls and from cancer patients. In both groups the muscles were clinically and morphologically normal. The phosphodiesterase activity was significantly increased in muscles from cancer patients using both cyclic AMP and cyclic GMP as substrate. These findings are in line with previous reports indicating that malignancy may interfere with metabolism of the host muscular tissues, and suggest the possibility that the observed biochemical changes might be an aspect of an early muscle neurogenic involvement.


Two-wavelength infrared responsive hydrogel actuators containing rare-earth photothermal conversion particles.
Two-wavelength infrared responsive soft actuators composed of rare-earth-oxide particles composited in a thermoresponsive hydrogel have been constructed. Because Nd2O3 and Yb2O3 particles possess independent narrow infrared adsorption at 808 and 980 nm, respectively, the vicinity of the particles in the gel can be individually heated by irradiation at each adsorption wavelength, inducing a local volume phase transition. The wavelength-selective volume phase transition can be controlled based on the combination of the particles incorporated in the gels and the wavelength of the irradiation laser at the optimized water temperature. Only the alternatively correct combinations successfully induced selective local clouding at the irradiation spots in the gel sheets. The original transparency of the gel was immediately recovered by turning off the light. Furthermore, rod-shaped block gels with Nd2O3 and Yb2O3 particles separately arranged on the left and right sides at the bottom of the rods were prepared to demonstrate wavelength-selective bending motion. The correct light combination caused reversible bending motion of only the side of the rod gel with the corresponding adsorbed particles.


Erratum: Towards decolonising research methods training: The development of a locally responsive online learning course on research methods for mental health in war and conflict for researchers and practitioners in the Gaza Strip - ERRATUM.
[This corrects the article DOI: 10.1017/gmh.2021.40.].


Minimum 1-year follow-up for patients with vertical shear sacroiliac joint dislocations treated with iliosacral screws: does joint ankylosis or anatomic reduction contribute to functional outcome?
To prospectively analyze a homogenous group of trauma patients with pure sacroiliac (SI) joint dislocations treated with iliosacral screws (ISS), with specific attention to functional outcome and its correlation with the presence or absence of SI joint ankylosis and quality of reduction. Retrospective chart and radiographic review of initial injury and treatment, with prospective long-term evaluation of radiographs, computed tomography (CT) scans, and functional assessments. Level One Regional Trauma Center. Twenty-three patients who were skeletally mature with traumatic vertical shear pelvic injuries associated with a pure SI joint dislocation. Treatment consisted of closed or open reduction in the supine or prone position and insertion of a single ISS placed percutaneously for the fixation of the posterior ring injury. Each patient was evaluated for functional outcome using version 2 of the Short-Form 36 (SF-36v2), the short version of the Musculoskeletal Functional Assessment (sMFA), the Iowa Pelvic Scoring System, and the Majeed Pelvic Scoring System. Additionally, at the follow-up visit, each patient received plain radiographs of the pelvis and CT scanning of the pelvis. Minimum follow-up was 1 year postindex procedure (13-120 months). In this subset of patients with pure SI dislocations treated with ISS alone, anatomic reduction was the only predictor of a more favorable functional outcome (P = 0.04). Specifically, SI joint ankylosis did not affect functional outcome in these patients. Based on the results of this study, in the treatment of vertically displaced, pure SI joint dislocations, an anatomic reduction (whether closed or open), followed by ISS fixation should be the goal because this appears to be the only predictor of a more favorable functional outcome in patients with this injury. Complete SI joint ankylosis appears to have no effect, either positive or negative, on functional outcome in these patients.


The Role of Imaging in Clinical Stroke Scales That Predict Functional Outcome: A Systematic Review.
Numerous stroke scales have been developed to predict functional outcomes following acute ischemic stroke. The goal of this study was to summarize functional outcome scores in stroke that incorporate neuroimaging with those that don't incorporate neuroimaging. Searches were conducted in Ovid MEDLINE, Ovid Embase, and the Cochrane Library Database from inception to January 23, 2015. Additional records were identified by employing the "Cited by" and "View References" features in Scopus. We included studies that described stroke prognosis models or scoring systems that predict functional outcome based on clinical and/or imaging data available on presentation. Score performance was evaluated based on area under the receiver operating characteristic curve (AUC). A total of 3300 articles were screened, yielding 14 scores that met inclusion criteria. Half (7) of the scores included neuroimaging as a predictor variable. Neuroimaging parameters included infarct size on magnetic resonance diffusion-weighted imaging, infarct size defined by computed tomography hypodensity, and hemodynamic abnormality on perfusion imaging. The modified Rankin Scale at 3 months poststroke was the most common functional outcome reported (13 of 14 scores). The AUCs ranged from 0.64 to 0.84 for scores that included neuroimaging as a predictor and 0.64 to 0.94 for scores that did not include neuroimaging. External validation has been performed for 7 scores. Due to the marked heterogeneity in the scores and populations in which they were applied, it is unclear whether current imaging-based scores offer advantages over simpler approaches for predicting poststroke function.


Region-based and pathway-based QTL mapping using a p-value combination method.
Quantitative trait locus (QTL) mapping using deep DNA sequencing data is a challenging task. In this study we performed region-based and pathway-based QTL mappings using a p-value combination method to analyze the simulated quantitative traits Q1 and Q4 and the exome sequencing data. The aims were to evaluate the performance of the QTL mapping approaches that were used and to suggest plausible strategies for QTL mapping of DNA sequencing data. We conducted single-locus QTL mappings using a linear regression model with adjustments for age and smoking status, and we also conducted region-based and pathway-based QTL mappings using a truncated product method for combining p-values from the single-locus QTL mapping. To account for the features of rare variants and common single-nucleotide polymorphisms (SNPs), we considered independently rare-variant-only, common-SNP-only, and combined analyses. An analysis of 200 simulated replications showed that the three region-based methods reasonably controlled type I error, whereas the combined analysis yielded the greatest statistical power. Rare-variant-only, common-SNP-only, and combined analyses were also applied to pathway-based QTL mappings. We found that pathway-based QTL mappings had a power of approximately 100% when the significance of the vascular endothelial growth factor pathway was evaluated, but type I errors were slightly inflated. Our approach complements single-locus QTL mapping. An integrated approach using single-locus, combined region-based, and combined pathway-based analyses should yield promising results for QTL mapping of DNA sequencing data.


Increased blood pressure variability in pheochromocytoma compared to essential hypertension patients.
Catecholamines are responsible for short and long-lasting blood pressure (BP) elevations in pheochromocytoma. We investigated whether in patients with pheochromocytoma this catecholamine excess would result in higher BP variability in comparison with patients suffering from essential hypertension (EH). We examined retrospectively 54 (26 treated with alpha1-blockers) patients with pheochromocytoma (30 patients also investigated after tumour removal) and 108 (42 treated with alpha1-blockers) patients with EH. They all underwent 24-h ambulatory BP monitoring. To assess the BP variability, coefficient of BP variability (SD of average BP/average BP) was used. In subjects with pheochromocytoma, a higher coefficient of BP variability was shown compared with EH during the 24-h period (0.12 +/- 0.03 versus 0.10 +/- 0.02, P = 0.003 for systolic BP in the treated group) and mainly during the daytime (0.11/0.13 +/- 0.04/0.03 versus 0.09/0.11 +/- 0.03/0.04, P = 0.007/0.06 for systolic/diastolic BP in the untreated group and 0.12/0.13 +/- 0.04/0.04 versus 0.09/0.12 +/- 0.04/0.02, P < 0.001/0.01 in the treated group). Tumour removal resulted in a decrease of the previously increased 24-h (0.11 +/- 0.03 versus 0.10 +/- 0.03, P = 0.04) and daytime (0.11 +/- 0.03 versus 0.09 +/- 0.03, P = 0.03) coefficient of systolic BP variation. Twenty-seven subjects with pheochromocytoma and inverted circadian BP rhythm (night-time BP > daytime BP) had a significantly higher 24-h (0.13 +/- 0.03 versus 0.10 +/- 0.03, P < 0.001 for systolic BP) and daytime coefficient of BP variation (0.13/0.15 +/- 0.04/0.03 versus 0.09/0.12 +/- 0.02/0.02, P < 0.001/<0.001) and also a higher occurrence of the isolated excretion of norepinephrine (14 versus seven subjects, P = 0.05) compared with the 27 subjects with pheochromocytoma without inverted circadian BP rhythm. The excess of catecholamines in patients with pheochromocytoma is associated with higher long-term BP variability in comparison with patients suffering from EH especially in subjects with inverted circadian BP rhythm. Tumour removal resulted in the amelioration of the previously increased BP variability.


The pharmacokinetics of furazlocillin in healthy humans.
The pharmacokinetics of the novel acylureidopenicillin furazlocillin, 6-[D-2-(3-furfurylidenamino-2-oxo-imidazolidine-1-carboxamido)-2 -(4-hydroxyphenyl)-acetamido]-penicillanic acid and of its penicilloic acid derivative were investigated in five healthy male volunteers after intravenous administration of 2 and 4 g dosages. The volunteers were either in a lying or sitting position throughout the duration of the studies. The concentrations of the drug in plasma and urine were measured by two different methods in parallel: a microbiological assay and a newly developed high pressure liquid chromatography method. The latter method was also applicable for quantitation of the penicilloic acid derivative in these biological fluids. The drug's plasma protein binding (66%) and apparent red cell-plasma partition coefficient (0.055) were concentration independent. The pharmacokinetics of the drug were first order only at the lower dose level. The apparent half lives of three distinguishable phases were, respectively, 4(t1/21), 18 (t1/22), and 64 (t1/2z) min. The total and renal clearances of the drug were, respectively, 303 and 79 ml/min. The latter value implied tubular secretion of the drug. Graphical and digital computer analyses of the data were performed with a linear three compartment body model. Small but consistent deviations from linear kinetics caused by the nonrenal elimination route were observed after administration of the higher dose (4 g). In contrast, renal elimination showed no such dose dependency and was first order. The disposition kinetics of furazlocillin were body position independent. The penicilloic acid derivative of furazlocillin was found in plasma and urine in all the five subjects tested. The percentage of the dose excreted renally as the derivative amounted, respectively, to 5.2 and 7.0% after the lower and higher dosage of furazlocillin, with significant inter- and intrasubject variability. The renal clearance of the derivative was 41 ml/min.


