Quality improvement program reduces venous thromboembolism in infants and children with long-gap esophageal atresia (LGEA).
Patients with long-gap esophageal atresia (LGEA) treated with the Foker process are at increased risk of venous thromboembolism (VTE). An institutional quality improvement program to decrease VTE risk factor exposure and utilize prophylactic anticoagulation was implemented. We aim to evaluate the efficacy and safety of a VTE risk-reduction program in patients with LGEA. Implementation and evaluation of a VTE risk-reduction program in patients with LGEA from 2012 to 2015 was performed. Symptomatic VTE with radiographic confirmation were defined as events. Post-program characteristics were evaluated and compared to a historical cohort. Sixty-seven patients were identified. Two developed VTE (7 %) post-program implementation; compared to 13/40 (33 %) VTE incidence in the historical cohort (p = 0.018). Baseline demographics were similar, including age, esophageal atresia type and gap length. Post-protocol patients had fewer paralysis episodes (p = 0.004), paralysis days (p = 0.003), central venous catheters (p = 0.003), thoracotomies (p < 0.001), ventilator hours (p = 0.02), and decreased hospital (p < 0.001) and ICU stay (p < 0.001). All patients in the VTE risk-reduction program were exposed to prophylactic anticoagulation. No bleeding complications and/or thrombosis-related mortality occurred. VTE risk-reduction program implementation decreased symptomatic VTE incidence with associated decreases in ICU and hospital length of stay. Prophylactic anticoagulation can be utilized safely in a complicated pediatric surgical population.


Experimental testing of the role of cytoskeleton in the solution by neurons of problems facing the brain.
Investigation of the influence of cAMP on neuronal electric activity suggests that nerve cells can solve problems using an intraneuronal calculating medium based on the cytoskeleton. When a new problem is posed, this structure has to be disassembled and assembled by the neuronal molecular computer according to the program recorded in DNA. If DNA lacks an appropriate program, the cytoskeleton will not be assembled. In our experiments, fishes which were rotated simultaneously around two mutually perpendicular axes lost their swimming ability, and some dramatic changes were observed in the cytoskeleton of their Mauthner neurons. These changes disappeared after a long-term rest: the cytoskeleton was restored simultaneously with the ability for normal swimming.


Enhanced particle-filtering framework for vessel segmentation and tracking.
A robust vessel segmentation and tracking method based on a particle-filtering framework is proposed to cope with increasing demand for a method that can detect and track vessel anomalies. We apply the level set method to segment the vessel boundary and a particle filter to track the position and shape variations in the vessel boundary between two adjacent slices. To enhance the segmentation and tracking performances, the importance density of the particle filter is localized by estimating the translation of an object's boundary. In addition, to minimize problems related to degeneracy and sample impoverishment in the particle filter, a newly proposed weighting policy is investigated. Compared to conventional methods, the proposed algorithm demonstrates better segmentation and tracking performances. Moreover, the stringent weighting policy we proposed demonstrates a tendency of suppressing degeneracy and sample impoverishment, and higher tracking accuracy can be obtained. The proposed method is expected to be applied to highly valuable applications for more accurate three-dimensional vessel tracking and rendering.


Epidemiology, classification, initial care, and administrative considerations for critically burned patients.
The care of major burn injuries is a critical care endeavor from the initial evaluation and admission until the patient is discharged from the burn intensive care unit. A thorough history and physical examination are essential and require expertise to classify each burn injury. The initial treatment of the burn must address stopping the burning process, insuring a patient airway, assessing inhalation injury, initiation of adequate fluid and electrolyte resuscitation, appropriate wound care, and institution of ancillary care, such as insertion of nasogastric tubes and urinary catheters, narcotic dosage, tetanus prophylaxis, laboratory studies, and environmental temperature control. Critical care units must be designed, equipped, and staffed to facilitate the safe and effective care of burned patients. A well trained and experienced multidisciplinary burn team under the direction of a surgeon who specializes in burns is essential to the ultimate outcome of the seriously burned patient. Effective communication among the burn team and with the burned patients requires formal protocols for general treatment as well as dynamic individualized care based on careful comprehensive observations and monitoring. The prognosis for these critically injured and ill patients depends on attention to every detail of their care, which can only be accomplished in a sophisticated critical care atmosphere with personnel skilled in intensive care techniques.


Lesch-Nyhan syndrome: the synthesis of inosine 5'-phosphate in the hypoxanthine-guanine phosphoribosyltransferase-deficient erythrocyte by alternate biochemical pathways.
Erythrocytes, obtained from a normal adult male and from a patient with Lesch-Nyhan syndrome, were incubated with [8-14C]adenine and [8-14C]hypoxanthine (Table 1). The labeled adenine was utilized to about the same extent for the synthesis of AMP by the normal subject's and the patient's erythrocytes. Deamination of AMP to IMP occurred to about the same extent in both samples. In contrast, hypoxanthine was utilized extensively for IMP synthesis in the normal erythrocyte only. The amount of total label in the IMP was about 100 times that of the Lesch-Nyhan erythrocyte, a consequence of the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity in the syndrome. No significant labeling of the AMP occurred. When aliquots of erythrocytes from both sources were incubated with 4-amino-5-imidazolecarboxamide (AICA) and sodium [14C]formate, extensive labeling of the IMP occurred in normal and in Lesch-Nyhan erythrocytes. The data suggest that AICA serves as a substrate for the adenine phosphoribosyltransferase (APRT) of the Lesch-Nyhan erythrocyte and that the ribotide of AICA, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), undergoes formylation by labeled N10-formyl tetrahydrofolic acid formed from the reaction of sodium [14C]formate with the tetrahydrofolic acid of the cell. The formyl-AICAR undergoes ring closure to IMP by a series of reactions comparable to those described for the normal erythrocyte. When 5-amino-1-ribosyl-4-imidazolecarboxamide (rAICA) and sodium [14C]formate were incubated with erythrocyte suspensions, extensive utilization for IMP synthesis was also observed in normal erythrocytes and in erythrocytes from Lesch-Nyhan patients (Table 2). The reaction sequence is somewhat different from that of AICA. AICA is not a substrate for the purine nucleoside phosphorylase of rabbit or human erythrocytes. The mechanism of rAICA utilization is visualized as a direct phosphorylation of the ribosyl compound, possibly by the adenosine kinase of the human cell. The ribotide, AICAR, formed by this mechanism, undergoes formylation and ring closure, yielding IMP. The glutamine antagonist, diazooxonorleucine (DON), was added to aliquots of patients' cells incubated with rAICA and sodium [14C]formate. DON is an effective inhibitor of the conversion of IMP to GMP and its presence in an incubation suspension resulted in a somewhat greater radioactivity of the total cellular IMP. The extension of the current studies to Lesch-Nyhan cells in culture may serve to assist in the direct evaluation of the regulatory role of IMP in the de novo pathway of purine nucleotide biosynthesis. Because of the substrate requirements of the reactions, the metabolism of AICA and rAICA may also serve to differentiate the roles of purine nucleotides and of phosphoribosylpyrophosphate (PRPP) in the pathway regulation. The findings presented also offer a possible therapeutic approach to the early treatment of the disease in the afflicted neonate...


A new front-face optical cell for measuring weak fluorescent emissions with time resolution in the picosecond time scale.
Recent developments of ultrafast fluorimeters allow measuring time-resolved fluorescence on the picosecond time scale. This implies one is able to monitor lifetimes and anisotropy decays of highly quenched systems and of systems that contain fluorophores having lifetimes in the subnanosecond range; both systems that emit weak signals. The combination of weak signals and very short lifetimes makes the measurements prone to distortions which are negligible in standard fluorescence experiments. To cope with these difficulties, we have designed a new optical cell for front-face optics which offers to the excitation beam a horizontal free liquid surface in the absence of interactions with optical windows. The new cell has been tested with probes of known lifetimes and anisotropies. It proved very useful in detecting tryptophan fluorescence in hemoglobin. If only diluted samples are available, which cannot be used in front-face optics, regular square geometry can still be utilized by inserting light absorbers into a cuvette of 1 cm path length.


Synthesis and characterization of mesoporous silica modified with chiral auxiliaries for their potential application as chiral stationary phase.
Novel chiral stationary phase (CSP) based on chiral aminoalcohol immobilized on ordered mesoporous silica SBA-15 1a and standard silica 1b and their copper complexes 1a' and 1b', respectively, was synthesized as potential material for chiral ligand exchange chromatography (CLEC). Microanalysis, inductively coupled plasma spectroscopy (ICP), thermo-gravimetric analysis (TGA), cross polarized magic angle spinning (CP-MAS) (13)C NMR, Powder X-ray diffraction (PXRD), FTIR, N(2) adsorption isotherm, scanning electron microscopy (SEM), transmitted electron microscope (TEM) and solid reflectance UV-vis spectroscopy were used to characterize these materials. All the chiral stationary phases thus synthesized were used for the separation of different racemic compounds such as mandelic acid, 2,2'-dihydroxy-1,1'-binaphthalene BINOL) and diethyl tartrate by simple medium-pressure column chromatography. Successful enantio-separation of racemic mandelic acid was achieved with all the stationary phases but 1a and 1b gave slightly better resolution than their copper complexes 1a' and 1b'. Remarkably these materials are stable under the given experimental conditions and can be used repeatedly for several cycles of enantioresolution. It was observed that the porosity and surface area of the stationary phase play an important role in the chiral separation.


Comparison of symmetrical and asymmetrical cleavage 2-cell embryos of porcine by Smart-seq2.
Early cleavage (EC) influences the development of the pre-implantation and post-implantation embryo. Symmetric cleavage (Sym) and asymmetric cleavage (Asy) have been observed in EC, but its molecular mechanism remains unclear. This study was designed to pick out the key candidate genes and signaling pathway between Sym and Asy embryos by applying Smart-seq2 technique. In in-vitro fertilization (IVF) 2-cell embryos, Sym embryos and Asy embryos accounted for 62.55% and 37.45%, respectively. The 2-cell rate, blastocyst rate and total blastocyst cells of Sym group were significantly higher than those of Asy group (31.38% vs 18.79%, 47.55% vs 29.5%, 71.33 vs 33.67, P < 0.05). The 2-cell rate, blastocyst rate and total blastocyst cell number in parthenogenetic activation (PA) embryos in Sym group were significantly higher than those in Asy group (40.61% vs 23.64%, 63.15% vs 30.11%, 50.75 vs 40.5, P < 0.05). A total of 216 differentially expressed genes (DEGs) incorporating 147 genes up-regulated and 69 genes down-regulated genes were screened under the p-value <0.05 and |log2 (fold change)| ≥ 1 when compared with Sym group. Further Gene Ontology (GO) analysis showed that these DEGs were related to the regulation of metabolic process, cell cycle, chromosome segregation, centromeric region and microtubule cytoskeleton. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the DEGs were mainly enriched to oocyte meiosis, cell cycle, p53 and Hippo signaling pathways. We concluded that asymmetric cleavage is a consequence of altered gene expression. Atg4c, Sesn2, Stk11ip, Slc25a6, Cep19 and Cep55 associated with mitochondrial function and cytoskeletal structure were probably the key candidate genesto determine the zygote cleavage pattern.


