Role of heparan sulphate proteoglycans as potential receptors for non-piliated Pseudomonas aeruginosa adherence to non-polarised airway epithelial cells.
Tight junctions seal polarised surface epithelial respiratory cells so as to prevent the passage of bacteria and toxins through the epithelial sheet. Disruption of tight junctions, which may occur during injury and repair processes of airway epithelium, favours potential bacterial interaction with receptors from cell basolateral membranes. Earlier studies reported that non-polarised and untight epithelial respiratory cells are highly susceptible to Pseudomonas aeruginosa adherence and internalisation. As heparan sulphate proteoglycans (HSP) from cell basolateral membranes in epithelial cells without tight junctions may become accessible to bacterial ligands, the present study investigated their role as potential receptors for non-piliate P. aeruginosa ligands. Treatment of cells with heparitinase I and II significantly reduced (51.2% and 51.7%, respectively) P. aeruginosa adherence to epithelial respiratory cells without tight junctions. The internalisation of bacteria was not affected by treatment with heparitinases. Treatment of the bacteria with heparin and heparan sulphate also significantly reduced their adherence to respiratory cells (34.3% and 43.7%, respectively). Treatment of cells with other enzymes (trypsin, lipase and chondroitinase ABC) or treatment of bacteria with chondroitin-4-sulphate did not modify the adherence to respiratory cells significantly. Both affinity chromatography and Western blotting assays showed the interaction of different P. aeruginosa outer-membrane proteins (OMPs) with heparin. Several bacterial strains showed differences in their profile of heparin-binding OMPs, but all exhibited low mol. wt (< 30 kDa) reactive proteins. Reactivity of whole bacterial cells with heparin was also observed by transmission electron microscopy. These results suggest that HSP are potential receptors for P. aeruginosa adherence to non-polarised and untight epithelial respiratory cells.


Five years investigation of female and male genotypes in périgord black truffle (Tuber melanosporum Vittad.) revealed contrasted reproduction strategies.
The Périgord black truffle (Tuber melanosporum Vittad.) is a heterothallic ascomycete that establishes ectomycorrhizal symbiosis with trees and shrubs. Small-scale genetic structures of female genotypes in truffle orchards are known, but it has not yet been studied in male genotypes. In this study, our aim was to characterize the small-scale genetic structure of both male and female genotypes over five years in an orchard to better understand the T. melanosporum sexual reproduction strategy, male genotype dynamics, and origins. Two-hundred forty-one ascocarps, 475 ectomycorrhizas, and 20 soil cores were harvested and genotyped using microsatellites and mating type genes. Isolation by distance analysis revealed pronounced small-scale genetic structures for both female and male genotypes. The genotypic diversity was higher for male than female genotypes with numerous small size genotypes suggesting an important turnover due to ascospore recruitment. Larger and perennial female and male genotypes were also detected. Only three genotypes (1.5%) were found as both female and male genotypes (hermaphrodites) while most were detected only as female or male genotype (dioecy). Our results suggest that germinating ascospores act as male genotypes, but we also proposed that soil mycelium could be a reservoir of male genotypes.


NO(+) but not NO radical relaxes airway smooth muscle via cGMP-independent release of internal Ca(2+).
We compared the effects of two redox forms of nitric oxide, NO(+) [liberated by S-nitroso-N-acetyl-penicillamine (SNAP)] and NO. [liberated by 3-morpholinosydnonimine (SIN-1) in the presence of superoxide dismutase], on cytosolic concentration of Ca(2+) ([Ca(2+)](i); single cells) and tone (intact strips) obtained from human main stem bronchi and canine trachealis. SNAP evoked a rise in [Ca(2+)](i) that was unaffected by removing external Ca(2+) but was markedly reduced by depleting the internal Ca(2+) pool using cyclopiazonic acid (10(-5) M). Dithiothreitol (1 mM) also antagonized the Ca(2+) transient as well as the accompanying relaxation. SNAP attenuated responses to 15 and 30 mM KCl but not those to 60 mM KCl, suggesting the involvement of an electromechanical coupling mechanism rather than a direct effect on the contractile apparatus or on Ca(2+) channels. SNAP relaxations were sensitive to charybdotoxin (10(-7) M) or tetraethylammonium (30 mM) but not to 4-aminopyridine (1 mM). Neither SIN-1 nor 8-bromoguanosine 3',5'-cyclic monophosphate had any significant effect on resting [Ca(2+)](i), although both of these agents were able to completely reverse tone evoked by carbachol (10(-7) M). We conclude that NO(+) causes release of internal Ca(2+) in a cGMP-independent fashion, leading to activation of Ca(2+)-dependent K(+) channels and relaxation, whereas NO. relaxes the airways through a cGMP-dependent, Ca(2+)-independent pathway.