[Regional anesthesia in daily clinical practice: an economic analysis based on case vignettes].
The economic effect is a crucial aspect of every medical procedure. This article analyzes the economic implications of various methods in anesthesia based on three case vignettes. The management of anesthesia of a forearm fracture with sufficient brachial plexus blockade, general anesthesia and insufficient brachial plexus blockade with subsequent general anesthesia was analyzed with respect to the relevant cost factors (personnel costs, durables, consumables, fixed assets costs, anesthesia-related overhead costs). Sufficient regional anesthesia was the least expensive method for a forearm fracture with 324.26 €, followed by general anesthesia with 399.18 € (+23% compared with regional anesthesia). Insufficient regional anesthesia was most the expensive method, which necessitated an additional general anesthesia (482.55 €, +49% compared with sufficient regional anesthesia). Even considering that this cost analysis was calculated based on data from only one medical institution (General Hospital of Vienna, Medical University of Vienna), regional anesthesia appeared to be cost efficient compared with other anesthesia procedures. Main cost drivers in this example were personnel costs.


The impact of air quality on international tourism arrivals: a global panel data analysis.
Using data from World Development Indicators (WDI), this research constructs panel data of 99 countries from 1996 to 2018 and employs a spatial econometric model to analyze the impact of air quality on international tourism arrivals. Evidence shows that Moran's I values are significantly positive, indicating a strong positive spatial dependence in each country and that poor air quality does have a negative impact on the number of tourist arrivals. The results of grouped data illustrate that middle-income countries, low-income countries, high concentrations of PM2.5, and countries with less numbers of tourists have negative effects on tourist arrivals in neighboring countries. The contrary groups, however, have positive effects on tourist arrivals - that is, the influence of air quality on the number of tourist arrivals exhibits heterogeneity. In addition, tests of the interaction term show that countries with higher R&D intensity have better air quality and thus attract more tourists. Therefore, countries with poor air quality should improve the environment through international cooperation and undertake technology transfer, thus ultimately increasing the number of tourists.


Molecular structure and vibrational spectra of 3-chloro-4-fluoro benzonitrile by ab initio HF and density functional method.
In this work, the experimental and theoretical spectra of 3-chloro-4-fluoro benzonitrile (3C4FBN) were studied. The Fourier transform infrared and Fourier transform Raman spectra of 3C4FBN were recorded in the solid phase. The optimized geometry was calculated by HF and B3LYP methods with 6-311++G(d,p) basis set. The harmonic-vibrational frequencies, infrared intensities and Raman scattering activities of the title compound were performed at and HF/B3LYP/6-311++G(d,p) level of theories. The scaled theoretical wave number showed very good agreement with the experimental values. The thermodynamic functions of the title compound was also performed at HF/6-31G(d,p) and B3LYP/6-311++G(d,p) level of theories. A detailed interpretation of the infrared and Raman spectra of 3C4FBN was reported. The theoretical spectrograms for FT-IR and FT-Raman spectra of the title molecule have been constructed.


A data correction method for surface measurement of vibration on the human body.
A data correction method to eliminate the effect of local tissue-accelerometer vibration from surface measurements of vibration over the spine has been developed and compared with previous direct measurements. A single degree-of-freedom linear model for the local tissue-accelerometer system in the vertical and the fore-and-aft axes is assumed. The natural frequency and the damping ratio of the local system are estimated so as to form a correction frequency function, using spectral analysis of the free vibration response of the local system caused by transient displacements of the accelerometer attached to the body surface. Accelerometers were attached to the skin over the spinous process of the vertebra L3 and on the abdominal wall. For four different masses and each site, correction frequency functions were computed. Seated subjects were then exposed to vertical random vibration (0.5-35 Hz) and acceleration transfer functions from the seat to each accelerometer were calculated. Different transfer functions were obtained with different additional masses but the differences were eliminated by the correction method so as to indicate the transfer functions to the spine and the viscera. For vertical responses, the correction method was effective at frequencies below the estimated natural frequencies of the local system. Fore-and-aft response over the spine did not require correction at frequencies below 35 Hz.


Exosomal circ_0091741 promotes gastric cancer cell autophagy and chemoresistance via the miR-330-3p/TRIM14/Dvl2/Wnt/β-catenin axis.
The importance of cancer cell-released exosomes in the treatment of various cancers has been well-characterized. The current study aims to examine the potential biological functions of gastric cancer (GC) cell-released exosomes delivering a novel circRNA circ_0091741 in GC and the underlying molecular mechanism. Expression of circ_0091741 was examined in the GC cells, (OXA)-resistant HGC-27 (HGC-27/OXA) cells, and isolated exosomes, after which its downstream miRNA was analyzed. The role and mechanism of the circ_0091741 transmitted by GC cells-derived exosomes in GC cell autophagy and chemoresistance were assessed using various molecular biological methods. A mouse tumor xenograft model was prepared to discern the effect of circ_0091741 on tumorigenesis in vivo. GC cells and their exosomes were characterized by upregulated circ_0091741 expression. circ_0091741 transferred by GC cell-derived exosomes induced the autophagy and OXA resistance of GC cells. circ_0091741 obstructed the binding of miR-330-3p to TRIM14 and increased the expression of TRIM14. TRIM14 could cause activation of the Wnt/β-catenin signaling pathway by stabilizing Dvl2. By this mechanism, the autophagy and OXA resistance of GC cells were augmented. In vivo assay unfolded that orthotopic implantation of exosomal circ_0091741 overexpressed GC cells into nude mice enhanced tumorigenesis. In conclusion, our study emphasized the promotive role of exosomal circ_0091741 in autophagy and chemoresistance of GC cells, thus laying the basis for the development of novel therapeutic targets for GC treatment.


Pharmacological differentiation of kainate receptors on neonatal rat spinal motoneurones and dorsal roots.
The objectives of this study, conducted on neonatal rat spinal cord and dorsal roots in vitro, were to characterise the actions of a range of willardiine analogues on GluR5-containing kainate receptors present in dorsal roots, to determine whether GluR5-containing receptors are also present on motoneurones, and to differentiate responses mediated by kainate receptors from those mediated by AMPA receptors on motoneurones. (S)-5-Trifluoromethyl-willardiine, (S)-5-iodowillardiine, (S)-5-iodo-6-azawillardiine and ATPA were found to be potent agonists of kainate receptors on dorsal roots (EC50 values 0.108 +/- 0.002, 0.127 +/- 0.010, 0.685 +/- 0.141 and 1.3 +/- 0.3 microM, respectively) being more potent but of lower efficacy than kainate (EC50 value 14.8 +/- 1.8 microM). (S)-5-Iodo-6-azawillardiine blocked kainate-induced depolarisations of the dorsal root, probably via its desensitising action. Kainate-induced responses of dorsal roots were weakly antagonised by (RS)-3,5-dicarboxyphenylglycine (DCPG) (apparent KD 1.5 +/- 0.4 mM). Kainate receptors containing GluR5 subunits do not appear to be present on motoneurones since (RS)-3,5-DCPG (1 mM) potentiated rather than antagonised kainate-induced depolarisations of motoneurones. Although (S)-5-iodowillardiine (a potent and selective agonist at GluR5-containing kainate receptors) depolarised motoneurones (EC50 value 5.8 +/- 0.6 microM), such depolarisations were antagonised by both (RS)-3,4- and (RS)-3,5-DCPG, which are selective AMPA receptor antagonists at motoneurones, showing a KD value of 73 microM (Schild slope, 0.96 +/- 0.09) and an apparent KD value of 123 +/- 38 microM, respectively. This accords with the previously reported activity of willardiine analogues at AMPA receptors. Since neither (RS)-3,4- nor (RS)-3,5-DCPG antagonised kainate-induced motoneuronal depolarisations but cyclothiazide enhanced and GYK153655 blocked these responses it is possible that a component of the kainate response may be mediated by a population of DCPG-insensitive AMPA receptors on motoneurones. However, it is also possible that a population of kainate receptors other than those containing GluR5 subunits, are responsible for these effects. The new compounds introduced in this study are likely to be useful tools for studying the physiological role of kainate receptors in CNS function.


Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.
Mutations in GJB2 encoding the gap junction protein connexin-26 (Cx26) have been established as the basis of autosomal recessive non-syndromic hearing loss. The involvement of GJB2 in autosomal dominant deafness has also been proposed, although the putative mutation identified in one family with both deafness and palmoplantar keratoderma has recently been suggested to be merely a non-disease associated polymorphism. We have observed a similar phenotype in an Egyptian family that segregated with a heterozygous missense mutation of GJB2, leading to a non-conservative amino acid substitution (R75W). The deleterious dominant-negative effect of R75W on gap channel function was subsequently demonstrated in the paired oocyte expression system. Not only was R75W alone incapable of inducing electrical conductance between adjacent cells, but it almost completely suppressed the activity of co-expressed wildtype protein. The Cx26 mutant W77R, which has been implicated in autosomal recessive deafness, also failed to form functional gap channels by itself but did not significantly interfere with the function of wildtype Cx26. These data provide compelling evidence for the serious functional consequences of Cx26 mutations in dominant and recessive deafness.