Machine Learning Guided Dopant Selection for Metal Oxide-Based Photoelectrochemical Water Splitting: The Case Study of Fe2 O3 and CuO.
Doping is an effective strategy for tuning metal oxide-based semiconductors for solar-driven photoelectrochemical (PEC) water splitting. Despite decades of extensive research effort, the dopant selection is still largely dependent on a trial-and-error approach. Machine learning (ML) is promising in providing predictable insights on the dopant selection for high-performing PEC systems because it can uncover correlations from the seemingly ambiguous linkages between vast features of dopants and the PEC performance of doped photoelectrodes. Herein, the authors successfully build ML model to predict the doping effect of 17 metal dopants into hematite (Fe2 O3 ), a prototype photoelectrode material. Their findings disclose the critical parameters from the 10 intrinsic features of each dopant. The model is further experimentally validated by the coherent prediction on Y and La dopants' behaviors. Further interpretation of the ML model suggests that the chemical state is the most significant selection criteria, meanwhile, dopants with higher metal-oxygen bond formation enthalpy and larger ionic radius are favored in improving the charge separation and transfer (CST) in the Fe2 O3 photoanodes. The generic feature of this ML guided selection criteria has been further extended to CuO-based photoelectrodes showing improved CST by alkaline metal ions doping.


[Leu31, Pro34] NPY, a selective functional postjunctional agonist at neuropeptide-Y receptors in anaesthetised rats.
Neuropeptide Y (NPY), a sympathetic cotransmitter, has both prejunctional and postjunctional actions in the cardiovascular system. In the bioassay system used here NPY attenuates cardiac vagal action (an indicator of prejunctional or Y2 action) and increases blood pressure (an indicator of postjunctional or Y1 action). [Leu31,Pro34]NPY has little or no prejunctional activity i.e. does not attenuate cardiac vagal action, but increases blood pressure as effectively as NPY. [Leu31,Pro34]NPY can therefore be used in functional experiments to distinguish between the two types of NPY receptor.


Non-enzymatic template-directed synthesis of RNA copolymers.
Cytosine-rich RNA copolymers facilitate the template-directed synthesis of complementary oligomers from mononucleotide 5'-phospho-2-methylimidazolides (Fig. 1). The efficiency of this reaction falls sharply as the ratio of cytosine to non-cytosine in the template is decreased. This is a severe limitation for self-replication because it means that any cytosine-rich polynucleotide that can serve as a good template will produce a cytosine-poor complementary strand that is unable to direct further rounds of synthesis. Studies with low-ratio random copolymer templates have shown that the efficiency can be increased by adjusting initial monomer concentrations and by providing additional activated monomers during later stages of the reaction. The oligomeric reaction products can be studied in detail using high performance liquid chromatography. It is possible to separate oligonucleotides on the basis of chain length and base composition. Thus a wealth of information is available to characterize the distribution of products over the course of the reaction and under a variety of reaction conditions.


Azathioprine-induced in vitro inhibition of prostaglandin E2 production by rabbit retina.
Although much work exists concerning the clinical and immunosuppressive effects of azathioprine, little is known of the mechanism of action of this drug. The present study reports that azathioprine at the concentrations of 0.1 and 0.05 micrograms/ml causes a significant suppression of in vitro prostaglandin E2 production by rabbit retinas. However, at concentrations below (0.01 microgram/ml) or above (1,10 micrograms/ml) azathioprine was not inhibitory effect. These results suggest a dose-dependent inhibitory effect of azathioprine on prostaglandin E2 production.


Does Menopausal Status Affect Dry Eye Disease Treatment Outcomes with OC-01 (Varenicline Solution) Nasal Spray? A Post Hoc Analysis of ONSET-1 and ONSET-2 Clinical Trials.
This study sought to compare the efficacy of OC-01 (varenicline solution) nasal spray for treatment of dry eye disease (DED) in postmenopausal women (PM+) versus women who were not postmenopausal (PM-). This was a post hoc subgroup analysis of data integrated from two prior randomized controlled clinical trials, ONSET-1 and ONSET-2. Women randomized to treatment with OC-01 (varenicline solution) nasal spray 0.03 mg or vehicle control (VC) whose self-reported menopausal status (PM+ versus PM-) was known were included. Outcomes included the treatment difference (the OC-01 [varenicline solution] nasal spray change from baseline [CFB] minus VC CFB) in Schirmer test score (STS, mm) with anesthesia and the eye dryness score (EDS) measured on a 100-mm visual analog scale (0 = no discomfort, 100 = maximal discomfort). Least-squares mean treatment differences were derived from analysis of covariance (ANCOVA) models. Overall, 449 female participants in the ONSET-1 and ONSET-2 trials randomized to the OC-01 (varenicline solution) nasal spray 0.03 mg or VC groups were included in this analysis. The treatment-menopausal status interaction terms in the STS and EDS ANCOVA and logistic regression models were not statistically significant (p > 0.05), indicating consistency of treatment effect between the PM- and PM+ groups. The treatment difference in STS was similar in the PM- and PM+ groups (6.7 and 5.5 mm, respectively). The treatment difference in EDS was similar in the PM- and PM+ groups (- 5.5 and - 4.1, respectively). OC-01 (varenicline solution) nasal spray demonstrated similar efficacy in promoting natural tear production and improving symptoms in both PM- and PM+ groups. As menopausal-related hormonal changes may be associated with more severe DED, these results may support OC-01 (varenicline solution) nasal spray as an effective treatment for DED in women regardless of presenting menopausal status. Post hoc subgroup analysis of data integrated from ONSET-1 (ClinicalTrials.gov identifier NCT03636061) and ONSET-2 (ClinicalTrials.gov identifier NCT04036292).


Effects of the mas-related gene (Mrg) C receptor agonist BAM6-22 on nociceptive reflex activity in naive, monoarthritic and mononeuropathic rats after intraplantar and intrathecal administration.
MrgC receptors are selectively expressed on peripheral and central terminals of small calibre nociceptive fibres. Peptide agonists of the MrgC receptor were reported to modulate nociceptive transmission exerting either pro- or antinociceptive effects depending on site of action and pain model used. Here, we investigated the effect of intraplantar and intrathecal administration of the selective MrgC receptor agonist BAM6-22 on mechanically and electrically evoked nociceptive reflex activity as a uniform readout measure in naïve, monoarthritic and mononeuropathic rats. In naïve rats, intraplantar BAM6-22 enhanced, whereas intrathecal BAM6-22 did not modulate mechanically-evoked nociceptive reflex activity. In monoarthritic rats, intraplantar BAM6-22 had no effect, whereas intrathecal BAM6-22 inhibited mechanically evoked nociceptive reflex activity. In mononeuropathic rats, BAM6-22 reduced mechanically evoked nociceptive reflex activity after both intraplantar and intrathecal administration. BAM6-22 did not modulate electrically evoked nociceptive reflex activity in any condition. Thus, the results of the present investigation confirm and add to previous studies demonstrating that site of action, (patho)-physiological state and stimulus modality determine the effect quality of MrgC receptor agonists. It still needs to be explored how concurrent activation of peripheral and spinal MrgC receptors modulates nociceptive processing under conditions of both acute and chronic pain to evaluate the therapeutic potential of putative small molecule MrgC receptor agonists as innovative analgesics.


Stromal protein degradation is incomplete in Arabidopsis thaliana autophagy mutants undergoing natural senescence.
Degradation of highly abundant stromal proteins plays an important role in the nitrogen economy of the plant during senescence. Lines of evidence supporting proteolysis within the chloroplast and outside the chloroplast have been reported. Two extra-plastidic degradation pathways, chlorophagy and Rubisco Containing Bodies, rely on cytoplasmic autophagy. In this work, levels of three stromal proteins (Rubisco large subunit, chloroplast glutamine synthetase and Rubisco activase) and one thylakoid protein (the major light harvesting complex protein of photosystem II) were measured during natural senescence in WT and in two autophagy T-DNA insertion mutants (atg5 and atg7). Thylakoid-localized protein decreased similarly in all genotypes, but stromal protein degradation was incomplete in the two atg mutants. In addition, degradation of two stromal proteins was observed in chloroplasts isolated from mid-senescence leaves. These data suggest that autophagy does contribute to the complete proteolysis of stromal proteins, but does not play a major degenerative role. In addition, support for in organello degradation is provided.


Correcting for baseline differences in the comparison of rates.
Statistical adjustment of baseline differences (bias attributable to confounding covariates) in the comparison of rates is often carried out by the stratification approach (e.g. the "direct standardization method"). However, this approach is usually not feasible for simultaneous adjustment of more than one confounding covariates given modest sample size. Also, the stratification approach requires grouping a continuous adjustment variable into broad categories, and consequently, residual confounding of the adjusted rates can still occur. These drawbacks can be overcome by multiple regression. This communication considers a statistical procedure for the comparison of occurrence rate of some event across two or more exposure or treatment groups adjusting for one or more confounding covariates. The procedure is based on the multiple logistic regression model. A detailed numeric example to illustrate the application of the method is presented. A computer program to carry out the statistical procedures is available from the authors.