Upregulation of hepatic prolactin receptor gene expression by 17beta-estradiol following trauma-hemorrhage.
Although studies show protective effects of 17beta-estradiol (E2) or prolactin (PRL) treatment in male rats after trauma-hemorrhage (TH), the mechanism of the salutary effects of these agents remains unknown. Because E2 modulates PRL receptor (PRL-R) expression in the liver, we examined whether E2 treatment after T-H has any effects on hepatic PLR-R gene expression. Male Sprague-Dawley rats were subjected to trauma (i.e., 5-cm midline laparotomy) and hemorrhage (35-40 mmHg for 90 min) followed by fluid resuscitation (Ringer lactate) or sham operation and then treated with E2 (50 microg/kg body wt sc) or vehicle immediately before resuscitation. Liver samples were collected at 3 h thereafter, and PRL-R mRNA expression was determined by PCR. Liver expression of PRL-R short-form gene was unaffected by T-H, whereas that of the long-form gene was suppressed. Treatment of T-H rats with E2 significantly increased PRL-R short-form gene expression and normalized PRL-R long-form gene expression to sham levels. In the isolated hepatocytes, PRL-R short-form gene expression was predominant compared with the long-form gene. In contrast, only the short form was detected in Kupffer cells. In vitro treatment by E2 demonstrated an increase in the PRL-R long-form gene in hepatocytes, but E2 had no effect on PRL-R short-form gene expression in either the Kupffer cells or hepatocytes. Thus E2 treatment after T-H in males appears to directly upregulate PRL-R long-form gene expression in hepatocytes. However, the upregulation of the PRL-R short form might involve the interaction of multiple cell types in the liver.


Presymptomatic treatment with acetylcholinesterase antisense oligonucleotides prolongs survival in ALS (G93A-SOD1) mice.
Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.


Synthesis of 1,N6-etheno-2-aza-adenosine (2-aza-epsilon-adenosine): a new cytotoxic fluorescent nucleoside.
1,N(6)-Etheno-2-aza-adenosine was synthesized by treating 1,N(6)-etheno-adenosine with alkali, followed by nitrosation. The mechanism of formation of this novel nucleoside was elucidated using adenosine tritiated at C-8 and C-2, and was found to deformylate exclusively at C-2. This new 2-aza nucleoside fluoresces at 494 nm when excited at 358 nm. Toxicity study showed the compound is active in a rat mammary tumor tissue culture line, but inactive in HeLa and Glioma 26 tissue culture lines. It was also found to selectively inhibit the thymidine incorporation into DNA in a rat mammary tumor, but exhibits no ill effect on normal proliferative tissue. The reactive intermediate 3-beta-D-ribofuranosyl-4-amino-5-(imidazol-2-yl) imidazole was identified and was found to be an active agent in tissue culture.


Changing BMI categories and healthcare expenditures among elderly Medicare beneficiaries.
To examine the association between changes in BMI categories and health-care expenditures among elderly Medicare beneficiaries using longitudinal data of the Medicare Current Beneficiary Survey (MCBS) 2000-2005. Changes in BMI were (i) Stayed Normal: individuals with a normal BMI at baseline and follow-up; (ii) Stayed Overweight individuals with overweight BMI at baseline and follow-up; (iii) Stayed Obese individuals with obese BMI at baseline and follow-up; (iv) Normal-Overweight: individuals with normal BMI at baseline and overweight BMI at follow-up; (v) Overweight-Obese: individuals with overweight BMI at baseline and obese BMI at follow-up; (vi) Overweight-Normal: individuals with overweight BMI at baseline and normal BMI at follow-up; (vii) Obese-Overweight: individuals with obese BMI at baseline and overweight BMI at follow-up. Ordinary Least Squares (OLS) models on logged Year 3 expenditures were used to analyze changes in expenditures between BMI categories. Overall, 35% Stayed Normal, 34% Stayed Overweight, 18% Stayed Obese, 4% gained weight from Normal-Overweight BMI, 3% gained weight from Overweight-Obese BMI, 5% lost weight from Overweight-Normal BMI, and 3% lost weight from Obese-Overweight BMI. Adjusted models revealed those who Stayed Obese had increased total and multiple expenditure types that were significantly higher than Stayed Normal including total (11%), outpatient (25%), prescription (9%), and medical provider (4%). Compared to Stayed Normal, total expenditures were both 26% higher for Obese-Overweight and Overweight-Obese. The current findings highlight the importance of maintaining a normal BMI in the elderly.