Combining systems thinking approaches and implementation science constructs within community-based prevention: a systematic review.
Systems science offers methods for designing population health interventions while implementation science provides specific guidance for successful implementation. Integrating systems and implementation science may strengthen implementation and enhance and sustain systemic change to achieve system-level outcomes. Little is known about the extent to which these two approaches have been integrated to date. This review aimed to identify and synthesise the peer-reviewed literature that has reported the combined use of systems thinking approaches and implementation science constructs (within the same study), to deliver population health interventions. A systematic literature search of peer-reviewed original research was conducted across six databases from 2009 to 2021. Journal manuscripts were included if they: (1) reported on a population health study conducted in a community, (2) reported the use of a systems method in the design of the intervention, and (3) used an implementation science theory, framework or model in the delivery of the intervention. Data extracted related to the specific systems methods and definitions and implementation science constructs used. The Mixed Methods Appraisal Tool (MMAT) was used to assess study quality. Of the 9086 manuscripts returned, 320 manuscripts were included for full-text review. Of these, 17 manuscripts that reported on 14 studies were included in the final extraction. The most frequently reported systems methods were a 'whole of community systems approach' (n = 4/14) and 'community-based system dynamics' (n = 2/14). Nineteen different implementation science theories, frameworks and models were used for intervention delivery, with RE-AIM being the only framework used in more than one study. There are few published peer-reviewed studies using systems thinking and implementation science for designing and delivering population health interventions. An exploration of synergies is worthwhile to operationalise alignment and improve implementation of systems thinking approaches. Review protocol registration PROSPERO CRD42021250419.


Subthreshold auditory inputs to extrastriate visual neurons are responsive to parametric changes in stimulus quality: sensory-specific versus non-specific coding.
A new subthreshold form of multisensory processing has been recently identified that results from the convergence of suprathreshold excitatory inputs from one modality with subthreshold inputs from another. Because of the subthreshold nature of the second modality, descriptive measures of sensory features such as receptive field properties or location are not directly apparent as they are for traditional bimodal neurons. This raises the question of whether or not subthreshold signals actually convey sensory-specific receptive field information as seen in their bimodal counterparts, or if they represent non-specific effects such as arousal. The present experiment addressed this issue in visually-responsive neurons from the cat posterolateral lateral suprasylvian cortex (PLLS). Single-unit electrophysiological techniques were used to record neuronal responses to visual, auditory and combined visual-auditory stimuli while the intensity of stimulation in the subthreshold auditory modality was systematically altered. The results showed that subthreshold multisensory neurons were sensitive to changes in auditory stimulus intensity. These receptive field sensitivities are similar to those observed in bimodal neurons and thereby represent sensory-specific, not arousal-related responses. In addition, these results provide further support for the notion that multisensory processing occurs along a dynamic continuum of neuronal convergence patterns from bimodal to purely sensory-specific.


Apolipoprotein L1 and Kidney Disease in African Americans.
Genetic variants in the Apolipoprotein L1 (APOL1) gene cause high rates of kidney disease in African Americans. These variants, found only in individuals with recent African ancestry, confer enhanced innate immunity against African trypanosomes. Although they are among the most powerful disease-causing common variants discovered to date, we are just beginning to understand how they promote kidney injury. Since APOL1 is present in only a few primate species, much of our current knowledge has come from natural experiments in humans and in vitro studies while awaiting the development of transgenic animal models. Understanding more about the function of ApoL1 and how the high-risk variants behave differently from other ApoL1 molecules is a high priority in kidney disease research.


Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis.
Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however, the effect of mammary adipocytes on breast cancer ferroptosis remains to be elucidated. Here, we established the co-culture system of adipocyte-breast cancer cells and revealed the protection of triple-negative breast cancer from ferroptosis by adipocytes. Then, we performed the lipidomics analysis comparing lipid metabolites of co-cultured and normal-cultured cells. Mechanistically, oleic acid secreted from adipocytes inhibited lipid peroxidation and ferroptosis of triple-negative breast cancer cells in the presence of ACSL3. Taken together, mammary adipocytes can protect breast cancer cells from ferroptosis through oleic acid in the presence of ACSL3. These findings could provide new ideas and targets for tumor treatment.


Understanding desaturation/hydroxylation activity of castor stearoyl Δ9-Desaturase through rational mutagenesis.
A recently proposed reaction mechanism of soluble Δ9 desaturase (Δ9D) allowed us to identify auxiliary residues His203, Asp101, Thr206 and Cys222 localized near the di-iron active site that are supposedly involved in the proton transfer (PT) to and from the active site. The PT, along with the electron transfer (ET), seems to be crucial for efficient desaturation. Thus, perturbing the major PT chains is expected to impair the native reaction and (potentially) amplify minor reaction channels, such as the substrate hydroxylation. To verify this hypothesis, we mutated the four residues mentioned above into their counterparts present in a soluble methane monooxygenase (sMMO), and determined the reaction products of mutants. We found that the mutations significantly promote residual monohydroxylation activities on stearoyl-CoA, often at the expense of native desaturation activity. The favored hydroxylation positions are C9, followed by C10 and C11. Reactions with unsaturated substrate, oleoyl-CoA, yield erythro-9,10-diol, cis-9,10-epoxide and a mixture of allylic alcohols. Additionally, using 9- and 11-hydroxystearoyl-CoA, we showed that the desaturation reaction can proceed only with the hydroxyl group at position C11, whereas the hydroxylation reaction is possible in both cases, i.e. with hydroxyl at position C9 or C11. Despite the fact that the overall outcome of hydroxylation is rather modest and that it is mostly the desaturation/hydroxylation ratio that is affected, our results broaden understanding of the origin of chemo- and stereoselectivity of the Δ9D and provide further insight into the catalytic action of the NHFe2 enzymes.


Reevaluation of the maximum tolerated dose of continuous venous infusion of 5-fluorouracil with pharmacokinetics.
5-Fluorouracil (5-FU) was administered as a continuous ambulatory venous infusion to 25 patients in a Phase I trial. The principal dose limiting toxic effect observed was mucositis. Skin rash and diarrhea occurred less frequently. Hematological toxicity was modest, and no hepatic toxicity was seen. One partial remission of 138 days duration was seen in a patient with metastatic breast carcinoma who was previously refractory to a 5-FU combination regimen. Patient tolerance of 5-FU delivered in this manner appeared highly variable. On the basis of this trial, we recommend that future studies evaluating the efficacy of long-term venous infusion of 5-FU should utilize a dosage of 450 mg/m2/day.


[Neuronal network].
Function of the central nervous system is based on mutual relations among the nerve cells. Description of nerve cells and their processes, including their contacts was enabled by improvement of optical features of the microscope and by the development of impregnation techniques. It is associated with the name of Antoni van Leeuwenhoek (1632-1723), J. Ev. Purkyne (1787-1869), Camillo Golgi (1843-1926), and Ramón y Cajal (1852-1934). Principal units of the neuronal network are the synapses. The term synapse was introduced into neurophysiology by Charles Scott Sherrington (1857-1952). Majority of the interactions between nerve cells is mediated by neurotransmitters acting at the receptors of the postsynaptic membrane or at the autoreceptors of the presynaptic part of the synapse. Attachment of the vesicles to the presynaptic membrane and the release of the neurotransmitter into the synaptic cleft depend on the intracellular calcium concentration and on the presence of several proteins in the presynaptic element.


Effects of dietary nano-selenium supplementation on Riemerella anatipestifer vaccinated and challenged Pekin ducklings (Anas platyrhynchos).
Riemerella anatipestifer (RA) is a common disease causing economic losses to duck farms worldwide. Novel supplements are crucially needed to control this bacterium, enhance poultry performance, and produce synergistic effects with vaccines in stimulating the immune system. This study investigated the effect of nano-selenium (Nano-Se) on the vaccinated (VAC) and challenged (Ch) Pekin ducklings (Anas platyrhynchos) with RA. Five experimental groups (G1-G5) were included in this study: G1 was the control group, G2 was the RA-challenged group, G3 was the Nano-Se+Ch group, G4 was the VAC+Ch group, and G5 was the Nano-Se+VAC+Ch group. The Nano-Se (0.3 mg/kg diet) was supplemented for 5 weeks post-vaccination (PV). The ducklings were vaccinated subcutaneously with the RA vaccine at 7 days of age and challenged with RA at the 3rd week PV. Blood, pharyngeal swabs and tissue samples were collected at the 3rd week PV and at different times post-challenge (PC). The growth performance (weight gain and feed conversion ratio), clinical signs, gross lesions, mortality, bacterial shedding, haematological, immunological, and biochemical parameters, cytokines production, and histopathological lesion scores showed significant differences (P < 0.05) between the challenged (G2) group and the supplemented (G3 & G5) groups. G5 showed the highest (P < 0.05) growth performance, phagocytic activity, IgM and IgG, splenic interleukin-2 (IL-2), IL-10, and interferon-gamma (IFN-γ) gene expressions, and the lowest mortality, bacterial shedding, hepatic and renal damage, heterophil/lymphocyte ratio and lesion scores compared to the other groups. In conclusion, the supplementation of nano-selenium for five weeks in the diet can improve the growth performance, immune status, and cytokines production in ducklings vaccinated and challenged with RA.


Karyotypic analyses of metastatic and non-metastatic mouse tumor cells by G- and C-banding.
Cytogenetic studies using G- and C-banding were performed in order to compare non-metastasizing BWO mouse thymoma cells with their metastatic BW-IS-Li and BW-O-Li1 variants. BW-IS-Li and BW-O-Li1 cells were obtained from liver metastases generated respectively after intra-splenic or intravenous inoculation of mice with BWO cells. BW-O-Li1 cells contained normal chromosomes 4 and 18 which were never found in BWO or BW-IS-Li cells. As they also contained several markers common to the BWO parental cell line, our data provide definite evidence that the BW-O-Li1 cell line results from spontaneous in vivo cell fusion between a BWO cell and a normal host cell. Chromosome 3 was also shown to be "rearrangement-prone" and was less represented among metastatic cell variants. These variants also lack a C-band-deficient marker chromosome which was found in most of the BWO cells. However, as many complex chromosome rearrangements were found in all 3 cell lines, at least some chromosomal material may be present in a hidden form. We were not able in this particular cell system to link the presence or absence of a single chromosome, chromosome fragment or rearrangement to the acquisition or expression of metastatic properties.