Hemodialysis hypotension: interaction of inhibitors, iNOS, and the interdialytic period.
Hypotension during hemodialysis in end-stage renal disease (ESRD) not explained by excessive ultrafiltration has been linked to an apparent increase in the synthesis of nitric oxide (NO). The authors tested whether the induction of NO synthase (iNOS) by cytokines or differences in the concentrations of inhibitors of NOS or both could account for variability in the amount of NO synthesized during hemodialysis. Plasma levels of an inhibitor of NOS, asymmetric dimethylarginine (ADMA), L-arginine, the substrate for NOS, the end-products N02+N03, iNOS activity in circulating buffy coat cells, and their interdialytic changes were measured in 10 patients during three treatments. Predialysis (0') levels of ADMA were markedly elevated with a mean of 0.008+/-0.002 micromol/mL of deproteinized plasma, compared to controls where ADMA is present in trace amounts. ADMA levels from 30 minutes to the end of dialysis correlated directly with the drop in blood pressure (BP), with levels being much higher in patients with severe hypotension. Postdialysis ADMA levels correlated directly with the 0' systolic BP and the drop in BP at the next dialysis treatment. NOS activity was detected in two thirds of the predialysis buffy coat samples, and appeared to increase as dialysis progressed. 0' iNOS activity correlated inversely with the 0' BP, but activities did not differ based on percent drop in BP. iNOS activity in the 0' samples correlated inversely with the time since the last dialysis, reflecting the greater accumulation of dialyzable inhibitors of NOS as the interval is prolonged. The interdialytic change in iNOS activity correlated inversely with the drop in BP. The isoform detected immunochemically in the buffy coat samples had an Mr of 130 kDa and was reactive with antihuman iNOS. Thus, iNOS is already induced in the cells of the buffy coat in many intermittently hemodialyzed ESRD subjects, but its expression may be masked by inhibitors. After 60 minutes of dialysis (too brief a time for the de novo induction of iNOS,) the appearance of or increase in iNOS activity suggests that an inhibitor had been removed. Because ADMA levels are associated with higher predialysis systolic BPs that result in a greater severity of hypotension, reduction in ADMA concentrations would appear to play a major role in the resumption of NO synthesis by various isoforms.


Impact of Pertussis on the Italian population: Analysis of hospital discharge records in the period 2001-2014.
The study aimed to analyze and update the impact of pertussis on the Italian population by evaluating pertussis-related hospital admissions in the period 2001-2014. Hospital Discharge Records (HDR) were provided by the National Archive of HDR data of the Ministry of Health. Only hospitalizations included in the primary diagnosis were evaluated. Significant trends over the considered years were assessed as average annual percent changes (AAPC) applying the Joinpoint model. A total of 7,102 hospital admissions for pertussis (main diagnosis) were registered; the trend of hospitalizations progressively decreased from >1/100,000 inhabitants in the years 2001-2004 to 0.64/100,000 inhabitants in 2014. A great part of hospitalizations (63.6%) involved subjects <1 year of life; almost 20% of cases were registered in the age class 5-14 years. The Joinpoint analysis showed a statistically significant variation in some age classes. Even if this study shows a decreasing trend in the number of pertussis-related hospitalizations, the impact of the disease in Italy in terms of hospital admissions continues to be relevant, especially in the <1 year age class. Pertussis therefore continues to be, in Italy as well as in other European countries, an important public health issue.


Polyethylene Oxide and Silicon-Substituted Hydroxyapatite Composite: A Biomaterial for Hard Tissue Engineering in Orthopedic and Spine Surgery.
Tissue engineering and biomaterials have made it possible to innovate bone treatments for orthopedic and spine problems. The aim of this study is to develop a novel polyethylene oxide (PEO)/silicon-substituted hydroxyapatite (Si-HA) composite to be used as a scaffold for hard tissue engineering in orthopedic and spine procedures. The composite was fabricated through the electrospinning technique. The applied voltage (5 kV) and PEO concentration (5%) were fixed. Processing parameters such as the flow rates (20 μl/min and 50 μl/min), distances from capillary tube to the collector (130 mm and 180 mm), spinning time (10 min and 20 min), and concentration of Si-HA (0.2% and 0.6%) were explored to find the optimum conditions to produce fine composite fibers. Scanning electron microscope images showed that 5% PEO, 5% PEO/0.2% Si-HA, and 5% PEO/0.6% Si-HA fibers were successively produced. Flow rates and working distances showed significant influence on the morphology of the polymeric and composite fibers. A high flow rate (50 μl/min) and a larger working distance (180 mm) resulted in larger fibers. The comparison between the mean fiber diameter of 5% PEO/0.2% Si-HA and 5% PEO/0.6% Si-HA showed to be significantly different. As the Si-HA concentration increased, certain fibers were having particles of Si-HA that were not properly integrated into the polymer matrix. Synthesis of a novel biomaterial for hard tissue scaffold through electrospinning was successful. In general, PEO/Si-HA fibers produced have the desired characteristics to mimic the extracellular matrix of bone.


Core Needle Biopsy Specimens Are More Appropriate than Surgical Specimens for Evaluating the Expression of Phosphoproteins as Biological Markers in Invasive Breast Cancer.
To evaluate whether core needle biopsy specimens (CNBS) would be better than surgical specimens (SS) for evaluating phosphoproteins as biological markers in breast cancer. This retrospective analysis included a total of 99 patients who had invasive breast cancer and were treated surgically between January 2012 and July 2013. The expression of phosphorylated ribosomal protein S6-kinase-1 (p-S6K1), phosphorylated protein kinase B (p-AKT), and estrogen receptor (ER) were assessed immunohistochemically on both CNBS and SS for each patient. The expression rate of phosphoprotein at any intensity was higher on CNBS than on SS (p-S6K1, 99.0% versus 59.6%; p-AKT, 94.9% versus 56.6%). p-S6K1and p-AKT expression was classified as negativity (absence to weak staining) or positivity (moderate to strong staining) for further analysis. For p-S6K1, 24.2% of patients showed positivity on CNBS and negativity on SS, while 7% of the patients showed negativity on CNBS and positivity on SS. For p-AKT, 70.7% of the patients showed positivity on CNBS and negativity on SS, while only 1.0% of patients showed negativity on CNBS and positivity on SS. CNBS may be the more appropriate specimen type for immunohistochemical examination of phosphoprotein expression in invasive breast cancer.


[The effects of orthodontic treatment on the morphology of temporomandibular joint of the adult with the low angle Class II malocclusions: a CT study].
To analyze the effects on the morphology of temporomandibular joint (TMJ) of the adult with the low angle Class II malocclusions before and after orthodontic treatment comparatively. To provide the references for the orthodontic treatment of the adults. 19 adult patients with low angle Class II malocclusions were chosen and treated with Damon self-ligating braces. The examinations of 16-slice spiral CT were taken before and after the orthodontic treatment. The parameters of skeletal morphology of TMJ were measured in the multiplanar reconstruction (MPR) images. The results were analysed statistically. The rate of condyles in a center position in the glenoid fossa after the treatment was 52.6%(20/38), and the rate of retrodisplacement was 31.6% (12/38). The position of the condyles before and after the orthodontic treatment had significant differences (P<0.05, chi2=4.41, chi2=5.32). The mean value of the anterior oblique angle of condyle decreased by 2.32 degrees +/- 1.78 degrees after treatment, meanwhile the average height of the condylar head increased by (1.07 +/- 0.29) mm. There were significant differences in both results before and after treatment (P<0.05). The orthodontic treatment can make the TMJ structures stable and beneficial to relieve the symptoms by moving the condyle forward, increasing the height and reconstructing the anterior oblique angle of condyle on adult patients with low angle Class II malocclusions.


Prefrontal hypoactivity associated with impaired inhibition in stimulant-dependent individuals but evidence for hyperactivation in their unaffected siblings.
A neurocognitive endophenotype has been proposed for stimulant dependence, based on behavioral measures of inhibitory response control associated with white matter changes in the frontal cortex. This study investigated the functional neuroimaging correlates of inhibitory response control, as functional activity serves as a more dynamic measure than brain structure, allowing refinement of the suggested endophenotype. Stimulant-dependent individuals (SDIs), their unaffected siblings (SIBs), and healthy controls (CTs) performed the stop-signal task, including stop-signal reaction time (SSRT) as a measure of response inhibition, while undergoing functional magnetic resonance imaging. SDIs had impaired response inhibition accompanied by hypoactivation in the ventrolateral prefrontal cortex (PFC). In addition, they demonstrated hypoactivation in the anterior cingulate when failing to stop. In contrast, no hypoactivations were noted in their unaffected SIBs. Rather, they exhibited increased activation in the dorsomedial PFC relative to controls, together with inhibitory performance that was intermediate between that of the stimulant group and the healthy CT group. Such hyperactivations within the neurocircuitry underlying response inhibition and control are suggestive of compensatory mechanisms that could be protective in nature or could reflect coping with a pre-existing vulnerability, thus expressing potential aspects of resilience. The functional activation associated with response inhibition and error monitoring showed differential patterns of results between SDIs and their unaffected first-degree relatives, suggesting that the proposed endophenotype does not generalize to functional brain activity.


Identification and tissue expression profile of genes from three chemoreceptor families in an urban pest, Periplaneta americana.
Periplaneta americana is a notorious urban pest prevalent in human habitats; very little is known about its chemosensory mechanism. Employing the advanced next-generation sequencing technique, in the present study, we conducted transcriptome sequencing and analysis of the antennae of the adult males and females as well as their mouthparts using an Illumina platform. This resulted in the discovery of a huge number of the members of all major known chemosensory receptor families in P. americana, including 96 odorant receptors (ORs), 53 ionotropic receptors (IRs), and 33 gustatory receptors (GRs). Tissue expression profiles showed most of them mainly expressed in antennae and phylogenetic analysis demonstrated the expansion in the clade distinguishing them from other functionally well-known Lepidoptera species. A high percentage of chemosensory receptor genes (ORs in particular) showing female antenna bias in mRNA expression was observed. Our results provide a basis for further investigations on how P. americana coordinates its chemosensory receptor genes in chemical communication with environments, and for development of novel pest management approaches.


Characterization of DOPA decarboxylase mRNA in rat pheochromocytoma.
Total poly (A+) RNA has been extracted from rat pheochromocytoma and translated in vitro by means of a reticulocyte lysate system. We show that two antisera, prepared against pig kidney DOPA decarboxylase (DDC) or rat pheochromocytoma DDC, immunoprecipitate an in vitro synthetized 50 kDa polypeptide identified as DDC by competition experiments with pure DDC. The proportion of specific mRNA has been calculated and represents 0.05% of total poly A+ mRNA. Its size has been established by electrophoresis in methylmercuric hydroxide containing agarose gel, corresponding to a 2.2 kb length mRNA.


Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers.
Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist and has been approved in the European Union and the USA for the reduction of clinical thrombotic events in patients with acute coronary syndromes. This study aimed to assess the effect of food on ticagrelor pharmacokinetics. The study was an open-label, randomized, 2-period crossover single-centre trial; 26 healthy volunteers received a single 270 mg (3×90 mg tablets) ticagrelor dose orally following: (i) a 10-h overnight fast; and (ii) after a standard high-fat, high-calorie breakfast. Ticagrelor and AR-C124910XX (a major pharmacologically active metabolite) plasma concentrations were quantified for pharmacokinetic analysis. Ticagrelor median time to maximum concentration (t(max); 2·5 h vs. 1·5 h) was slightly delayed in the fed vs. fasting state. Maximum concentration of ticagrelor (C(max)) was comparable between the two states with 95% confidence intervals (CI) of the geometric least-squares (GLS) mean ratio (0·85-1·03) being within no-effect limits (0·80-1·25). Ticagrelor exposure was slightly higher with food intake; area under the plasma concentration-time curve from zero to infinity (AUC) was 21% higher compared with fasting state (95% CI of GLS mean ratio=1·13-1·30). For AR-C124910XX, AUC (95% CI of GLS mean ratio=0·93-1·07) was unaffected by food consumption. Median t(max) of the metabolite was slightly longer in the fed than fasting state (3·5 h vs. 1·5 h). Mean C(max) for AR-C124910XX was slightly lower (22%) with food intake vs. fasting (95% CI of GLS mean ratio 0·69-0·88). Food effects on ticagrelor AUC and AR-C124910XX C(max) were small and are considered to be of minimal clinical significance. Thus, ticagrelor can be administered with or without food.


High-field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy.
We analyzed specimens of histologically normal human cerebrum obtained at surgery for medically refractory epilepsy using proton magnetic resonance spectroscopy. Perchloric acid extracts of anterolateral temporal lobe cortex contained greater concentrations of creatine, N-acetylaspartate, gamma-aminobutyric acid, alanine, and glutamate than the under lying white matter, which contained more acetate. Frontal and temporal lobe specimens composed of both gray and white matter failed to show statistically significant differences in the concentrations of creatine, N-acetylaspartate, alanine, aspartate gamma-aminobutyric acid, glutamate, glycine, taurine, threonine, valine, acetate, choline, beta-hydroxybutyric acid, inositols, lactate pyruvate, or succinate.


Neonatal adrenal hemorrhage presenting as an acute scrotum: A case report on the rare presentation of right adrenal hemorrhage and contralateral left scrotal hematoma.
Acute swelling and discoloration of the scrotum in a newborn is a rare condition and can have several causes such as testicular torsion, trauma, inguinal hernia, hydrocele, or adrenal hemorrhage. We report a neonate of adrenal hemorrhage presenting clinically as the acute scrotum. Definitive diagnosis was defined by ultrasonography and computed tomography scan, and the conservative management was successfully performed. Adrenal hemorrhage should be considered as one of the causes of acute scrotum in newborns. The abdominal ultrasonography, as well as the scrotal ultrasonography, should be performed routinely to achieve a definitive diagnosis to avoid unnecessary invasive procedures.


Structural insights into LINC complexes.
Communication between nucleus and cytoplasm extends past molecular exchange and critically includes mechanical wiring. Cytoskeleton and nucleoskeleton are connected via molecular tethers that span the nuclear envelope. Sad1, UNC84 (SUN)-domain proteins spanning the inner nuclear membrane and Klarsicht, ANC-1 and SYNE/Nesprin-1 and -2 Homology (KASH)-peptide bearing proteins residing in the outer nuclear membrane directly bind and constitute the core of the LInkers of Nucleoskeleton and Cytoskeleton (LINC) complex. These connections appear critical for a growing number of biological processes and aberrations are implicated in a host of diverse diseases, including muscular dystrophies, cardiomyopathies, and premature aging. We discuss recent developments in this vibrant research area, particularly in context of first structural insights into LINC complexes reported in the past year.


The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS).
The fentanyl HCl patient-controlled transdermal system (PCTS) is a noninvasive, needle-free, credit card-sized drug delivery system designed for the on-demand management of acute pain in a medically supervised setting. The objective of these studies was to determine the effect of dosing frequency on the pharmacokinetics of fentanyl delivered by the PCTS. All three studies were single-centre, open-label, randomised, crossover studies. The fentanyl HCl PCTS was applied to the upper outer arm of all participants. In the first study, participants (n = 30) received three fentanyl HCl PCTS 25 microg treatments: two sequential doses hourly for 23.33 hours, six sequential doses every 3 hours for 22 hours, and 72 doses continuously over 12 hours. Participants (n = 31) in the second study received three fentanyl HCl PCTS 40 microg treatments: two sequential doses hourly over 23.33 hours, six sequential doses every 3 hours over approximately 10 hours, and 80 doses continuously over 13.33 hours. In the third study, participants (n = 28) received four fentanyl HCl PCTS 40 microg treatments: 6, 18, 36 and 80 doses over 1, 3, 6 and 13.33 hours, respectively. Naltrexone was used to block the opioid effects of fentanyl. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)) were determined. In the first study, the dose-normalised AUC (AUCn) values for the 2- and 6-dose sequence treatments were not significantly different (p = 0.937), suggesting that the frequency of dosing has little effect on the amount of fentanyl absorbed; however, the AUCn for the 72-dose treatment was significantly lower than that of the other treatments (p = 0.001), which were of longer duration. The results of the second study paralleled those from the first, suggesting that the bioavailability of fentanyl delivered by the PCTS increases as a function of time and is likely to be independent of dosing frequency. Results from the third study suggested that approximately 40% of the nominal 40 microg fentanyl dose is absorbed during the first hour of treatment, with the full nominal dose absorbed after approximately 10 hours. The fentanyl HCl PCTS was well tolerated. The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.


Human milk calcium and phosphate levels of mothers delivering term and preterm infants.
Human milk calcium (Ca) and phosphate (P) content from mothers of 10 term and 15 preterm infants was evaluated during the first month of lactation. Ionized Ca of preterm milk was higher than term milk on day 14, 6.70 +/- 0.26 (mean +/- SEM) vs. 5.47 +/- 0.09 mg/dl, and on day 30, 6.35 +/- 0.14 vs. 5.67 +/- 0.13 mg/dl (t test, p less than 0.05). Total Ca and P levels of term and preterm milk were not different, and decreased during the first month of lactation. Nursing preterm infants had higher serum P than term infants on day 14 and 30. Serum Ca and 25-OH D values were not different between nursing preterm and term infants or between the lactating mothers.


Comparative effects of platelet activating factor, leukotriene D4 and histamine on guinea pig trachea, bronchus and lung parenchyma.
The myotropic effect of platelet activating factor (PAF), leukotriene D4 (LTD4) and histamine were compared on guinea pig pulmonary tissues. The initial administration of PAF induced a contraction of strips of trachea, bronchus and lung parenchyma. However subsequent injections were characterized by relaxation of trachea and bronchus and a highly reduced (if any) contraction of the parenchyma. The three tissues of the guinea pig respiratory system contracted strongly to leukotriene D4 and histamine. Indomethacin blocked PAF-induced relaxation of the trachea and bronchus and reduced the contraction of the lung parenchyma. The injection of PAF in the pulmonary circulation stimulated the release of substance(s) causing the contraction of the trachea, bronchus and parenchyma. This study suggests that PAF is not a direct agonist of bronchoconstriction.


Polymerization shrinkage and contraction stress of dental resin composites.
The aim of this study was to evaluate the shrinkage, contraction stress, tensile modulus, and the flow factor of 17 commercially available dental resin composites. The volumetric shrinkage measurements were performed by mercury dilatometry, and the contraction stress and tensile modulus were determined by means of stress-strain analysis. The statistical analysis was conducted by ANOVA and Tukey's post hoc test, and linear regression. Strong linear correlation for most resin composites were found for (i) contraction stress and shrinkage (ii) contraction stress and tensile modulus, and (iii) shrinkage and tensile modules. For most of the materials the unpolymerized resin content determines the amount of shrinkage, contraction stress and tensile modules. The pre-polymerized clusters in Heliomolar results in improved shrinkage/contraction stress properties. The shrinkage/contraction stress for Filtek Z100, Aelite Flo, and Flow-it was too high for the amount of resin in the resin composite. This was rationalized by high polymerization rates, a flow factor, and the nature of the resin. High shrinkage and/or high contraction stress may lead to failure of the bond between the resin composites and the tooth structure. This study shows that the unpolymerized resin content determines the amount of shrinkage, contraction stress and tensile modules. Therefore, using pre-polymerized clusters will improve shrinkage/contraction stress properties, as was shown in Heliomolar, while high polymerization rates, and low flow factors have a deteriorative effect on the shrinkage/contraction stress properties.


[Application of recombinant human epidermal growth factor on chronic ulcer wound].
To observe the effect of recombinant human epidermal growth factor (rhEGF) on healing of chronic ulcer wound. From January 1999 to January 2001, twenty-six patients with chronic wounds were adopted in this study. Among them, there were 17 males and 9 females, aged from 12 to 61 years. The area of the chronic wound varied from 3 cm x 3 cm to 5 cm x 8 cm and the disease course was 7 to 16 days. These patients were treated with rhEGF in the way of sprinkling locally (400 U/10 cm2). Another 26 patients with chronic wounds were adopted as the control group and were treated with 0.9% saline in the same way. The healing time of wounds and the local and systemic reactions of patients were observed. The healing time of chronic wounds was shorter obviously to about 7 days with rhEGF than that of the control group and there was significant difference between the two groups(P < 0.01). rhEGF can obviously promote the healing of chronic ulcer wound.


Cylindrin from Imperata cylindrica inhibits M2 macrophage formation and attenuates renal fibrosis by downregulating the LXR-α/PI3K/AKT pathway.
Imperata cylindrica, a medicinal plant used in Traditional Chinese Medicine, has been used to treat chronic kidney disease. Extracts of I. cylindrica display anti-inflammatory, immunomodulatory, and anti-fibrotic properties. However, the active components of the extracts and their protective mechanisms have not been fully elucidated. In this study, we explored the ability of cylindrin, the main active compound extracted from I. cylindrica, to protect against renal fibrosis and to investigate the potential mechanisms involved. At high doses, cylindrin exerted protective effects against folic acid-induced kidney fibrosis in mice. Bioinformatic analysis predicted the LXR-α/PI3K/AKT pathway as a target of regulation by cylindrin. This was supported by our in vitro and in vivo results showing that cylindrin significantly downregulated the expression of LXR-α and phosphorylated PI3K/AKT in M2 macrophages and mouse renal tissues. Furthermore, high-dose cylindrin inhibited M2 polarization of IL-4-stimulated macrophages in vitro. Our results suggest that cylindrin alleviates renal fibrosis by attenuating M2 macrophage polarization through inhibition of the PI3K/AKT pathway via downregulation of LXR-α.