Optical tweezers for synchrotron radiation probing of trapped biological and soft matter objects in aqueous environments.
Investigations of single fragile objects manipulated by optical forces with high brilliance X-ray beams may initiate the development of new research fields such as protein crystallography in an aqueous environment. We have developed a dedicated optical tweezers setup with a compact, portable, and versatile geometry for the customary manipulation of objects for synchrotron radiation applications. Objects of a few micrometers up to a few tens of micrometers size can be trapped for extended periods of time. The selection and positioning of single objects out of a batch of many can be performed semi-automatically by software routines. The performance of the setup has been tested by wide-angle and small-angle X-ray scattering experiments on single optically trapped starch granules, using a synchrotron radiation microbeam. We demonstrate here for the first time the feasibility of microdiffraction on optically trapped protein crystals. Starch granules and insulin crystals were repeatedly raster-scanned at about 50 ms exposure/raster-point up to the complete loss of the structural order. Radiation damage in starch granules results in the appearance of low-angle scattering due to the breakdown of the polysaccharide matrix. For insulin crystals, order along the densely packed [110] direction is preferentially maintained until complete loss of long-range order.


Embryogenesis and early larval development in wild-caught Levantine scraper, Capoeta damascina (Valenciennes, 1842).
Levantine scraper, Capoeta damascina is a candidate species for future stock assessments, conservation studies, and hatchery efforts. Herein, we documented embryonic and early larval development, from egg activation to the exogenous feeding period, using morphological and histological landmarks. Embryos were obtained by in vitro fertilization from hormonally induced wild-caught broodstock, and subsequent development was monitored at temperatures coinciding with native conditions. Embryonic development from fertilization to hatch lasted ~105-110 hr. Larvae emerged with unpigmented eyes and body morphology, as well as an undifferentiated digestive tract. The mouth was closed at hatch by the oropharyngeal membrane and opened by the early endogenous feeding period. Trabeculae cartilage, quadrate bone, and Meckel's cartilage of the endoskeleton were present during the endogenous feeding period. During this period, the larvae underwent considerable changes in craniofacial morphology, locomotion, and organogenesis of the digestive tract. The cartilaginous floor of the neurocranium developed and the first four ceratobranchials appeared simultaneously at the end of endogenous feeding period. The digestive tract was differentiated into buccopharynx, esophagus, and small intestine during the endogenous feeding period. The intestinal valve and numerous longitudinal folds at the posterior region of the intestine formed together by the endo-exogenous feeding period. Major developmental events in retinogenesis occurred during the endogenous feeding period. When larvae entered exogenous feeding the mouth was fully-functional. Additionally, liver size and eye diameter increased. Our analysis of embryonic and early larval development in Levantine scraper aligned with other freshwater fishes.


Programme for specialization in family medicine.
A programme for specialized training in family medicine at Tel Aviv University Medical School provides four years of postgraduate study, two of which are in recognized hospital departments and two in clinics recognized for training in family medicine. At the end of this four-year period the graduate must submit a thesis of original work or an approved research project on an aspect of family medicine. Continuing contact of the trainee with both the family medicine clinic and the hospital departments is maintained throughout the period. While in hospital the trainee spends half a day a week in the family clinic with his personal tutor, and when in the clinic he spends half a day a week in the hospital.This programme has been provisionally accepted as meeting the formal requirements of the Israel Medical Association for specialization in family medicine, and the first physician has started training.


Anaesthesia and surgery in sepsis.
Administration of anaesthesia to patients with sepsis and its effects on the progression of infection in the postoperative period is an important consideration both for surgeons and anaesthetists. All cases of abdominal sepsis carry a surgical mortality of around 50%. Though appropriate therapy is virtually always surgical, limiting initial surgical stress to simple closure and irrigation, supplemented with a proper anaesthetic regime, nutritional care and antibiotic cover, can improve the outcome.