Technique for Resonance® stent exchange in patients with extrinsic obstruction: description of a novel approach and literature review.
Malignant ureteral obstruction is a morbid diagnosis and can be difficult to manage. Ureteral stents often fail as the disease progresses. Metallic stents have provided a longer-term option for decompression as they inherently resist compression and require changes left often. However, changing metallic stents is challenging as it cannot be done over a wire as is done with plastic stents. We present a novel technique for safe and efficient exchange of the Resonance(®) metallic stent. We also review the literature on metallic stents.


Emergency department social work: a program description and analysis.
This article reports on the development of a social work component in the Emergency Department of a teaching-research hospital. It examines the rationale for developing the service and the objectives of the program. It also presents a statistical analysis of the first 2 full years of service. Finally, some of the major problems experienced in establishing such a program are discussed and possible solutions recommended.


Progression of myopic maculopathy in a Caucasian cohort of highly myopic patients with long follow-up: a multistate analysis.
This study aims to determine the probability of progression of myopic maculopathy according to age. This is a longitudinal observational study of single-center retrospective cohort of Caucasian patients formed by 212 consecutive adults with high myopia. Main outcome measures were age, visual acuity (VA), refractive error (RE), follow-up time, and the macular status assessed at least 5 years apart according to the Meta-Analysis of Pathologic Myopia Study Group. The progression rate was calculated based on per 1000 eyes/year. Multistate models were fitted to identify the predictive factors and to calculate the most probable age of progression onset using the Aalen-Johansen estimator. We studied 220 eyes of 122 Caucasian patients. Mean age was 48.18 ± 14.1, mean follow-up 12.73 ± 5.81 years. One-hundred and fifty-two (69.1%) eyes progressed of category, and 96 (44%) worsened a mean of 0.3 logMAR units during follow-up. The progression rate was 32.21/1000 eyes/year. The probability of progressing increased with age; it was higher in women if there was a family history of myopia, worse VA, higher RE, or wide macular staphyloma. The probability of progressing from category 1 was > 0.6 after 70 years of age; from category 2, it was 0.7 after 70 years; and 0.5 from category 3 after 75 years. If choroidal neovascularization (CNV) appeared, this probability exceeded 0.7 between ages 45 and 55 for all categories. The progression rate is lower than in a Japanese series. The vision worsened with disease progression, and the probability of both happening increased after the age of 70-75. If CNV appears, the risk of progression is very high at the age of 45-55.


Peripheral vascular responses to fluorocarbon administration.
To detect the local effect of hyperoxia on skeletal muscle vasculature, 2.5-ml boluses of oxygenated or deoxygenated fluorocarbon emulsion (F-O2 or F-N2) were washed through the hindlimb of anesthetized dogs at prevailing arterial pressure. Instantaneous hematocrit changes at the outflow were registered and stored in digital form with the red cells serving as the nondiffusible tracer in the resulting washout curves. A gamma density function was fitted and the gamma index (1/square root of alpha) was derived as a measure of skewness or perfusion heterogeneity. After recovery from the initial hypotensive reaction to fluorocarbon emulsion, washout curves for F-O2 and F-N2 were registered and blood samples were taken during 40 min of normoxia followed by 40 min of hypoxic hypoxia. The initial reaction to fluorocarbon significantly increased the gamma index so that the experiments began with a high index of perfusion heterogeneity in the limb vasculature. No significant difference was seen between F-O2 and F-N2 in normoxia but F-O2 maintained greater heterogeneity during hypoxia. The increased heterogeneity observed after the fluorocarbon reaction correlated highly with the severity of the hypotensive reaction which was also found to correlate inversely with the ability of the limb musculature to increase the O2 extraction ratio with onset of hypoxia. This blunting of microcirculatory reactivity to hyperoxia and hypoxia was attributed, in part, to the initial transient fluorocarbon reaction, possibly mediated by complement activation.


Development of Diphenyl carbonate-Crosslinked Cyclodextrin Based Nanosponges for Oral Delivery of Baricitinib: Formulation, Characterization and Pharmacokinetic Studies.
The aim of the present investigation is to prepare baricitinib (BAR)-loaded diphenyl carbonate (DPC) β-cyclodextrin (βCD) based nanosponges (NSs) to improve the oral bioavailability. BAR-loaded DPC-crosslinked βCD NSs (B-DCNs) were prepared prepared by varying the molar ratio of βCD: DPC (1:1.5 to 1:6). The developed B-DCNs loaded with BAR were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), % yield and percent entrapment efficiency (%EE). Based on the above evaluations, BAR-loaded DPC βCD NSs (B-CDN3) was optimized with mean size (345.8±4.7 nm), PDI (0.335±0.005), Yield (91.46±7.4%) and EE (79.1±1.6%). The optimized NSs (B-CDN3) was further confirmed by SEM, spectral analysis, BET analysis, in vitro release and pharmacokinetic studies. The optimized NSs (B-CDN3) showed 2.13 times enhancement in bioavailability in comparison to pure BAR suspension. It could be anticipated that NSs loaded with BAR as a promising tool for release and bioavailability for the treatment of rheumatic arthritis and Covid-19.


Titania-functionalized graphene oxide for an efficient adsorptive removal of phosphate ions.
Titania-functionalized graphene oxide (T-F GO), synthesized by a sol-gel process, was used as a highly efficient material to remove phosphate ions from the simulated wastewater. X-ray diffraction spectra, Fourier transform infrared spectra and scanning electron micrographs of T-F GO confirmed that titania particles were successfully grown on graphene oxide (GO) surface. The phosphate ion adsorption capacities of GO, titania and T-F GO as a function of the contact time and the pH were investigated by a UV-visible spectrophotometer. Results showed that T-F GO could absorb phosphate ions better than titania and GO could. This indicated the synergistic effect between titania and GO in the phosphate ion adsorption. The pH increment lowered the absorption capacities due to increasing the repulsion between phosphate anions and the charges on the T-F GO surface, whereas the addition of sodium ions increased the adsorption capacities. Also, phosphate ions were absorbed by specific sites of T-F GO and formed a monolayer on its surface. Finally, the maximum adsorption capacity of T-F GO was 33.11 mg/g at pH 6, much higher than those of GO and titania. Therefore, T-F GO could be a promising material to remove phosphate ions from wastewater in the future.


Human phenotypes associated with GATA-1 mutations.
GATA-1 is one of the six members of the GATA gene family, a group of related transcription factors discovered in the 1980s. In the past few decades, the crucial role of GATA-1 in normal human hematopoiesis has been delineated. As would be expected, mutations in GATA-1 have subsequently been found to have important clinical significance, and are directly linked to deregulated formation of certain blood cell lineages. This paper reviews the functional consequences of GATA-1 mutations by linking specific errors in the gene, or its downstream protein products, to documented human diseases. These five human diseases are: X-linked thrombocytopenia (XLT), X-linked thrombocytopenia with thalassemia (XLTT), congenital erythropoietic porphyria (CEP), transient myeloproliferative disorder (TMD) and acute megarakaryoblastic leukemia (AMKL) associated with Trisomy 21, and, lastly, a particular subtype of anemia associated with the production of GATA-1s, a shortened, mutant isoform of the wild-type GATA-1. The different phenotypic expressions associated with GATA-1 mutations illustrate the integral function of the transcription factor in overall body homeostasis. Furthermore, these direct genotype-phenotype correlations reinforce the importance of unraveling the human genome, as such connections may lead to important therapeutic or preventive therapies.


From simple to complex oscillatory behaviour: analysis of bursting in a multiply regulated biochemical system.
We analyze the transition from simple to complex oscillatory behaviour in a three-variable biochemical system that consists of the coupling in series of two autocatalytic enzyme reactions. Complex periodic behaviour occurs in the form of bursting in which clusters of spikes are separated by phases of relative quiescence. The generation of such temporal patterns is investigated by a series of complementary approaches. The dynamics of the system is first cast into two different time-scales, and one of the variables is taken as a slowly-varying parameter influencing the behaviour of the two remaining variables. This analysis shows how complex oscillations develop from simple periodic behaviour and accounts for the existence of various modes of bursting as well as for the dependence of the number of spikes per period on key parameters of the model. We further reduce the number of variables by analyzing bursting by means of one-dimensional return maps obtained from the time evolution of the three-dimensional system. The analysis of a related piecewise linear map allows for a detailed understanding of the complex sequence leading from a bursting pattern with p spikes to a pattern with p + 1 spikes per period. We show that this transition possesses properties of self-similarity associated with the occurrence of more and more complex patterns of bursting. In addition to bursting, period-doubling bifurcations leading to chaos are observed, as in the differential system, when the piecewise-linear map becomes nonlinear.


Novel cytocidal compounds, oxopropalines from Streptomyces sp. G324 producing lavendamycin. I. Taxonomy of the producing organism, fermentation, isolation and biological activities.
In the course of our investigation aimed at the discovery of novel antitumor antibiotics from microorganisms, Streptomyces sp. G324 was found to produce the antitumor antibiotic, lavendamycin, and also, to yield the novel beta-carboline compounds, oxopropalines. We isolated five compounds as oxopropalines A, B, D, E and G. Oxopropalines B, D and G showed cytocidal activities against human or murine tumor cell lines in vitro.


Entanglement and indistinguishability in a quantum ontology of properties.
The aim of the present article is to address the problem of entanglement in the case of indistinguishable particles from a perspective based on the algebraic formalism of quantum mechanics, which is the natural formal counterpart of an ontology of properties, devoid of the ontological category of object. On the basis of this perspective, an algebraic definition of entanglement is adopted, which supplies a unified conception, valid for both the distinguishable and the indistinguishable cases. An additional advantage of this algebraic definition is that it does justice to the relativity of entanglement, a feature that cannot be ignored.