[The genus Fusarium in Argentina. II. Identification of species which affect crops in the La Plata region].
Isolations from different hosts were performed to identify by their morphological, biometric and culture characteristics the species of the genus Fusarium commonly affecting crops in La Plata and its surroundings. An identification index was designed with the species isolated and a comparative chart was constructed through a revision of the genus to establish equivalents between the main classification systems.


Total endovascular repair of a malpositioneted frozen elephant trunk with Thoraflex hybrid prosthesis: A case report.
We report a case of a 56-year-old male who underwent Frozen Elephant Trunk procedure for residual type A chronic aortic dissection, complicated by the release of the distal endovascular portion of the hybrid prosthesis in the false lumen. This complication was successfully treated with a totally endovascular approach.


Clinicopathological Significance of Pathologic Complete Lymph Node Regression After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.
Pathologic complete lymph node regression (LNR), where the lymph nodes show evidence of neoadjuvant treatment effect but have no viable residual tumor cells, is sometimes observed following neoadjuvant treatments and has been shown to be prognostic; conflicting results exist in the current literature. Patients who received neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for squamous carcinoma (ESCC) were retrospectively reviewed and classified according to their LNR score; 0: N(-) with no evidence of tumor involvement or regression; 1: N(-) with evidence of complete regression; 2: N(+) with < 50% viable tumor; and 3: N(+) with > 50% viable tumor. In total, 136 patients, comprising 73, 25, 16, and 22 patients with LNR scores of 0, 1, 2, or 3, respectively, were included. Pathologic complete LNR (LNR 1) was significantly associated with lower risks of lymphovascular invasion (0%, p < 0.001) and perineural invasion (4%, p = 0.038), and a higher rate of pathologic complete response in the primary tumor (76%, p < 0.001). The 5-year overall survival rates were 42.1%, 52.8%, and 8.0% in patients with an LNR score of 0, 1, and 2/3, respectively (p < 0.001). There was no significant difference between patients with LNR scores of 0 and 1 in overall survival (p = 0.454), disease-free survival (p = 0.501), and cumulative incidence of recurrences (hazard ratio 0.84, 95% confidence interval 0.432-1.623, p = 0.601). Pathologic complete LNR could be an indicator of nCRT sensitivity and can be regarded as a good prognostic factor in patients with ESCC. In the survival curve analysis that included patients with lymph node regression (LNR) scores of 0 (blue), 1 (red), and 2/3 (green), we found that patients with pathologic complete LNR (LNR 1), which suggests prior positive nodal involvement, had similar outcomes as those without evidence of prior tumor involvement in lymph node (LNR0).


Vascular endothelial cell proliferation: regulation of cellular polyamines.
The aims were to investigate the requirement for and regulation of cellular polyamines during vascular endothelial cell proliferation. Proliferation of cultured bovine pulmonary artery endothelial cells was determined after cellular polyamine depletion. In addition, polyamine synthesis and uptake mechanisms were examined in the presence and absence of trophic stimuli and density dependent inhibition of cell proliferation. Serum stimulated, subconfluent cells ceased cell division following the inhibition of ornithine decarboxylase (ODC), a rate limiting enzyme for polyamine biosynthesis. The addition of 10 microM putrescine, the product of the enzyme reaction catalysed by ODC, completely reversed the inhibition of cell growth. Serum deprivation reduced cytosolic ODC activity to near non-detectable levels. Readdition of 10% fetal bovine serum (FBS) resulted in transient increases in ODC activity which preceded DNA synthesis and mitosis. Basic fibroblast growth factor also stimulated ODC activity in a dose dependent manner with levels approximating the maximum obtainable with FBS. In contrast, platelet derived growth factor and epidermal growth factor did not stimulate ODC activity. Finally, mitogenic stimuli did not induce ODC activity in density arrested cells. The uptake of radiolabelled putrescine from the cell medium was time dependent and saturable. Kinetic studies from dividing cells revealed a single transport component for putrescine uptake [maximum rate of uptake (Vmax) = 11.2(SEM 2.0) pmol.10(5) cells-1.h-1; Michaelis constant (Km) = 1.1(0.3) microM]. Putrescine uptake by density arrested cells was characterised by a 57% decrease in Vmax with no change in Km. Readdition of FBS to serum deprived subconfluent cells, in the presence of ODC inhibitors, resulted in a rapid increase in the rate of putrescine uptake with Vmax increasing by 533% over FBS alone by 48 h. These data suggest that polyamines are essential for endothelial cell proliferation and that synthesis and uptake mechanisms are regulated according to cell growth.


Pharmacokinetics and safety of rilpivirine in healthy Japanese subjects and exploration of ethnic sensitivity of rilpivirine pharmacokinetics with physiologically based pharmacokinetic model approach.
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.


Activated Langerhans cells release tumor necrosis factor.
Langerhans cells act as antigen-presenting cells in immune reactions in the skin. What other roles they may play in inflammation is less well defined. We have tested whether these cells can produce TNF-alpha, an important mediator of inflammation. Resting Langerhans cells produce less than 0.1 U TNF-alpha/ml. Langerhans cells stimulated with phorbol myristate acetate (PMA) and lipopolysaccharide (LPS) release 4-5 U TNF-alpha/ml. Specificity of the released TNF-alpha in an L929 cytotoxicity assay was confirmed by using neutralizing anti-TNF-alpha monoclonal antibodies, and the identity of TNF-alpha was further confirmed by Northern blot hybridization with an TNF-alpha oligomer DNA probe. Activated Langerhans cells may contribute to inflammation in the skin by releasing TNF-alpha, which is known to effect fibroblast growth, endothelial cell activation, and lymphocyte function.


[Effect of the total flavonoids from red clover and chick-pea on the lipid content in the blood and liver of rats].
Total flavonoids from clover red and nut, containing isoflavones, decreased the content of cholesterol and triglycerides in intact rats, inhibited the development of hyperlipidemia, caused by Triton WR-1339, prevented accumulation of triglycerides in rat liver and blood caused by ethanol administration. The flavonoids from these plants inhibited lipolysis, stimulated by adrenaline.


Growth faltering in childhood related to diarrhea: a longitudinal community based study.
This study aimed to evaluate the association of diarrhea and acute lower respiratory tract infections (ALRI) with growth of preschool children. A longitudinal community-based study over a 12-month period. Children were followed up with thrice-weekly household visits for collection of morbidity data. Every 4 months (round) clinical and anthropometric examinations were performed. At baseline a questionnaire was used to collect socioeconomic family data and environmental household variables. Generalized estimating equation was used in the statistical analysis. The variations in weight-for-age or height-for-age Z-scores in each round were the dependent variables, while the main independent variables were the number of days with diarrhea and ALRI. Serrinha, located in Northeast Brazil. In total, 487 children, aged 6-48 months at baseline, with 1-y complete follow-up. The number of sick days with diarrhea or ALRI was not associated with mean changes in weight-for-age Z-scores. However, the mean of height-for-age Z-scores was found to decrease in those children with 7 or more days of diarrhea (beta=-0.0472; P=0.016) but not with 1 or more days of ALRI (beta=0.0022; P=0.406) in all rounds of the follow-up period. Results of the study reinforce the concept of diarrhea burden as a major determinant of poor growth in children under 5 y of age. Actions targeted to decrease the risk factors for the occurrence of diarrhea may represent an important component of interventions aimed to ensure satisfactory child growth.


5-Aminolevulinic acid production in engineered Corynebacterium glutamicum via C5 biosynthesis pathway.
ALA (5-aminolevulinic acid) is an important intermediate in the synthesis of tetrapyrroles and the use of ALA has been gradually increasing in many fields, including medicine and agriculture. In this study, improved biological production of ALA in Corynebacterium glutamicum was achieved by overexpressing glutamate-initiated C5 pathway. For this purpose, copies of the glutamyl t-RNA reductase HemA from several bacteria were mutated by site-directed mutagenesis of which a HemA version from Salmonella typhimurium exhibited the highest ALA production. Cultivation of the HemA-expressing strain produced approximately 204 mg/L of ALA, while co-expression with HemL (glutamate-1-semialdehyde aminotransferase) increased ALA concentration to 457 mg/L, representing 11.6- and 25.9-fold increases over the control strain (17 mg/L of ALA). Further effects of metabolic perturbation were investigated, leading to penicillin addition that further improves ALA production to 584 mg/L. In an optimized flask fermentation, engineered C. glutamicum strains expressing the HemA and hemAL operon produced up to 1.1 and 2.2g/L ALA, respectively, under glutamate-producing conditions. The final yields represent 10.7- and 22.0-fold increases over the control strain (0.1g/L of ALA). From these findings, ALA biosynthesis from glucose was successfully demonstrated and this study is the first to report ALA overproduction in C. glutamicum via metabolic engineering.


TGF-beta-induced apoptosis in endothelial cells mediated by M6P/IGFII-R and mini-plasminogen.
Transforming growth factor-beta (TGF-beta), a key modulator of endothelial cell apoptosis, must be activated from the latent form (LTGF-beta) to induce biological responses. In the present study, we report activation of TGF-beta by functional and physical co-operation of the mannose-6-phosphate/insulin-like-growth-factor-II receptor (CD222) and the urokinase-type plasminogen activator receptor (CD87). We show that endothelial cells express CD222 and CD87 in a membrane complex and demonstrate that the association of these two receptors is essential for the release of active TGF-beta in the transduced mouse fibroblast used as model cells. By contrast, smooth-muscle cells, which express CD222 and CD87 at similar density to endothelial cells but not in complexed form, do not activate TGF-beta. We also have found that mini-plasminogen is a high-affinity ligand for CD222 and is essential for the activation of TGF-beta by the CD87-CD222 complex to induce apoptosis in endothelial cells. This specific mechanism of TGF-beta-mediated apoptosis in endothelial cells is thus a potential novel target to be considered for treatment of pathological vascular disorders (e.g. tumor angiogenesis).