Characteristics of dental pulp in human upper first premolar teeth based on immunohistochemical and morphometric examinations.
Teeth extracted for orthodontic reasons are commonly considered as healthy. Therefore, it is possible to examine structure of the dental pulp can be fully recognized and how it is affected by malocclusion. The aim of the study was to evaluate by immunohistochemistry (IHC) and morphometry dental pulp in human upper first premolar teeth extracted for orthodontic reasons. The material comprised 36 teeth of 20 patients in the age range 16-26 years. By the use of IHC markers the presence of immunocompetent cells (CD20, CD45RO, and CD68), blood vessels (CD31) and nerves (PGP9.5) were examined in the pulp. Inflammatory infiltrates and tissue atrophy were observed in 24 and 10 teeth, respectively. Strong positive correlation between the width of the odontoblastic layer, the number of rows of odontoblast nuclei and the increase of MVA (microvessel area) in the pulp of atrophic teeth was found. The cellular infiltrations found in H&E-stained sections were identified by IHC as memory T cells (CD45RO+) and B lymphocytes (CD20+) with macrophages (CD68+) present at the periphery. The CD20 antigen was intensively expressed in 13 teeth, CD45RO in 33 teeth, and CD68 in 20 teeth. Thus, despite the lack of any clinical signs of pulp disease many teeth extracted for orthodontic reasons show focal pulp inflammation and atrophy which probably results from the malocclusion stress accompanying teeth crowding.


Chemiluminescence of cigarette smoke.
Chemiluminescence from cigarette smoke (aerosol) and smoke "extracts" (suspensoids) are described. The emissons from aqueous and organic suspensoids persist for hours, are proportional to oxygen solubilities, possess energy of at least 1.8 electron volts, and display characteristics which suggest that the emissions may be partially sensitized by singlet oxygen.


The pharmacokinetics study of ginkgolide A, B and the effect of food on bioavailability after oral administration of ginkgolide extracts in beagle dogs.
Ginkgolides are the primarily active components in Ginkgo products that are popular worldwide. However, few studies have evaluated the bioavailability of ginkgolides and the effects of food on it after oral administration of ginkgolides. In this article, pharmacokinetics and absolute bioavailability of the primary components in ginkgolide extracts were evaluated in beagle dogs. For the first time, we showed that the fed dogs had significantly increased area under the concentration-time curve and peak concentration relative to the fasted dogs based on the data from both the prototype form and total lactones of ginkgolide A (GA) and ginkgolide B (GB). In terms of the free form of the prototype ginkgolides, the absolute bioavailabilities of GA and GB were 34.8 and 5.2% in the fasted dogs, respectively, which significantly increased to an average of 78.6 and 17.0%, respectively, in the fed dogs. In terms of acidified total lactones, the absolute bioavailabilities of GA and GB were 7.5 and 14.5% in the fed dogs, and the percentages declined to 4.1 and 3.7% in the fasted dogs, respectively. It was suggested that administration of ginkgolides after meals could promote the in vivo exposure and the bioavailability of GA and GB, and hence potentially enhance therapeutic outcomes.


[Effect of qiangji jianli capsule on metabolism of acetylcholine receptor].
To explore the action mechanism of Qiangji Jianli Capsule (QJJLC) treating myasthenia gravis. Internal receptor permeation and degradation test were performed. Volume of receptor permeation in the group with QJJLC at 96 hours was 902.50 +/- 37.48 cpm/mg, while that of control group 738.45 +/- 35.41 cpm/mg. Half-life of receptor degradation in treatment group was 52 hours and that of control 38 hours. Their difference was very significant (P < 0.001). QJJLC could accelerate permeation of N-aectylcholine receptor to surface of diaphragm cell membrane and decelerate receptor degradation. It could also increase accumulative amounts of functional receptor in unit time and keep dynamic equilibrium of receptor metabolism in pathologic condition.


Deep learning-based motion artifact removal in functional near-infrared spectroscopy.
Significance: Functional near-infrared spectroscopy (fNIRS), a well-established neuroimaging technique, enables monitoring cortical activation while subjects are unconstrained. However, motion artifact is a common type of noise that can hamper the interpretation of fNIRS data. Current methods that have been proposed to mitigate motion artifacts in fNIRS data are still dependent on expert-based knowledge and the post hoc tuning of parameters. Aim: Here, we report a deep learning method that aims at motion artifact removal from fNIRS data while being assumption free. To the best of our knowledge, this is the first investigation to report on the use of a denoising autoencoder (DAE) architecture for motion artifact removal. Approach: To facilitate the training of this deep learning architecture, we (i) designed a specific loss function and (ii) generated data to mimic the properties of recorded fNIRS sequences. Results: The DAE model outperformed conventional methods in lowering residual motion artifacts, decreasing mean squared error, and increasing computational efficiency. Conclusion: Overall, this work demonstrates the potential of deep learning models for accurate and fast motion artifact removal in fNIRS data.