Child and adolescent psychopharmacology. Important developmental issues.
This article begins with an overview of developmental variations in pharmacokinetics and pharmacodynamics and then discusses issues related to decision making before beginning treatment with medication, including diagnosis, impairment, and consent. Subsequently, specific disorders, such as attention deficit hyperactivity disorder, mood disorders, and obsessive-compulsive disorder, are briefly discussed, with focus on issues relevant to a developmental approach to pediatric psychopharmacology.


Short-term training-dependent plasticity of the corticospinal diaphragm control in normal humans.
Mammalian ventilation is driven by automatic structures producing "metabolic" ventilation. Respiratory neuroplasticity can adapt this control to developmental, environmental, and disease-related changes. A corticospinal diaphragm pathway accounts for behavioural disruptions of metabolic ventilation. It should be sensitive to use-dependent short-term plasticity. However, the brainstem-generated permanent diaphragm activity could alter the learning-related corticospinal plasticity (metaplasticity). To test this hypothesis, eight healthy volunteers (six women, 21-25) were studied before and after having learnt to produce prominent diaphragm contractions during voluntary inspiratory manoeuvres. Diaphragm training resulted in (1) a decreased liminal stimulation intensities; (2) an increased number of responding sites on the diaphragm mapping with focal stimulation (5.1+/-3.3 versus 9+/-4.4, p=0.004 in relaxed conditions; 8.9+/-5 versus 15.3+/-4.5, p<0.0001, with underlying voluntary facilitation); (3) shortened motor evoked potentials latencies in response to non-focal stimulation (17.2+/-1.6 ms versus 16.2+/-1.4 ms, p=0.03 in relaxed conditions, and 16.8+/-1.1 ms versus 15.2+/-1.6 ms, p=0.003, with facilitation). These results are closely comparable with similar data in locomotor muscle. They provide a neurophysiological basis for the capacity of normal humans to rapidly acquire diaphragmatic skills.


Perceptions from epidemiologic research in an endemic war.
Several endemic wars have developed since the second world war. In these wars, like endemic diseases, war becomes an accepted and expected activity incorporated into the lives of a large proportion of the population. This paper illustrates some of the special problems of epidemiologic research in an endemic war based on a number of studies conducted in Lebanon over the past decade. The special problems faced by epidemiologists in an endemic war include; a situation of dynamic change where long term planning is next to impossible, the military sensitivities involved in data collection, and the compromises one has to make with scientific rigor. The paper concludes with a perspective for action by health professionals in wartime. It recommends preventive action in wartime in addition to relief and an involvement in the search for alternative approaches to conflict resolution.


Weighted gene co-expression network analysis to identify key modules and hub genes associated with paucigranulocytic asthma.
Asthma is a heterogeneous disease that can be divided into four inflammatory phenotypes: eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA). While research has mainly focused on EA and NA, the understanding of PGA is limited. In this study, we aimed to identify underlying mechanisms and hub genes of PGA. Based on the dataset from Gene Expression Omnibus(GEO), weighted gene coexpression network analysis (WGCNA), differentially expressed genes (DEGs) analysis and protein-protein interaction (PPI) network analysis were conducted to construct a gene network and to identify key gene modules and hub genes. Functional enrichment analyses were performed to investigate the biological process, pathways and immune status of PGA. The hub genes were validated in a separate dataset. Compared to non-PGA, PGA had a different gene expression pattern, in which 449 genes were differentially expressed. One gene module significantly associated with PGA was identified. Intersection between the differentially expressed genes (DEGs) and the genes from the module that were most relevant to PGA were mainly enriched in inflammation and immune response regulation. The single sample Gene Set Enrichment Analysis (ssGSEA) suggested a decreased immune infiltration and function in PGA. Finally six hub genes of PGA were identified, including ADCY2, CXCL1, FPRL1, GPR109B, GPR109A and ADCY3, which were validated in a separate dataset of GSE137268. Our study characterized distinct gene expression patterns, biological processes and immune status of PGA and identified hub genes, which may improve the understanding of underlying mechanism and provide potential therapeutic targets for PGA.


Efficacy of a povidone iodine preparation in reducing nasal methicillin-resistant Staphylococcus aureus in colonized patients.
In a randomized, nonblinded, placebo-controlled trial, a single application of a 10% povidone iodine preparation significantly reduced nasal methicillin-resistant Staphylococcus aureus at 1 and 6 hours after application, but suppression was not sustained at 12 or 24 hours. Twice-daily treatment for 5 days did not reduce nasal methicillin-resistant S aureus measured 12 hours postdosing in comparison to controls. These results suggest that single preoperative applications of povidone iodine will be effective for short-term suppression of S aureus during the perioperative period.


Infrared studies of protein-induced perturbation of lipids in lipoproteins and membranes.
The paper reviews the main recent publications concerning infrared (IR) spectroscopy as applied to the study of lipid-protein interactions in model and cell membranes, lipoproteins, and related systems (e.g. lung surfactant). The review focuses mainly on transmission IR. Based on the available data, a number of general conclusions are presented on the perturbations caused by proteins on either the hydrocarbon chains, the polar headgroups or the interface region. Lipid-protein interactions in native cell membranes do not reveal significant differences from what is observed in semisynthetic model systems.


Event-related potentials following contraction of respiratory muscles in pre-term and full-term infants.
Involuntary isolated body movements are prominent in pre-term and full-term infants. Proprioceptive and tactile afferent feedback following limb muscle contractions is associated with somatotopic EEG responses. Involuntary contractions of respiratory muscles, primarily the diaphragm - hiccups - are also frequent throughout the human perinatal period during active behavioural states. Here we tested whether diaphragm contraction provides afferent input to the developing brain, as following limb muscle contraction. In 13 infants on the neonatal ward (30-42 weeks corrected gestational age), we analysed EEG activity (18-electrode recordings in six subjects; 17-electrode recordings in five subjects; 16-electrode recordings in two subjects), time-locked to diaphragm contractions (n = 1316) recorded with a movement transducer affixed to the trunk. All bouts of hiccups occurred during wakefulness or active sleep. Each diaphragm contraction evoked two initial event-related potentials with negativity predominantly across the central region, and a third event-related potential with positivity maximal across the central region. Involuntary contraction of the diaphragm can be encoded by the brain from as early as ten weeks prior to the average time of birth. Hiccups - frequently observed in neonates - can provide afferent input to developing sensory cortices in pre-term and full-term infants.


Interaction of retinoids and bilirubin with the binding of arachidonic acid to human alpha-fetoprotein.
Human alpha-fetoprotein (HAFP) has three binding sites for polyunsaturated fatty acids with association constant Ka = 1.8 X 10(7) M-1. One of these binding sites overlaps with a retinoid binding site with Ka = 2.6 X 10(6)M-1. Competition experiments with bilirubin showed that this compound does not compete neither with fatty acids nor with retinoids. Thus, the two bilirubin binding sites previously demonstrated appear as two additional binding sites on HAFP. Nevertheless, the close proximity of two fatty acid binding sites and two bilirubin binding sites resulted in a modification of the binding constants for fatty acids. It is hypothesised that the binding properties of HAFP reflect the three domain structures of the protein recently deduced from the study of the nucleotide sequence of HAFP mRNA and AFPcDNA segments.


The effects of three different LDL-apheresis methods on the plasma concentrations of E-selectin, VCAM-1, and ICAM-1.
Plasma concentrations of cellular adhesion molecules are associated with atherosclerotic diseases and major cardiovascular risk factors. It was shown that LDL-apheresis with dextran sulfate lowers the levels of E-selectin and ICAM-1 in patients with familial hypercholesterolemia. The effects of different LDL-apheresis methods have not been studied yet. Cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, fibrinogen, and the adhesion molecules E-selectin, VCAM-1, and ICAM-1 were measured in 20 patients with coronary heart disease and severe hyperlipoproteinemia immediately before and after regular LDL-apheresis. Treatment was performed by different apheresis methods (direct absorption, DA, n = 6; dextran sulfate adsorption, DS, n = 7; heparin precipitation, HP, n = 7). Rebound data of adhesion molecule levels were obtained from 2 patients of each group. Lipids were reduced similarly in all groups. The concentrations of all adhesion molecules were lowered during apheresis. The reduction of E-selectin (-31 +/- 7 vs. -6 +/- 5 and -6 +/- 5%, respectively, P < 0.001) was most prominent in the patients treated by heparin precipitation. Depending on the method of LDL-apheresis, the concentrations of VCAM-1 and E-selectin in the outlets of the LDL-apheresis columns were significantly lower compared to the concentration in the inlets. Plasma concentrations of adhesion molecules increased to their pre-apheresis values within 2 to 4 days following LDL-apheresis. The reductions of adhesion molecule levels observed during LDL-apheresis are at least partly due to adsorption to the LDL-apheresis column. The extent of absorption depends on the principle of extracorporeal LDL elimination.


[Malignant lymphoma present almost simultaneously in two brothers (author's transl)].
A diagnosis of poorly differentiated, nodular, lymphocytic malignant lymphoma was made in two brothers. One had been operated 10 years earlier for an adenocarcinoma of the descending colon. In addition, another brother had died from a primary tumor of the liver. Although a genetic factor is not proved, the case is suggestive.