Codeine induces increased resistance at the esophagogastric junction but has no effect on motility and bolus flow in the pharynx and upper esophageal sphincter in healthy volunteers: A randomized, double-blind, placebo-controlled, cross-over trial.
Chronic opioid use can induce esophageal dysfunction with symptoms resembling achalasia and a manometric pattern of esophagogastric junction-outflow obstruction (EGJ-OO). However, the effect of opioids in acute setting on pharyngeal function and esophageal body contractility has not been investigated. After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60 mg) or placebo (glucose syrup) was infused intragastrically. Forty-five minutes post-infusion, participants received liquid, semi-solid, and solid boluses to assess esophageal and pharyngeal function. HRiM analysis was performed adhering to the Chicago classification v3.0. (CC v3.0). Pressure flow analysis (PFA) for the esophageal body and the pharynx was performed using the SwallowGateway™ online platform. Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4 s values resulted in significantly reduced deglutitive EGJ relaxation and distal latency was significantly shorter. Distal contractility was similar in both conditions. Bolus flow resistance at the EGJ and distention pressures increased significantly after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV (p = 0.0003 vs. placebo). Codeine administration induced no significant alterations in any of the pharyngeal PFA metrics. In HV, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES. ClinicalTrials.gov number, NCT03784105.


Magnetic resonance imaging pelvimetry predicts the technical difficulty of rectal surgery.
The relationships between the pelvimetry and technical difficulties in performing rectal surgery for mid-low rectal cancer remain unclear. Two hundred and twenty-one cases of mid-low rectal cancer patients who underwent sphincter-preserved total mesorectum excision (TME) were analyzed. The data of the pelvimetry and the relative position between trocar site and tumor were measured with magnetic resonance imaging (MRI). Univariate analysis showed that the interspinous diameter, the sacrococcygeal distance, and the angle of sacral promontory inclination were significantly associated with the technical difficulty during laparoscopic surgery, but only the interspinous diameter remained an independent risk factor in multivariate analysis. The simulated trocar angle θ was an independent risk factor affecting the operation time during laparoscopic surgery, simulated trocar angle η was significantly related to intraoperative blood loss in both laparoscopic surgery and transanal TME (taTME) surgery groups. Interspinous diameter can predict difficulty in laparoscopic surgery and may provide useful information for preoperative planning and consideration of approach.


Sex-disaggregated population analysis in patients with hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a common chronic inflammatory skin disease, which affects both sexes. Identification of sex-specific risk factors, comorbidity, clinical manifestations, and treatments in HS patients. A non-interventional, cross-sectional, mono-centric study with 500 HS patients. All patients were examined by dermatologists. Prospectively collected demographic, anamnestic, clinical data, and blood parameters were evaluated. There were no significant differences in age at HS onset and in disease duration between female and male patients. Furthermore, no differences regarding the family history for HS were found between sexes. Regarding further risk factors for HS, central obesity was more frequent in women while extensive cigarette smoking and acne vulgaris were more commonly found among male patients. Regarding comorbidity, lower HDL-levels were significantly more frequent in men. Female patients were found to suffer significantly more often from back pain, especially in the neck/shoulder region and lower back. Analyzing the clinical manifestation of HS, the groin was more frequently involved in women and the axillae in men. Women showed a higher number of skin sites with inflammatory nodules, whereas fistulas were observed more frequently in men. Nevertheless, there was no difference in HS treatment applied to female vs. male patients. Data were obtained from a mono-centric study. Significant differences in HS risk factors, comorbidity, and clinical manifestation exist between female and male patients. Thus, sex-specific differences should be taken into account in the prevention as well as medical and surgical treatment of HS patients.


The effect of loss of occlusal support on mandibular morphology in growing rats.
To evaluate the effects of unilateral and bilateral premature loss of posterior occlusal support on mandibular bone dimensions in growing rats. Thirty female Wistar rats (5 weeks old) were randomized into three groups: control, unilateral mandibular molar teeth extraction, and bilateral mandibular molar teeth extraction. After 8 weeks, animals were sacrificed and acrylic rapid-prototyped templates of the mandibles were constructed. Mandibular length, ramus height, intercondylar distance, and body weight were measured and analyzed by one-way analysis of variance (Tukey test as post hoc test; α = .05). Mandibular length and intercondylar distance were significantly shorter in experimental animals, while no difference was observed for ramus height and body weight. Unilateral and bilateral premature loss of posterior occlusal support in growing rats results in a smaller mandible at skeletal maturity.


Hsa_circ_0060467 promotes breast cancer liver metastasis by complexing with eIF4A3 and sponging miR-1205.
Breast cancer (BC) is the most common cancer and the top cause of female mortality worldwide. The prognosis for patients with breast cancer liver metastasis (BCLM) remains poor. Emerging studies suggest that circular RNAs (circRNAs) are associated with the progression of BC. Exploration of circRNAs presents a promising avenue for identifying metastasis-targeting agents and improving the prognosis of patients with BCLM. Microarray and bioinformatic analyses were used to analyze differentially expressed circRNAs between three pairs of BCLM and primary BC. The roles of hsa_circ_0060467 (circMYBL2) and its target gene E2F1 in BC cells were explored by multiple functional experiments. And xenograft mouse models and hepatic metastases of BC hemi-spleen models were used to illustrate the function of circMYBL2 in vivo. The intrinsic molecular mechanism involving circMYBL2 was confirmed by bioinformatics analyses, RIP assays, CHIRP assays, luciferase reporter assays, and rescue experiments. CircMYBL2 was overexpressed in BCLM tissues and BC cells. Functionally, circMYBL2 can facilitate the proliferation and liver metastasis of BC. Mechanistically, circMYBL2 upregulated the transcription factor E2F1 by sponging miR-1205 and complexing with eukaryotic translation initiation factor 4A3 (eIF4A3) and then facilitated the epithelial-mesenchymal transition (EMT) process in BC cells. Our findings showed that circMYBL2 promoted the tumorigenesis and aggressiveness of BC through the circMYBL2/miR-1205/E2F1 and circMYBL2/eIF4A3/E2F1 axes, which may provide a novel targeted therapy for patients with BCLM.


Facilitators and barriers to the transition from registered nurse to nurse practitioner in Canada.
Understanding factors that affect integration of NPs is likely to address barriers and provide reform strategies that shape a cost-effective, sustainable, accessible, and efficient health care system. There are a limited number of current and high-quality studies examining the transition process of registered nurses (RNs) to nurse practitioners (NPs), especially in Canada. To explore the experiences of RNs transitioning to NPs in Canada. Thematic analysis of audio-recorded semi-structured interviews was conducted to explore the experiences of 17 RNs as they transitioned to NPs. A purposive sampling of 17 participants was completed in 2022. Six main themes emerged from analysis of 17 interviews. The content of themes varied according to NPs' years of experience and the NP school they attended. Peer support and mentorship programs were facilitators in the transition from RN to NP. Conversely, shortcomings in education, financial stressors, and the lack of NP role definition were seen as barriers. Legislation and regulations supportive of NPs, diverse and comprehensive education, and improved availability of mentorship programs may strengthen transition facilitators and help NPs overcome related barriers. Legislation and regulations supportive of the NP role are needed, focusing on defining the NP role and establishing an independent and consistent remuneration structure for NPs. A more in-depth and diversified educational curriculum is needed, with increased support from faculty and educators and continual encouragement of initiation and perpetuation of peer support. A mentorship program is beneficial to reduce transition shock from the role of the RN to the NP.


Beta1 and beta2-adrenergic receptor polymorphisms and idiopathic ventricular arrhythmias.
Idiopathic ventricular arrhythmias commonly refer to ventricular tachycardia (VT) and/or frequent/monomorphic premature ventricular contractions (PVC) in patients with structurally normal heart. Activation of sympathetic tone has been shown to play an important role in the provocation and maintenance of these arrhythmias. We investigated whether common single nucleotide polymorphisms in the beta(1) and beta(2)-adrenergic receptors are associated with idiopathic ventricular arrhythmias. A total of 143 unrelated patients presenting with idiopathic ventricular arrhythmias were prospectively included in a case-control association study. Patient population was matched by age and gender to the unrelated, healthy control subjects (N = 307). All study subjects were of Turkish (Anatolian Caucasian) descent. Allele and genotype frequencies of the Gly389Arg and Ser49Gly polymorphisms of the beta(1)-adrenergic receptor and Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms of the beta(2)-adrenergic receptor were compared between patient population and control subjects. The genotype frequencies were in Hardy-Weinberg equilibrium. Patients with idiopathic ventricular arrhythmias had higher frequency of Arg389Arg genotype (22.4% vs 1.6%, P < 0.001), Arg389Gly49 (5.24% vs 0.73%, P = 0.005), and Arg389Ser49 (36.7% vs 13.6%, P < 0.001) haplotypes of the beta(1)-adrenergic receptor, and higher frequency of Gly16Gly (31.5% vs 13.4%, P < 0.001), Glu27Glu genotypes (18.2% vs 10.1%, P = 0.006) and Gly16Gln27Thr164 (15.3% vs 7.4%, P = 0.002), Gly16Glu27Thr164 (13.1% vs 7%, P = 0.004), and Gly16Glu27Ile164 (13.2% vs 6%, P = 0.002) haplotypes of the beta(2)-adrenergic receptor compared to control subjects. Our data suggest that common single nucleotide polymorphisms in the beta(1) and beta(2)-adrenergic receptors are significantly associated with idiopathic ventricular arrhythmias in Turkish population.


Psychosocial and Clinical Correlates of Fatigue in Haemodialysis Patients: the Importance of Patients' Illness Cognitions and Behaviours.
Fatigue is commonly experienced in end-stage kidney disease (ESKD) and is associated with poor outcomes. Currently, little research has examined the psychosocial correlates of fatigue severity and its impact on renal disease patients. We predicted that psychological factors (distress, cognitions and behaviours) would be associated with fatigue severity and impairment in ESKD patients even when controlling for clinical and disease factors. One hundred seventy-four haemodialysis patients completed the Chalder Fatigue Questionnaire (fatigue severity) and the Work and Social Adjustment Scale (fatigue-related impairment) in addition to measures evaluating distress, fatigue perceptions, symptom beliefs and behaviours. Demographic and clinical data were also collected. Fatigue severity was not related to haemoglobin levels, serum albumin or dialysis vintage. In hierarchical regression models, demographic and clinical factors explained 20 % of the variance in fatigue (ethnicity, body mass index, exercise, log C-reactive protein and multimorbidity). Psychological distress (beta = 0.21, p < 0.01), negative beliefs about fatigue (beta = 0.10, p = 0.01) and unhelpful behaviours (all-or-nothing behaviour [beta = 0.28, p < 0.01] and avoidance [beta = 0.16, p < 0.01]) explained an additional 36.4 % of the variance. Fatigue-related impairment was associated with psychological distress, perceptions that symptoms indicate damage, avoidance behaviour and the level of fatigue severity. Patients' mood, beliefs and behaviours are associated with fatigue in dialysis patients. Psychological interventions to alter these factors may reduce fatigue severity and fatigue-related disability in ESKD patients.