Exploring the binding sites and proton diffusion on insulin amyloid fibril surfaces by naphthol-based photoacid fluorescence and molecular simulations.
The diffusion of protons along biological surfaces and the interaction of biological structures with water are fundamental areas of interest in biology and chemistry. Here, we examine the surface of insulin amyloid fibrils and follow the binding of small molecules (photoacids) that differ according to the number and location of their sulfonic groups. We use transient fluorescence combined with a spherically-symmetric diffusion theory to show that the binding mode of different photoacids determines the efficiency of proton dissociation from the photoacid and the dimensionality of the proton's diffusion. We use molecular dynamics simulations to examine the binding mode and mechanism of the photoacids and its influence on the unique kinetic rates and diffusion properties of the photoacid's dissociated proton, where we also suggest a proton transfer process between one of the photoacids to proximal histidine residues. We show that the photoacids can be used as fluorescent markers for following the progression of amyloidogenic processes. The detailed characterisation of different binding modes to the surface of amyloid fibrils paves the way for better understanding of the binding mechanism of small molecules to amyloid fibrils.


A budget impact analysis of gilteritinib for the treatment of relapsed or refractory FLT3 mut+ acute myeloid leukemia in a US health plan.
To estimate the economic impact of the introduction of gilteritinib for the treatment of relapsed/refractory (R/R) FLT3 mutation-positive (FLT3 mut+) acute myeloid leukemia (AML) from a US payer's perspective. A budget impact model (BIM) was developed to evaluate the 3-year total budgetary impact of treating adults with R/R FLT3 mut+ AML eligible for gilteritinib in a hypothetical US health plan. Total costs (drugs/administration, hospitalization, monitoring, adverse events, transfusions, subsequent hematopoietic stem cell transplantation, post-progression, and FLT3 testing) were estimated before and after gilteritinib entry. The budget impact was the total cost difference between the two scenarios. The target population size and cost inputs were based on public data or published literature, drug market share was informed by market research data, and the model included recommended treatments for R/R FLT3 mut+ AML per clinical guidelines. Deterministic sensitivity analyses (DSAs) and scenario analyses varying key model inputs and assumptions were conducted to test for robustness. In a hypothetical health plan with 1 million members, 20.9 adults with R/R FLT3 mut+ AML were estimated to be eligible for gilteritinib. Of these, it was assumed 30.0% would be treated with gilteritinib in Year 1 following gilteritinib entry, increasing the total plan budget by $663,795 and the per-member-per-month (PMPM) cost by $0.055. In Years 2-3, the market share of gilteritinib increased to 45.0%, increasing the total plan budget impact by $1,078,371 and $1,087,230, and the PMPM cost by $0.090 and $0.091, respectively. The model results remained robust in DSAs and scenario analyses, with the largest impact observed when the projected uptake of gilteritinib was changed. The results of this BIM are contingent upon the model's assumptions and inputs. Adding gilteritinib to the formulary for the treatment of adults with R/R FLT3 mut+ AML had a minimal budget impact from a US payer's perspective.


Systematic Review of the Relationship Between Autism Stigma and Informal Caregiver Mental Health.
Families play a crucial role in determining the mental health of the autistic individual(s) they are caring for. However, the stigma associated with autism can impair caregiver health. To investigate this, empirical evidence pertaining to stigma's impact on informal caregivers' mental health was systematically reviewed. All twelve included studies (n = 1442 informal caregivers) consistently reported the impact of autism related stigma upon caregiver mental health to be significant, meaningful and complex. A new theoretical framework describing the relationship between stigma and caregiver mental health is constructed. Moderating variables include those both changeable through intervention (e.g. hopelessness, self-esteem, self-compassion) and not changeable (gender, culture, financial burden and time since diagnosis). Implications and recommendations for professionals, interventions and future research are proposed.


Brucellosis in the Addis Ababa dairy cattle: the myths and the realities.
Bovine brucellosis is considered as an important disease among livestock and people in sub-Saharan African countries including Ethiopia. A cross-sectional study was conducted from November 2016 to May 2017 to estimate the prevalence and associated risk factors, and to assess knowledge-attitude and practices (KAP) of farm workers about bovine brucellosis in Addis Ababa dairy farms. A total of 1550 cattle from 127 dairy farms were serially tested using the Rose Bengal Plate Test (RBPT), Competitive Enzyme-Linked Immunosorbant Assay (c-ELISA) and Complement Fixation Test (CFT). Forty-three (2.77%) of the collected sera were positive by the RBPT and only one of these was positive by c-ELISA (0.06%) and none was positive by CFT. The knowledge of farm workers towards the disease was very low and risk factors associated with Brucella infection were apparent in the study area. Seropositivity for Brucella spp. was found in only a very small percentage by c-ELISA test, although risk factors for transmitting Brucella infection were present. The results suggest that bovine brucellosis is currently not a generalized problem in dairy cattle of Addis Ababa. Since this favorable disease situation is not the result of informed policy, there is no guarantee that it will continue unchanged. Setting clear policy in control of the disease and implementing "One Health" are the most constructive approaches recommended.