Cyclical aggregation extends in vitro expansion potential of human mesenchymal stem cells.
Mesenchymal stem cell (MSC)-based therapy has shown great promises in various animal disease models. However, this therapeutic potency has not been well claimed when applied to human clinical trials. This is due to both the availability of MSCs at the time of administration and lack of viable expansion strategies. MSCs are very susceptible to in vitro culture environment and tend to adapt the microenvironment which could lead to cellular senescence and aging. Therefore, extended in vitro expansion induces loss of MSC functionality and its clinical relevance. To combat this effect, this work assessed a novel cyclical aggregation as a means of expanding MSCs to maintain stem cell functionality. The cyclical aggregation consists of an aggregation phase and an expansion phase by replating the dissociated MSC aggregates onto planar tissue culture surfaces. The results indicate that cyclical aggregation maintains proliferative capability, stem cell proteins, and clonogenicity, and prevents the acquisition of senescence. To determine why aggregation was responsible for this phenomenon, the integrated stress response pathway was probed with salubrial and GSK-2606414. Treatment with salubrial had no significant effect, while GSK-2606414 mitigated the effects of aggregation leading to in vitro aging. This method holds the potential to increase the clinical relevance of MSC therapeutic effects from small model systems (such as rats and mice) to humans, and may open the potential of patient-derived MSCs for treatment thereby removing the need for immunosuppression.


In situ off-line extracorporeal photopheresis conducted in a real-life situation at a Hemobiotherapy Department in France: A comparison of costs vs on-line procedure.
The off-line extracorporeal photopheresis (ECP) procedure requires photosensitization in an external cell therapy laboratory as per the French regulatory requirement. This regulation results in higher time and costs compared with the on-line alternative performed entirely at the patient's bedside. Recently, full in situ execution of the off-line procedure has been implemented in the Pitié-Salpêtrière Hospital Hemobiotherapy Department (Paris, France). This report summarizes the center's experience regarding the organizational and costs impacts of this change compared with the on-line procedure. ECP was broken down into stages, and several procedures were monitored prospectively in real-life settings. The total costs associated with both procedures were the sum of the fixed costs and variable costs related to all stages of the procedures, nursing-time costs, property costs, and patient-related production loss costs. Eight off-line ECP and fourteen on-line ECP procedures were monitored during five consecutive days. Procedure duration was not different (median 137.5 vs 154.0 minutes, P = .29). Times and costs associated with nursing were higher but offset by lower fixed costs of the off-line ECP. Total direct costs per procedure associated with using the off-line ECP were significantly lower than those of the on-line procedure (459.6 ± 7.1 EUR vs 953.8 ± 6.5 EUR; P = .0002). Similar results were observed when including the costs of patient production loss. As a competitive time procedure, the in situ off-line method proved to be cost-efficient by effectively offering similar patient treatment per year compared with the on-line procedure.


Sampling schedule design towards optimal drug monitoring for individualizing therapy.
We study the individualization of therapy by simultaneously taking into account the design of sampling schedule and optimal therapeutic drug monitoring. The sampling schedule design in this work is to determine the number of samples, the sampling times, the switching time from the loading to the maintenance period, and the drug dosages. A closed-loop control policy is employed to determine the sampling schedule, and an advanced stochastic global optimization algorithm, which integrates the stochastic approximation and simulated annealing techniques, is implemented to search the optimal sampling schedule. A simulated one-compartment model of intravenous theophylline therapy is used to illustrate our method. This method can be readily extended to multiple compartment systems and allow incorporating other criteria of drug control. While currently the method is mainly of theoretical interest, it offers a starting point for practical applications and thus is hopefully of great value for the clinically individualizing therapy in the future.


Phototherapy using narrowband ultraviolet B and psoralen plus ultraviolet A is beneficial in steroid-dependent antihistamine-refractory chronic urticaria: a randomized, prospective observer-blinded comparative study.
Literature on the efficacy of phototherapy in steroid-dependent antihistamine-refractory chronic urticaria (CRU) is limited. To assess and compare the efficacy of psoralen plus ultraviolet A (PUVA) and narrowband ultraviolet B (NB-UVB) in steroid-dependent CRU. In this randomized, prospective observer-blinded comparative study, 50 patients with steroid-dependent CRU (6 months of spontaneous urticaria with no response after 3 consecutive months of antihistamines and steroid dependence) were administered either PUVA (group A) or NB-UVB (group B) for 90 days, with a post-treatment follow-up of 90 days. The treatment efficacy was assessed using the average urticaria activity score 7 (aUAS7) and outcome scoring scale (OSS) every 2 weeks. The mean values of aUAS7 progressively decreased from 4·9 ± 0·8 and 5·0 ± 0·7 at baseline to 1·9 ± 0·7 and 1·4 ± 0·7 in groups A and B, respectively, by day 90. This further decreased to 1·5 ± 0·8 and 1·4 ± 1·0 at day 180 in both groups. The values of OSS progressively increased from baseline (1·6 ± 0·5 in group A and 1·3 ± 0·5 in group B) to 3·9 ± 0·3 and 4·0 ± 0·3 in groups A and B, respectively, by day 90, and 3·9 ± 0·5 and 4·0 ± 0·6 by day 180. NB-UVB fared statistically better than PUVA at different time points. Adverse events encountered were minimal and did not warrant treatment discontinuation. Phototherapy, especially NB-UVB, is an effective, safe and affordable therapeutic modality for steroid-dependent CRU and should be tried prior to third-line treatment options such as omalizumab, ciclosporin and other immunosuppressants.


Phase 2 trial of the topoisomerase II inhibitor, amrubicin, as second-line therapy in patients with metastatic urothelial carcinoma.
The purpose of this investigator-initiated multicenter phase II study was to determine the activity of the third-generation synthetic anthracycline, amrubicin, administered as second-line therapy in patients with advanced urothelial carcinoma. Patients with progressive metastatic urothelial cancer despite first-line chemotherapy were eligible for enrollment. Amrubicin was initially administered at a dose of 40 mg/m(2)/day daily × 3 every 21 days, and the dose was subsequently reduced to 35 mg/m(2)/day daily × 3 every 21 days. Prophylactic granulocyte colony-stimulating factor was administered to all patients, and prophylactic antibiotics were administered to patients at high risk of febrile neutropenia. Treatment was administered for up to six cycles in the absence of intolerable toxicity or disease progression. The primary endpoint was the objective response rate. A total of 22 patients were enrolled. Among the first three patients enrolled, all developed grade 4 neutropenia and one patient died of neutropenic sepsis. The starting dose of amrubicin was subsequently reduced, there were no further episodes of febrile neutropenia, and only one patient required a subsequent dose reduction. The most common adverse events were hematologic; grade ≥3 neutropenia occurred in 27 %, and other grade ≥3 adverse events were uncommon. Partial responses were achieved in three patients [13.6, 95 % confidence interval (CI) 0-28 %), while stable disease was the best response in 12 patients (54.5, 95 % CI 33.7-75.3 %). The trial was closed prematurely due to a development decision by the funder. Amrubicin as second-line therapy in advanced urothelial carcinoma is associated with modest single-agent activity. While there remains a role for the introduction of novel cytotoxic agents in the management of metastatic urothelial cancer, optimal development of such therapies will likely require patient selection biomarkers.


Reproductive performance following hysteroscopic treatment of intrauterine adhesions: single surgeon data.
Intrauterine adhesions can negatively affect reproductive outcomes by causing infertility, miscarriage and preterm birth in women. Hysteroscopic surgery is now widely accepted as the treatment of choice in symptomatic women to restore reproductive function. To analyse the patient characteristics and long-term reproductive outcomes of women who received treatment for intrauterine adhesions under the care of a single surgeon. In this retrospective analysis, all women who underwent hysteroscopic surgery for intrauterine adhesions under the care of the same surgeon between January 2001 and December 2019 were identified and their data were evaluated. Relevant demographic, diagnostic and reproductive outcome data was procured from patient notes. Referring doctors and patients were contacted to obtain missing information. Live birth and miscarriage rates. 126 women were treated for intrauterine adhesions. Of those women who were trying to conceive, 71.4% (65/91) achieved pregnancy, 58.2% (53/91) had live births and 13.2% (12/91) had miscarriages. No statistically significant difference was found in the live birth rates when data was analysed in subgroups based on age, reason for referral/aetiology and severity of pathology. Hysteroscopic surgery leads to live birth in the majority of women with intrauterine adhesions. The lack of statistically significant difference in live birth rates across subgroups, including advanced age and severe pathology, suggests that surgery in all women wanting to conceive can be justified. Hysteroscopic treatment can lead to successful outcomes even in the presence of severe adhesions and in older women with appropriate treatment.


Comprehensive blood coagulation potential in patients with acquired hemophilia A: retrospective analyses of plasma samples obtained from nationwide centers across Japan.
Global coagulation potential was assessed in 59 patients with acquired hemophilia A (PwAHA) by clot waveform analysis (CWA) and/or thrombin and plasmin generation assay. Relationships between factor VIII activity (FVIII:C) and the parameters from CWA and T/P-GA in patients with congenital HA were compared by grading coagulation potential related to FVIII:C: T1 (FVIII:C < 1 IU/dL), T2 (1 ≤ , ≤ 5 IU/dL), T3 (5 < , 12 ≤ IU/dL), and T4 (12 < , ≤ 50 IU/dL). The median FVIII:C and inhibitor titers in PwAHA on admission were 3.3 IU/dL and 63.0 BU/mL, respectively, but global coagulation parameters corresponded to T1 or less. Median FVIII:C levels during follow-up in PwAHA were 1.7-9.6-6.7-40.0-21.7 IU/dL on days 0-14-28-56-93, respectively. CWA-based data corresponded to less than T2 until day 28, but more closely reflected FVIII:C after day 56. Peak thrombin was severely low (near T1) until day 28 and improved modestly after day 56 but remained less than T2. Peak plasmin was lower than T1 until day 56, and returned to T4 on day 93. In conclusion, global coagulation function in PwAHA was impaired to a greater extent than could be anticipated from assays of FVIII:C, until approximately 1 month after immunosuppression and treatment with FVIII-bypassing agents.