The Use of Spectral Imaging to Follow the Iron and pH-Dependent Accumulation of Fluorescent Coumarins.
Plants challenged with iron deficiency produce in their roots and secrete into the rhizosphere several small molecules named coumarins that derive from the phenylpropanoid pathway. Coumarins are biosynthesized in different root cell types and transported to the root epidermis prior to their secretion in the surrounding media. Taking advantage of the natural fluorescence of most coumarins glycosides when exposed to UV light, we developed a method to uncover their individual cellular localization and accumulation. This approach couples spectral imaging acquisition and linear unmixing analysis. In this protocol, we describe guidelines, experimental setup, and conditions for the analysis of coumarins localization and accumulation in Arabidopsis thaliana root seedlings grown in control and iron deficiency conditions, at both acidic and alkaline pH.


Relationship between reactive group chemistry and printing properties of heterofunctional reactive dyes via screen printing.
Screen printing of cotton fabric using newly synthesized azo reactive dyes was carried out in the present study. Functional group chemistry and its effect on the printing properties of cotton fabric by varying the nature, number and position of reactive groups of synthesized azo reactive dyes (D1-D6) was studied. Different printing parameters (Temperature, alkali and urea) and their effect was explored on the physicochemical printing properties e.g., fixation, color yield, and penetration of the dyed cotton fabric. Data revealed that dyes with more reactive groups and having linear and planar structures (D-6) showed enhanced printing properties. Spectraflash spectrophotometer was used to evaluate the colorimetric properties of screen-printed cotton fabric and results showed superb color buildup. Printed cotton samples displayed excellent to very good ultraviolet protection factor (UPF). Presence of sulphonate groups and excellent fastness properties may entitle these reactive dyes as commercially viable for urea free printing of cotton fabric.


Learning from clinical work: the roles of learning cues and credibility judgements.
How learners interpret their clinical experiences to create meaningful learning has not been well studied. We explored experiences considered by doctors to be influential in their learning in order to better understand this process. Using a grounded theory approach, we interviewed 22 academic doctors who had been in practice for ≤ 5 years. Participants were asked to reflect on experiences they considered to have been influential during their training. Constant comparative analysis for emerging themes was conducted iteratively with data collection. A model of clinical learning emerged in which the clinical work itself is central. As they observe and participate in clinical work, learners can attend to a variety of sources of information that facilitate the interpretation of the experience and the construction of knowledge from it. These 'learning cues' include feedback, role models, clinical outcomes, patient or family responses, and comparisons with peers. The integration of a cue depends on the learner's judgement of its credibility. Certain cues, such as clinical outcomes or feedback from patients, are seen as innately credible, whereas other cues, particularly feedback from supervisors, are subjected to critical judgement. Learners make complex judgements regarding the credibility of information about clinical performance. Credibility judgements influence the learning that arises from the clinical experience. Further understanding of how such judgements are made could guide educators in providing credible information to learners.


Low-level hyperinsulinism with hypoglycemic spells in an infant with mosaic Turner syndrome and mild Kabuki-like phenotype: a case report and review of the literature.
Impaired glucose tolerance and type 2 diabetes are well-known features in patients with Turner syndrome. To the best of our knowledge, there is only one reported case of hyperinsulinemic hypoglycemia associated with a complex mosaic Turner syndrome available in the current literature. We report on the case of a 13-month-old girl with a complex mosaic Turner genotype and mild hyperinsulinemic hypoglycemia responsive to diazoxide therapy. Cytogenetic analyses showed two or possibly three cell lines. Sixty percent of the cell lines had a 45,X genotype and the rest had 46,XX with a marker ring chromosome. Diagnosis of a mosaic Turner syndrome and mild Kabuki-like phenotype was confirmed. Despite the rareness of this case, clinicians should be aware of the possibility of hyperinsulinemic hypoglycemia in patients with Turner syndrome to prevent further brain damage caused by hypoglycemic episodes and seizures. Although the mechanism leading to hyperinsulinism in this condition is still unknown, the present report discusses this rare presentation and gives an overview on the current literature regarding this case.


A method to quantify aggressiveness in Japanese quail (Coturnix c. japonica).
Testing procedures which rely on paired fights are unsuitable for measuring individual aggressiveness because the outcome of initial encounters influences subsequent dominance status. In an effort to circumvent this problem, we developed a test system which quantifies aggressiveness in individual Japanese quail by measuring locomotor and pecking activity of test birds presented with the visual stimulus of a conspecific. Using this procedure, we demonstrate that aggression is specific to sexually mature males; however, the intensity of the behavior varies widely among individuals. Scores for each bird are constant with time, reproducible, independent of the gender or behavior of the stimulus bird and accurately predict the outcome of a subsequent paired fight. In addition, we show that fighting per se produces increases and decreases in aggressiveness of dominant and subordinate birds, respectively, and re-orders the rank of a group of birds. This test procedure, therefore, confirms earlier studies which indicate that dominance hierarchies are influenced by initial encounters. Finally, repeat testing is reliable and gives an absolute, not relative, measure of aggressiveness. We conclude that this behavioral test can be applied to future studies addressing the social, developmental and endocrine basis of aggressiveness and dominance in quail and other vertebrates.


Ca2+ sensitization pathways accessed by cholinergic neurotransmission in the murine gastric fundus.
Ca(2+) sensitization of contraction has typically been investigated by bathing muscles in solutions containing agonists. However, it is unknown whether bath-applied agonists and enteric neurotransmission activate similar Ca(2+) sensitization mechanisms. We investigated protein kinase C (PKC)-potentiated phosphatase inhibitor protein of 17 kDa (CPI-17) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation in murine gastric fundus muscles stimulated by bath-applied carbachol (CCh) or cholinergic motor neurotransmission. CCh increased MYPT1 phosphorylation at Thr696 (pT696) and Thr853 (pT853), CPI-17 at Thr38 (pT38), and myosin light chain at Ser19 (pS19). Electrical field stimulation (EFS) only increased pT38. In the presence of neostigmine, EFS increased pT38, pT853 and pS19. In fundus muscles of W/W(v) mice, EFS alone increased pT38 and pT853. Atropine blocked all contractions and all increases in pT696, pT853, pT38 and pS19. The Rho kinase (ROCK) inhibitor SAR1x blocked increases in pT853 and pT696. The PKC inhibitors Go6976 and Gf109203x or nicardipine blocked increases in pT38 and pT696. These findings suggest that cholinergic motor neurotransmission activates PKC-dependent CPI-17 phosphorylation. Bath-applied CCh recruits additional ROCK-dependent MYPT1 phosphorylation due to exposure of the agonist to a wider population of muscarinic receptors. Intramuscular interstitial cells of Cajal (ICC-IMs) and cholinesterases restrict ACh accessibility to a select population of muscarinic receptors, possibly only those expressed by ICC-IMs. These results provide the first biochemical evidence for focalized (or synaptic-like) neurotransmission, rather than diffuse 'volume' neurotransmission in a smooth muscle tissue. Furthermore, these findings demonstrate that bath application of contractile agonists to gastrointestinal smooth muscles does not mimic physiological responses to cholinergic neurotransmission.


Regulatory T cells in skin lesions and blood of patients with bullous pemphigoid.
Although regulatory T cells (Tregs) are affected in several autoimmune skin diseases, only two studies have been performed in patients with bullous pemphigoid (BP) with contrasting results. To characterize Tregs and to determine the serum levels of regulatory cytokines in patients with BP. In BP lesional skin, immunohistochemistry and confocal microscopy were performed for CD4(+) , CD25(+) , forkhead/winged helix transcription factor (FOXP3)(+) , transforming growth factor (TGF)-β(+) and interleukin (IL)-10(+) cells. In addition, the number of CD4(+) CD25(++) FOXP3(+) Tregs in peripheral blood was assessed by flow cytometry, and the levels of TGF-β and IL-10 were determined in serum samples by enzyme-linked immunosorbent assay before and after steroid therapy. Controls included patients with psoriasis, atopic dermatitis (AD) and healthy donors. The frequency of FOXP3(+) cells was significantly reduced in skin lesions from patients with BP (P < 0.001) compared with psoriasis and AD. Moreover, the number of IL-10(+) cells was lower in BP than in psoriasis (P < 0.001) and AD (P = 0.002), while no differences were observed in the number of TGF-β(+) cells. CD4(+) CD25(++) FOXP3(+) Treg in the peripheral blood of patients with BP was significantly reduced compared with healthy controls (P < 0.001), and augmented significantly after steroid therapy (P = 0.001). Finally, TGF-β and IL-10 serum levels were similar in patients with BP compared with healthy controls. However, after therapy, BP patients showed significantly higher IL-10 serum levels than before therapy (P = 0.01). These data suggest that the depletion of Tregs and of IL-10 in patients with BP may be an important factor in the pathogenesis of the disease.


[Relations between productivity and rehabilitation measures in cardiovascular diseases in the aged].
The rehabilitation of patients in older age is depended from physical, psychical and social activity. But the limited possibility of adaptation, the broad individual spreeding of the character, and the polymorbidity in the older age have to taken into consideration. Hence follow some peculiarities in the rehabilitation process. The main aim of rehabilitation of patients in older age has to be the effort of social reintegration, the obtaining of an economic self-sufficiency as well as the production of self-reliance.


Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Nordic Society of Paediatric Haematology and Oncology (NOPHO)
In a multinational, population-based study from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2648 children below 15 y of age were diagnosed with acute lymphoblastic leukaemia (ALL) in the years 1981-1996. The annual incidence was 3.9/100000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification of therapy, based on multidrug chemotherapy including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. For children with non-B-cell ALL (n=2602), the event-free survival (p-EFS) increased from 0.53+/-0.02 (diagnosed 7/81-6/86) to 0.67+/-0.02 (7/86-12/91) to 0.78+/-0.02 (1/92-12/96). The corresponding p-EFS values at 5 y were 0.57, 0.70 and 0.78, respectively. The main improvements were seen in the group of children with non-high risk leukaemia, with 5-y p-EFS values increasing from 0.60 to 0.76 and 0.85 for the three periods. In high-risk patients, progress has been moderate, especially in children with high white blood cell values at diagnosis. During the last 5-y period, only 10% of the patients received cranial irradiation in first remission while 90% of the patients received high doses of cytostatic infusions (methotrexate isolated or combined with cytarabinoside) and multiple intrathecal injections of methotrexate as CNS-adjusted treatment without any indication of an increased CNS relapse rate.


Consensus residues at the acetylcholine binding site of cholinergic proteins.
The nicotinic (nAcChR) and muscarinic (mAcCh) acetylcholine receptors and acetylcholinesterase (AcChEase) are structurally unrelated but share a common functional property: interaction with acetylcholine (AcCh). Alignment of the probable AcCh binding site regions of the nAcChR and mAcChR protein sequences revealed the presence of ten nearly identically spaced consensus residues, six of which contain potentially ligand-interactive side chains. Important elements of the consensus residues also were found in one unique sequence region of the AcChEases. Alignments among the two receptors and AcChEase outside the apparent binding region were rare, and the consensus AcCh binding residues were largely substituted in the homologous proteins, which do not bind AcCh. The consensus residues include two possible anionic subsite Asp residues and a Ser that may hydrogen bond to the AcCh carbonyl in the receptors. These residues correspond to positions Asp-166, Ser-173, and Asp-200 in the neuromuscular nAcChR; Asp-71, Ser-78, and Asp-105 in the M1 mAcChR; and Asp-93 and Asp-128 in Torpedo AcChEase. No corresponding consensus Ser is found in the AcChEase sequence; this is expected because of a downstream esterase active-site Ser-200 (Torpedo). A receptor-conserved and disulfide-linked Cys corresponding to neuromuscular nAcChR residue 193 and M1 mAcChR residue 97 may be important in energy transduction associated with agonist-mediated events. The presence of additional binding-site aromatic residues that may form a hydrophobic environment near the anionic subsite are aligned within, but not between, the three cholinergic protein groups. These observations target specific regions and residues within these proteins for structure-function studies of the cholinergic binding domain.


Acmella oleracea extracts as green pesticides against eight arthropods attacking stored products.
Developing sustainable control tools for managing noxious pests attacking stored foodstuffs is a timely research challenge. Acmella oleracea (L.) R. K. Jansen is a crop widely cultivated for its multiple usages on an industrial level. In this study, the extracts prepared with A. oleracea aerial parts were applied on wheat kernels for the management of eight important arthropod pests attacking stored products, i.e., Cryptolestes ferrugineus, Tenebrio molitor, Oryzaephilus surinamensis, Trogoderma granarium, Tribolium castaneum, Tribolium confusum, Alphitobius diaperinus (adults/larvae), and Acarus siro (adults/nymphs). Extraction of A. oleracea was optimized on the base of the yield and content of spilanthol and other N-alkylamides which were analysed by HPLC-DAD-MS. Two concentrations of n-hexane or methanol extracts (500 ppm and 1000 ppm), obtained through Soxhlet extraction, were tested to acquire mortality data on the above-mentioned pests after 4, 8, and 16 h and 1 to 7 days of exposure. Both extracts achieved complete mortality (100.0%) of C. ferrugineus adults. In the case of A. diaperinus adults, mortalities were very low at any concentrations of both extracts. In general, the n-hexane extract was more efficient than methanol extract against almost all species and stages. Considering both extracts, the susceptibility order, from most to least susceptible species/stage, was C. ferrugineus adults > A. diaperinus larvae > C. ferrugineus larvae > T. granarium adults > T. molitor larvae > O. surinamensis adults > O. surinamensis larvae > T. confusum larvae > T. castaneum larvae > A. siro adults > T. molitor adults > A. siro nymphs > T. granarium larvae > T. castaneum adults > T. confusum adults > A. diaperinus adults. Our research provides useful knowledge on the efficacy of N-alkylamides-rich A. oleracea extracts as grain protectants, pointing out the importance of targeting the most susceptible species/ developmental stages.


Monthly runoff prediction by a multivariate hybrid model based on decomposition-normality and Lasso regression.
The intensified non-stationary, skewness, non-linear nature of runoff series due to the comprehensive influences of meteorological events and human activities has brought new challenges to accurate runoff prediction. To solve the issues, a multivariate hybrid model introducing decomposition-normality mode into SVR was proposed. The normal transformation techniques, Box-Cox transformation, and W-H inverse transformation were employed to transform the input variables of the model into normal distribution to overcome the error caused by skewness of the runoff data. The results show that decomposition-normality mode can improve the performance of the models. In particular, WT-BC-LSVR accurately predicted peak flow and low flow during the testing, and the mean relative errors are less than 16%, Rs and Nash-Sutcliffe efficiencies are greater than 0.97 and 0.94, respectively. The study demonstrates that the proposed multivariate hybrid model based on the decomposition-normality mode is a novel promising prediction model with satisfactory performance that can accurately predict complex monthly runoff.


Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation.
Aberrant expression of circular RNA contributes to human diseases. Circular RNAs regulate gene expression by sequestering specific microRNAs. In this study, we investigated whether circMAP3K5 (circular mitogen-activated protein kinase 5) could act as a competing endogenous microRNA-22-3p (miR-22-3p) sponge and regulate neointimal hyperplasia. Circular RNA profiling from genome-wide RNA sequencing data was compared between human coronary artery smooth muscle cells (SMCs) treated with or without platelet-derived growth factor. Expression levels of circMAP3K5 were assessed in human coronary arteries from autopsies on patients with dilated cardiomyopathy or coronary heart disease. The role of circMAP3K5 in intimal hyperplasia was further investigated in mice with adeno-associated virus 9-mediated circMAP3K5 transfection. SMC-specific Tet2 (ten-eleven translocation-2) knockout mice and global miR-22-3p knockout mice were used to delineate the mechanism by which circMAP3K5 attenuated neointimal hyperplasia using the femoral arterial wire injury model. RNA sequencing demonstrated that treatment with platelet-derived growth factor-BB significantly reduced expression of circMAP3K5 in human coronary artery SMCs. Wire-injured mouse femoral arteries and diseased arteries from patients with coronary heart disease (where platelet-derived growth factor-BB is increased) confirmed in vivo downregulation of circMAP3K5 associated with injury and disease. Lentivirus-mediated overexpression of circMAP3K5 inhibited the proliferation of human coronary artery SMCs. In vivo adeno-associated virus 9-mediated transfection of circMap3k5 (mouse circular Map3k5) specifically inhibited SMC proliferation in the wire-injured mouse arteries, resulting in reduced neointima formation. Using a luciferase reporter assay and RNA pull-down, circMAP3K5 (human circular MAP3K5) was found to sequester miR-22-3p, which, in turn, inhibited the expression of TET2. Both in vitro and in vivo results demonstrate that the loss of miR-22-3p recapitulated the antiproliferative effect of circMap3k5 on vascular SMCs. In SMC-specific Tet2 knockout mice, loss of Tet2 abolished the circMap3k5-mediated antiproliferative effect on vascular SMCs. We identify circMAP3K5 as a master regulator of TET2-mediated vascular SMC differentiation. Targeting the circMAP3K5/miR-22-3p/TET2 axis may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis and atherosclerosis.


Balloon dilation of critical pulmonary stenosis in the first week of life.
Although balloon dilation of valvular pulmonary stenosis is established in infants and children, the techniques for and results of balloon dilation in neonates with critical pulmonary stenosis remain largely unreported. Since January 1, 1985, six successive neonates with critical pulmonary stenosis (aged 1 to 6 days) underwent attempted balloon dilation. Each was cyanotic and three of the six were on prostaglandin E1 therapy and three required tracheal intubation and ventilation. All had suprasystemic right ventricular pressures (mean 122.8 +/- 6.8 mm Hg). After hemodynamic evaluation and right ventricular angiography, the valve was crossed in five patients, and was first dilated with a low profile, 5 or 6 mm diameter, 2 cm long balloon. At least one more balloon was used in each patient, the largest being 95 to 133% of the diameter of the pulmonary valve anulus. The anulus size was 6.8 +/- 1.1 mm and the largest balloon size used was 6 to 10 mm. Right ventricular pressure decreased to nearly systemic level or less in five of five patients (58.8 +/- 6.7 mm Hg). Pressure gradients, measured in four infants, were 7, 12, 16 and 35 mm Hg, respectively, but were unreliable indicators of obstruction because of a patent ductus arteriosus. The five patients were discharged 3 to 8 days after balloon dilation. All are currently symptom free 10.6 +/- 11.7 months later, and all but one are believed clinically to have mild obstruction. Complications included iliac vein occlusion (n = 1) and complete right bundle branch block (n = 1). Although follow-up has been brief, neonates with critical pulmonary stenosis can safely undergo balloon dilation, usually with good short-term results.


The use of antiseptics in wound care: Critique II.
This frequently referenced paper is a review of the use of antiseptics and antimicrobials in wound healing. It is often used in support of arguments for banning antiseptics. Careful reading suggests that this is a misinterpretation. The authors, while accepting the ritualistic approach of many clinicians in treating chronic wounds, state that there is a need to question procedure, particularly in relation to the use of antiseptics and antimicrobials.


Persistent left superior vena cava: Case report.
Persistent left superior vena cava (PLSVC) is a rare anomaly of the systemic venous circulation. We report the case of a 22-year-old female that had history of multiple repair surgeries for her esophageal atresia, as well as a right lobectomy for bronchiectasis 15 years prior. She was admitted to the surgical ward for complete resection of the right lung. A trans-thoracic echocardiography was performed as part of the pre-surgical work-up and it revealed a dilated coronary sinus which led us to suspect the presence of a PLSVC. The latter was confirmed by a simple "Bubble study" and confirmed by CT angiogram. We will discuss throughout this paper, the clinical and radiological features, as well as the embryology of this anomaly, so that the knowledge of the existence of this anatomical variant, especially if surgery or catheterization is at reach of the medical team, may lead to avoid serious complications.


Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties.
As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.