Radioelectric brain stimulation in the treatment of generalized anxiety disorder with comorbid major depression in a psychiatric hospital: a pilot study.
Generalized anxiety disorder (GAD) is often presented with major depression (MD). GAD-MD can be a chronic and disabling condition, and patients suffering from this disorder often respond poorly to psychopharmacological treatment and experience side effects with medication. Therefore, there is a high demand for effective nonpharmacological therapy for GAD-MD patients. The current study explores the use of a radioelectric asymmetric conveyer (REAC) device in the treatment of GAD-MD. Participants were 24 patients diagnosed with GAD-MD being treated at a public psychiatric center. All patients were dissatisfied with their current pharmacological treatment. Patients were evaluated using the 21-item Hamilton Depression (HAM-D) rating scale and the Symptom Check List-90-Revised (SCL-90R) before and after REAC brain stimulation treatment cycles. After REAC brain stimulation treatment, all patients experienced a significant reduction in anxiety and depression. These results were confirmed by physician examination, HAM-D scores, and SCL-90R total scores. These results indicate a role for REAC brain stimulation in the management of psychiatric conditions, specifically, GAD-MD comorbidity. REAC treatments are synergistic to drug therapy and appear to be helpful in reducing the side effects of medication. Future studies should evaluate the long-term effects of REAC treatment.


Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study.
Repeated periods of stimulation of the spinal cord and training increased the ability to control movement in animal models of spinal cord injury. We hypothesised that tonic epidural spinal cord stimulation can modulate spinal circuitry in human beings into a physiological state that enables sensory input from standing and stepping movements to serve as a source of neural control to undertake these tasks. A 23-year-old man who had paraplegia from a C7-T1 subluxation as a result of a motor vehicle accident in July 2006, presented with complete loss of clinically detectable voluntary motor function and partial preservation of sensation below the T1 cord segment. After 170 locomotor training sessions over 26 months, a 16-electrode array was surgically placed on the dura (L1-S1 cord segments) in December 2009, to allow for chronic electrical stimulation. Spinal cord stimulation was done during sessions that lasted up to 250 min. We did 29 experiments and tested several stimulation combinations and parameters with the aim of the patient achieving standing and stepping. Epidural stimulation enabled the man to achieve full weight-bearing standing with assistance provided only for balance for 4·25 min. The patient achieved this standing during stimulation using parameters identified as specific for standing while providing bilateral load-bearing proprioceptive input. We also noted locomotor-like patterns when stimulation parameters were optimised for stepping. Additionally, 7 months after implantation, the patient recovered supraspinal control of some leg movements, but only during epidural stimulation. Task-specific training with epidural stimulation might reactivate previously silent spared neural circuits or promote plasticity. These interventions could be a viable clinical approach for functional recovery after severe paralysis. National Institutes of Health and Christopher and Dana Reeve Foundation.


Instrument to evaluate the perception of minimal contrasts in Chilean Sign Language - reliability evidence.
Obtain evidence of the test reliability to evaluate the perception of minimum contrasts in Chilean Sign Language (LSCh). Ten deaf children and adolescents aged between 7 and 14 years participated in this study. They were evaluated with the test of perception of minimal contrasts in LSCh. The test was reapplied 11 and 14 days after the first application (test-retest reliability). Spearman's Rho correlation was performed. During the first application, authorization was requested from the parents of the children and adolescents to record the responses of the participants so that another evaluator could re-score the protocols, in order to obtain inter-rater reliability. First-order agreement coefficient (AC1) Gwet's was used for data analysis. Test-retest obtained a strong and significant correlation (Rho= 0.741; p=0.014). The concordance values obtained inter-rater vary between 0.962 and 1 (p<0.001), indicating that the test presents almost perfect concordance. The minimum pairs perception test in LSCh presents satisfactory test-retest and inter-rater reliability.