Potassium fluxes and ouabain binding in growing, density-inhibited and Rous sarcoma virus-transformed chicken embryo cells.
Potassium fluxes, ouabain binding, and Na+ and K+ intracellular concentrations were determined for cultures of growing normal, density-inhibited and Rous sarcoma virus-transformed chicken embryo fibroblasts. No significant differences in K+ influx or ouabain binding were detected between growing normal cells and Rous sarcoma virus-transformed cells; however, ouabain binding and ouabain-sensitive K+ influx were 1.5- to 1.8-fold lower in density-inhibited cells. Thus, potassium influx in this system can be classified as a growth-related, but not transformation-specific change. As determined by both flame photometry and radioisotopic (42K) equilibration, growing normal and density-inhibited cells had similar potassium contents, whereas transformed cells exhibited 1.4-fold higher potassium levels. Sodium ion levels, as measured by flame photometry, were also 2- to 4.5-fold higher in transformed than normal or density-inhibited cells. Complementary studies of potassium efflux showed a 1.3- to 1.5-fold higher rate (based on the percentage of pool exiting the cell) in growing normal versus density-inhibited or transformed fibroblasts. Because of the larger potassium pool in transformed cells, efflux based on absolute number of potassium ions is similar in normal and transformed chicken embryo fibroblasts.


Cognitive enhancing effects of an AMPA receptor positive modulator on place learning in mice.
This study presents an in vivo investigation of the arylpropylsulfonamide α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive modulator (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD). The pharmacokinetics of the drug were examined in male C57BL/6J mice and the drug concentration in blood plasma determined after subcutaneous injection of 1mg/kg b.w. This analysis revealed a rapid increase of the plasma concentration, peaking within 30min after administration with a T(1/2) of approximately 30min and a peak plasma concentration of about 2μM. Analysis of brain tissue homogenates also indicated blood-brain barrier permeability of the compound. Cognitive enhancing effects of the drug were then studied on place learning in male C57BL/6J mice in a water maze. In order to elucidate the potential positive effects of PIMSD on spatial learning the muscarinergic antagonist scopolamine was utilized, which is known to impair spatial learning ability. The mice were divided into four groups and subjected to two sequential subcutaneous injections administered 25min prior to behavioural testing: (1) vehicle/vehicle; (2) PIMSD/vehicle; (3) scopolamine/vehicle; (4) PIMSD/scopolamine. PIMSD at a dose of 3mg/kg b.w. was able to partially reverse the impairment given by 0.5mg/kg b.w. scopolamine. These results suggest that arylpropylsulfonamides such as PIMSD may have a therapeutic use in the enhancement of cognitive function and support the hypothesis that AMPA receptor potentiation is one mechanism that can be targeted for diseases of cognitive impairment.


Assessment of renal and skeletal components of hypercalcemia.
The management of hypercalcemia of malignancy is guided by assessments of its various components. Since the intestine usually makes no contribution to hypercalcemia under these circumstances, the problem is to measure the net efflux of calcium out of bone and the ability of the kidneys to excrete the unwanted calcium load. Established relationships between serum and urinary calcium excretion rates allow the quantitation of the relative contribution of an impaired glomerular filtration rate, of reduced renal tubular calcium reabsorption, and of increased bone resorption. Since the renal handling of calcium is closely related to that of sodium in the proximal nephron, the rate of sodium excretion is an important variable in these measurements. A practical approach to the separation of hypercalcemia into its renal and skeletal components is described in this article. Examples of how these measurements can be used to assess the responses to various types of therapy for malignancy-associated hypercalcemia are also given.


A critical appraisal of semi-quantitative analysis of 2-deoxyglucose autoradiograms.
Semi-quantitative analysis (e.g. optical density ratios) of [14C]2-deoxyglucose autoradiograms is widely used in neuroscience research. We demonstrate that a fixed ratio of 14C-concentrations in the CNS does not yield a constant optical density ratio but is dependent upon the exposure time in the preparation of the autoradiograms and the absolute amounts of 14C from which the concentration ratio is derived. The failure of a fixed glucose utilization ratio to result in a constant optical density ratio represents a major interpretative difficulty in investigations where only semi-quantitative analysis of [14C]2-deoxyglucose autoradiograms is undertaken.


Sphingosine-1-phosphate and Sphingosine-1-phosphate receptors in the cardiovascular system: pharmacology and clinical implications.
Sphingosine-1-phosphate (S1P) is a lipid that binds and activates five distinct receptor subtypes, S1P1, S1P2, S1P3, S1P4, S1P5, widely expressed in different cells, tissues and organs. In the cardiovascular system these receptors have been extensively studied, but no drug acting on them has been approved so far for treating cardiovascular diseases. In contrast, a number of S1P receptor agonists are approved as immunomodulators, mainly for multiple sclerosis, because of their action on lymphocyte trafficking. This chapter summarizes the available information on S1P receptors in the cardiovascular system and discusses their potential for treating cardiovascular conditions and/or their role on the clinical pharmacology of drugs so far approved for non-cardiovascular conditions. Basic research has recently produced data useful to understand the molecular pharmacology of S1P and S1P receptors, regarding biased agonism, S1P storage, release and vehiculation and chaperoning by lipoproteins, paracrine actions, intracellular non-receptorial S1P actions. On the other hand, the approval of fingolimod and newer generation S1P receptor ligands as immunomodulators, provides information on a number of clinical observations on the impact of these drugs on cardiovascular system which need to be integrated with preclinical data. S1P receptors are potential targets for prevention and treatment of major cardiovascular conditions, including hypertension, myocardial infarction, heart failure and stroke.


The neural correlates of individual differences in numerosity perception: A voxel-based morphometry study.
Numerosity perception is a fundamental cognitive function in humans and animals. Using an individual difference approach with a comprehensive dataset (N = 249), we performed a voxel-based morphometry analysis to unravel the neuroanatomical substrates associated with individual differences in numerosity perception sensitivity, measured by a classical non-symbolic numerical judgment task. Results showed that greater gray matter volume (GMV) in the left cerebellum, right temporal pole, and right parahippocampal was positively correlated to higher perceptual sensitivity to numerosity. In contrast, the GMV in the left intraparietal sulcus, and bilateral precentral/postcentral gyrus was negatively correlated to the sensitivity of numerosity perception. These findings indicate that a wide range of brain structures, rather than a specific anatomical structure or circuit, forms the neuroanatomical basis of numerosity perception, lending support to the emerging network view of the neural representation of numerosity. This work contributes to a more comprehensive understanding of how the brain processes numerical information.


Transfer of learned dynamics between different surgical robots and operative configurations.
Using the da Vinci Research Kit (dVRK), we propose and experimentally demonstrate transfer learning (Xfer) of dynamics between different configurations and robots distributed around the world. This can extend recent research using neural networks to estimate the dynamics of the patient side manipulator (PSM) to provide accurate external end-effector force estimation, by adapting it to different robots and instruments, and in different configurations, with additional forces applied on the instruments as they pass through the trocar. The goal of the learned models is to predict internal joint torques during robot motion. First, exhaustive training is performed during free-space (FS) motion, using several configurations to include gravity effects. Second, to adapt to different setups, a limited amount of training data is collected and then the neural network is updated through Xfer. Xfer can adapt a FS network trained on one robot, in one configuration, with a particular instrument, to provide comparable joint torque estimation for a different robot, in a different configuration, using a different instrument, and inserted through a trocar. The robustness of this approach is demonstrated with multiple PSMs (sampled from the dVRK community), instruments, configurations and trocar ports. Xfer provides significant improvements in prediction errors without the need for complete training from scratch and is robust over a wide range of robots, kinematic configurations, surgical instruments, and patient-specific setups.


Ethno-ophthalmology in the Egyptian delta: an historical systems approach to ethnomedicine in the Middle East.
Ethnomedical studies of the Middle East may be enriched by a long-term historical perspective, which takes into consideration the complex syncretism, through time, of both literate and nonliterate medical systems in this region, as well as the tumultuous history of conquest and colonialism in the Middle East. In this paper, the authors place the seemingly idiosyncratic, local, 'ethno-ophthalmological' practices of one northern Egyptian community, which is afflicted by the binding eye disease, trachoma, into a broader historico-political context, through examination of the four major literate medical systems of Egypt and the imperialistic forces responsible for their entrenchment.


NA-OR: A path optimization method for manipulators via node attraction and obstacle repulsion.
This paper is concerned with the issue of path optimization for manipulators in multi-obstacle environments. Aimed at overcoming the deficiencies of the sampling-based path planning algorithm with high path curvature and low safety margin, a path optimization method, named NA-OR, is proposed for manipulators, where the NA (node attraction) and OR (obstacle repulsion) functions are developed to refine the path by iterations. In the iterations of path optimization, the node attraction function is designed to pull the path nodes toward the center of their neighbor nodes, thereby reducing the path curvature and improving the smoothness. Also, the obstacle repulsion function is developed to push the path nodes out of the potentially unsafe region by generating a repulsive torque on the path nodes, thus improving the safety margin of the motion. By introducing the effect of NA-OR, the optimized path has a significant improvement in path curvature and safety margin compared with the initial path planned by Bi-RRT, which meaningfully enhances the operation ability of manipulators for the applications that give a strong emphasis on security. Experimental results on a 6-DOF manipulator in 4 scenarios demonstrate the effectiveness and superiority of the proposed method in terms of the path cost, safety margin, and path smoothness.