Global mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genes.
DNA methylation patterns are reprogrammed in primordial germ cells and in preimplantation embryos by demethylation and subsequent de novo methylation. It has been suggested that epigenetic reprogramming may be necessary for the embryonic genome to return to a pluripotent state. We have carried out a genome-wide promoter analysis of DNA methylation in mouse embryonic stem (ES) cells, embryonic germ (EG) cells, sperm, trophoblast stem (TS) cells, and primary embryonic fibroblasts (pMEFs). Global clustering analysis shows that methylation patterns of ES cells, EG cells, and sperm are surprisingly similar, suggesting that while the sperm is a highly specialized cell type, its promoter epigenome is already largely reprogrammed and resembles a pluripotent state. Comparisons between pluripotent tissues and pMEFs reveal that a number of pluripotency related genes, including Nanog, Lefty1 and Tdgf1, as well as the nucleosome remodeller Smarcd1, are hypomethylated in stem cells and hypermethylated in differentiated cells. Differences in promoter methylation are associated with significant differences in transcription levels in more than 60% of genes analysed. Our comparative approach to promoter methylation thus identifies gene candidates for the regulation of pluripotency and epigenetic reprogramming. While the sperm genome is, overall, similarly methylated to that of ES and EG cells, there are some key exceptions, including Nanog and Lefty1, that are highly methylated in sperm. Nanog promoter methylation is erased by active and passive demethylation after fertilisation before expression commences in the morula. In ES cells the normally active Nanog promoter is silenced when targeted by de novo methylation. Our study suggests that reprogramming of promoter methylation is one of the key determinants of the epigenetic regulation of pluripotency genes. Epigenetic reprogramming in the germline prior to fertilisation and the reprogramming of key pluripotency genes in the early embryo is thus crucial for transmission of pluripotency.


Solitary extrahepatic intraabdominal metastasis from hepatocellular carcinoma after liver transplantation.
A liver transplantation is a treatment option in selected patients with hepatocellular carcinoma (HCC). Despite the adequate selection of candidates, recurrences of HCC may still develop. Solitary extrahepatic metastasis from HCC after a liver transplantation is rare. Here we report two cases of HCC demonstrated extrahepatic recurrence to the adrenal gland and spleen, respectively, within one year after a liver transplantation. Since the treatment of solitary extrahepatic metastasis from HCC after a liver transplantation is not standardized, surgical resection was performed. In the case of HCC adrenal metastasis, innumerable intrahepatic metastases were found two months after the adrenalectomy. And 16 months after adrenalectomy, the patient expired due to tumor progression and hepatic failure. In the case of HCC splenic metastasis, postoperative radiation therapy was performed. However, two recurrent HCC nodules were found 15 months after the splenectomy and received transarterial chemoembolization (TACE). And 29 month after the splenectomy, the patient also expired as same causes of former patient.


Leonurine Attenuates Hyperalgesia in Mice with Induced Adenomyosis.
BACKGROUND Adenomyosis, defined as the invasion of endometrial glands and stroma into the myometrium, is a common gynecological disorder. In the present study we report on the effect of leonurine on ICR mice with adenomyosis induced by neonatal tamoxifen. MATERIAL AND METHODS After being treated with tamoxifen for 4, 8, and 12 weeks, we assessed body weight and pain modulation in mice in hotplate tests. The mice were divided into 5 groups: a low-dose leonurine treatment group, a high-dose leonurine treatment group, a valproic acid (VPA) treatment group, a vehicle only treatment group, and a blank control group. We evaluated body weight, pain modulation in hotplate tests, and the depth of myometrial infiltration. Immunoreactivity staining of progesterone receptor (PR), nuclear factor-κB phosphorylated-p65 (p-p65), cyclooxygenase-2 (COX-2), and oxytocin receptor (OTR) was evaluated by immunohistochemistry. RESULTS The measurement of the body weight, myometrial infiltration, and pain modulation showed that neonatal tamoxifen treatment led to adenomyosis. Leonurine treatment appeared to decrease hyperalgesia and myometrial infiltration. Immunoreactivity staining showed decreased p-p65, COX-2, and OTR protein expressions. CONCLUSIONS Our results indicate that leonurine attenuates hyperalgesia in mice with induced adenomyosis via down-regulating expressions of p-P65, COX-2, and OTR, and could be beneficial for treating adenomyosis.