The effects of full weight-bearing mobilization on clinical outcomes and subsidence in cemented and uncemented hemiarthroplasty in osteoporotic patients: A retrospective single-center study.
Early full weight-bearing mobilization is controversial in osteoporotic patients who have undergone uncemented hemiarthroplasty (UCH). The aim of the study was to compare the results of early full weight-bearing mobilization in CH and uncemented hemiarthroplasty (UCH). The effect of subsidence on the results was also evaluated. Fifty-nine patients who underwent CH and UCH were evaluated. The mean age was 79.8 years (10 females, 15 males) for CH and 75.5 years (10 females, 24 males) for UCH. All patients started immediate full weight-bearing mobilization and weight-bearing exercises. There was no difference between the groups according to the Harris Hip Score. Both groups were evaluated in subgroups according to whether there is varus in the femoral stem. There was no difference between subgroups according to the Harris Hip Score. The femoral subsidence was not determined in CH group. In the UCH group, the subsidence was 1.13 ± 1.03 mm in varus femoral stem subgroup and 0.81 ± 0.85 mm in without femoral stem varus subgroup. There was no difference in subsidence between femoral stem with varus and without varus. The subsidence did not affect the Harris Hip Score. Full weight-bearing mobilization could be safely preferred in UCH, as in CH. Femoral stem varus below 5 degrees does not affect the results and subsidence.


Lesions of the inferior alveolar nerve in sagittal osteotomy of the ramus -- experimental-study.
An experimental study on 30 hemimandibles in which sagittal osteotomy of the ramus was performed, after cleansing of the mandibular canal and filling it with wax, shows how inferior alveolar nerve lesions can occur. The use of a fine spatula is advocated for the splitting, in order to reduce the number of nerve lesions.


iTRAQ-based proteomic analysis of the hepatopancreas from Litopenaeus vannamei after trans-vp28 gene Synechocystis sp. PCC6803 immunization.
Litopenaeus vannamei (Pacific white shrimp) is one of the most commercially important varieties of shrimp cultivated in the world. Shrimp farming is a high-risk, capital-intensive industry that is susceptible to periodic outbreaks of diseases caused by viral and bacterial pathogens. Thus, there is a need to develop economically viable methods of disease control. The hepatopancreas of crustaceans are known to have an important role in their innate immune response. In this study, we have explored the immune response of the hepatopancreas from L. vannamei fed with trans-vp28 gene Synechocystis sp. PCC6803 using iTRAQ-based proteomics. A total of 214 differentially expressed proteins (DEPs) were identified, of which 143 were up-regulated and 71 were down-regulated. These proteins have diverse roles in the cell cytoskeleton and cell phagocytosis, antioxidant defense process and the response of immune related proteins. Among these proteins, the immunity associated with the functional annotation of L. vannamei was further analysed. In addition, 4 DEPs (act1, N/A, H and C7M84_013542) were analysed using parallel reaction monitoring (PRM). This is the first report of proteomics in the hepatopancreas of L. vannamei immunized with trans-vp28 gene Synechocystis sp. PCC6803.


Comparison of monoclonal and polyclonal antibodies in a two-site binding enzyme immunoassay for alphafetoprotein (AFP).
A two-site binding enzyme immunoassay for the detection of alphafetoprotein (AFP) was developed by using either a combination of two monoclonal antibodies or of one monoclonal antibody and polyclonal antibodies. The conjugation of the monoclonal antibodies to peroxidase by the periodate method yielded a somewhat higher sensitivity in the enzyme immunoassay (EIA), when compared to conjugates produced by the glutaraldehyde method. The detection limit was 10 micrograms AFP per litre when using only monoclonal antibodies in the assay. Simultaneous incubation of the sample and the monoclonal labelled antibody should be avoided unless using at least two different dilutions of the sample for investigation.


Units of measurement for fractal extent, applied to the coastal distribution of bald eagle nests in the Aleutian Islands, Alaska.
Attempts to measure the nesting density or territory size of bald eagles led to a fundamental difficulty, inherent in all such measurements on organisms which are distributed along an irregular boundary, such as a coastline. The "length" of such a boundary is not a meaningful measure, and neither can a meaningful "area" be associated with each nest. Mandelbrot's (1983) fractal geometry applies to the problem, but has not previously supplied practical units of measurement for fractals such as coastlines or rugged surfaces. A practical method is given for measuring the "extent" of such fractals, introducing a unit of variable dimension, the "metron", which includes the existing SI units of length, area and volume as special cases. A linear measure, the "spacing" allows densities on fractals of different dimensions to be compared directly. The method is applied to the distribution of bald eagle nests along the coastlines of two islands in the Aleutians, and an extension of the method to handle distributions on mountainsides and island surfaces is indicated.


Consent Practices for Assisted Vaginal Births (AVB) at Two Tertiary Care Hospitals: A Retrospective Review of Physician Documentation.
To determine whether assisted vaginal birth (AVB) consent documentation, a surrogate for in vivo consent, aligns with Canadian practice guidelines at 2 Canadian tertiary-level obstetric centres. This was a retrospective review of AVBs (vacuum and forceps) from July 2019 to December 2019 at 2 tertiary-level hospitals with template-based (Site 1) or dictation-based (Site 2) documentation. We extracted, from obstetric and neonatal charts, AVB type, physician and documenter types (resident/fellow/family doctor/generalist obstetrics and gynecology [OBGYN]/maternal-fetal medicine), and consent elements (present/absent) based on a predetermined checklist. Data were summarized and comparisons were made using chi-square test, Fisher exact test, and logistic regression, where appropriate. We identified 551 AVBs (156 forceps, 395 vacuum) with most documentation completed by generalist OBGYNs or residents (333/551, 60.5%). Most vacuum-assisted deliveries documented no specific maternal (366/395, 92.7%) or neonatal (364/395, 92.2%) risks, and 107/156 (68.6%) and 106/156 (67.9%) forceps-assisted deliveries lacked specific documentation of maternal and neonatal risk, respectively. At Site 2, postpartum hemorrhage risk at vacuum-assisted deliveries was more commonly documented (6/90 [6.7%] vs. 2/395 [0.7%], P = 0.002) as was at least 1 neonatal risk and risk of obstetrical anal sphincter injury at forceps-assisted deliveries (50/133 [37.6%] vs. 0/23 [0%], P < 0.001) and (43/133 [32.3%] vs. 0/23 [0%], P = 0.001), respectively. Opportunity to improve AVB consent documentation exists, warranting quality improvement initiatives.


Novel cellular immunotherapy using NKG2D CAR-T for the treatment of cervical cancer.
Cellular immunotherapy, including chimeric antigen receptor (CAR) modified T cell therapy, has been regarded as one of the most potential antineoplastic drugs for hematological malignancies and solid tumor. However, due to lacking the suitable target, there is no CAR-T drug had been appoved by FDA for the treatment of cervical cancer, one of the most malignant cancers for women. In current study, we designed a NKG2D CAR-T targeting NKG2DL. The NKG2D CAR-T exhibited high-efficient anti-tumor capacity for NKG2DL positive cervical cancer cell line in vitro. In addition, the amount of cytokines secreted from CAR-T cells have had significantly enhanced after co-cultured with NKG2DL positive tumor cell in vitro. In vivo, NKG2D CAR-T cells presented a robust capacity of significantly suppressing tumor growth. Moreover, there was no obvious off-target toxicity after NKG2D CAR-T infusion. Taken together, NKG2D CAR-T showed excellent therapy effect for cervical cancer and might be used as a novel cellular therapeutic agent for treating cervical cancer.


Decreased interferon-α production in response to CpG DNA dysregulates cytokine responses in patients with multiple sclerosis.
Type I interferons (IFNs), represented by IFN-α and β, activate immune effector cells belonging to the innate and adaptive immune systems. Plasmacytoid dendritic cells (pDCs) produce IFN-α in response to CpG DNA. We aimed to examine the impact of pDC-produced IFN-α on the adaptive immune system in Multiple Sclerosis (MS). Our results demonstrated that CpG DNA-induced IFN-α production was significantly decreased in PBMCs from MS patients. Decreased levels of IL-12 p70, IFN-γ, and IL-17 and increased level of IL-10 were found in CpG DNA-treated PBMCs of healthy subjects unlike in those from MS patients. In samples pre-treated with IFN-α and IFN-β, decreased levels of IL-12 p70, IFN-γ, and IL-17 and increased level of IL-10 were detected in PBMCs from MS patients. These results suggest that CpG DNA-induced decreased IFN-α production causes pro-inflammatory cytokine secretion, and either IFN-α or IFN-β induces anti-inflammatory cytokine secretion in the adaptive immune system in MS.


Red blood cell distribution width and long-term outcome in patients undergoing percutaneous coronary intervention in the drug-eluting stenting era: a two-year cohort study.
Previous studies suggest the higher the red blood cell distribution width (RDW) the greater the risk of mortality in patients with coronary artery disease (CAD). However, the relationship between RDW and long-term outcome in CAD patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) remains unclear. This study was designed to evaluate the long-term effect of RDW in patients treated with drug-eluting stent for CAD. In total of 2169 non-anemic patients (1468 men, mean age 60.2 ± 10.9 years) with CAD who had undergone successful PCI and had at least one drug-eluting stent were included in this study. Patients were grouped according to their baseline RDW: Quartile 1 (RDW<12.27%), Quartile 2 (12.27% ≤ RDW <13%), Quartile 3 (13% ≤ RDW<13.5%), and Quartile 4 (RDW ≥ 13.5). The incidence of in-hospital mortality and death or myocardial infarction was significantly higher in Quartiles 3 and 4 compared with Quartile 1 (P<0.05). After a follow-up of 29 months, the incidence of all-cause death and stent thrombosis in Quartile 4 was higher than in Quartiles 1, 2, and 3 (P<0.05). The incidence of death/myocardial infarction/stroke and cardiac death in Quartile 4 was higher than in Quartiles 1 and 2 (P<0.05). Multivariate Cox regression analysis showed that RDW was an independent predictor of all-cause death (hazard ratio (HR) = 1.37, 95% confidence interval (CI) = 1.15-1.62, P<0.001) and outcomes of death/myocardial infarction/stroke (HR = 1.21, 95% CI = 1.04-1.39, P = 0.013). The cumulative survival rate of Quartile 4 was lower than that of Quartiles 1, 2, and 3 (P<0.05). High RDW is an independent predictor of long-term adverse clinical outcomes in non-anemic patients with CAD treated with DES.