Disciplining migration aspirations through migration-information campaigns: A systematic review of the literature.
In the past few years, governmental agencies have developed a diverse repertoire of migration-management measures to steer migration flows and discipline unwanted migration. Migration-information campaigns have become a prominent tool aimed at communicating directly to migration aspirations of the targeted population in transit and sending countries. Through these information campaigns the geographical locus of control is shifted toward where the receiving state seeks to steer migration flows. This review paper is a research synthesis on literature engaging with migration-information campaigns. The study is based on 17 peer-reviewed journal articles from the years 2010-2020. Articles were coded based on discipline, type of research, research perspective, geographic origin and focus of the campaigns, objectives and rationale of the campaigns, tools and methods used in those campaigns, campaign funding, actor constellations, and a general assessment of each article. Findings from this study identify prominent trends as well as blind spots in the current research and indicate that there is still little research available on information campaigns concerning irregular migration, and even fewer studies report on their effectiveness. By implication future research is advised to focus on empirical studies on the impact of information campaigns on migrants' aspirations.


Elemental Analysis of Asian Elephant (Elephas maximus) Teeth Using X-ray Fluorescence and a Comparison to Other Species.
Elemental composition in bone of the different species has variation depending on genetic and environmental factors especially their food habitat. The aims of this study were to conduct an elemental analysis of Asian elephant teeth, both deciduous (first molar, second molar, and tusk) and permanent (molar and tusk), and compare the elemental composition of permanent teeth among 15 species, mostly mammalian. These teeth were analyzed using X-ray fluorescence at two voltages: 15 and 50 kV. In Asian elephants, deciduous tusk showed a lower Ca/Zn ratio compared to permanent tusk, because of the lack of Zn in permanent molars. Ca/Fe ratio was higher in deciduous than permanent molars. For permanent teeth, elephant molars presented a high Ca/Pb ratio but no Ca/Zn, Ca/Sr, and Zn/Fe ratios because of the lack of Zn and Sr in the samples tested. The key elemental ratios for differentiating elephant deciduous and permanent tusk were Ca/P and Ca/Zn. The considerable variation in elemental ratio data across 15 species was observed. All tooth samples contained Ca and P, which was not surprising; however, Pb also was present in all samples and Cd in a large majority, suggesting exposure to environmental contaminants. From discriminant analysis, the combination of Ca/P+Ca/Zn+Ca/Pb+Ca/Fe+Ca/Sr+Zn/Fe can generate two equations that successfully classified six (dog, pig, goat, tapir, monkey, and elephant) out of 15 species at 100 % specificity. In conclusion, determining the elemental profile of teeth may serve as a tool to identify the tooth "type" of elephants and to potentially classify other species.


The society for craniofacial genetics and developmental biology 38th annual meeting.
The mission of the Society for Craniofacial Genetics and Developmental Biology (SCGDB) is to promote education, research, and communication about normal and abnormal development of the tissues and organs of the head. The SCGDB welcomes as members undergraduate students, graduate students, post doctoral researchers, clinicians, orthodontists, scientists, and academicians who share an interest in craniofacial biology. Each year our members come together to share their novel findings, build upon, and challenge current knowledge of craniofacial biology. © 2016 Wiley Periodicals, Inc.


Immunisation status and determinants of left-behind children aged 12-72 months in central China.
Many parents move from rural China to urban areas in search of job opportunities, and leave their children behind to be raised by relatives. We aimed to assess the immunisation coverage, including the 1:3:3:3:1 vaccine series (one dose of Bacilli Chalmette-Guérin vaccine; three doses of live attenuated oral poliomyelitis vaccine; three doses of diphtheria, tetanus and pertussis combined; three doses of hepatitis B vaccine; and one dose of measles-containing vaccine), in children aged 12-72 months and identify the determinants of immunisation uptake among left-behind children in Hubei Province, Central China, in 2014. In this cross-sectional study using the World Health Organization's cluster sampling technique, we surveyed 1368 children from 44 villages in 11 districts of Hubei Province. The socio-demographic and vaccination status data were collected by interviewing primary caregivers using a semi-structured questionnaire and reviewing the immunisation cards of the children. Univariate and multivariate analyses were used to identify the determinants of complete vaccination and age-appropriate vaccination. For each dose of the five vaccines, the vaccination coverage in the left-behind and non-left-behind children was >90%; however, the age-appropriate vaccination coverage for each vaccine was lower in left-behind than in non-left-behind children. For the five vaccines, the fully vaccinated rate of left-behind children were lower than those of non-left-behind children (89·1%, 92·7%; P = 0·013) and age-appropriate immunisation rate of left-behind children were lower than those of non-left-behind children (65·7%, 79·9%; P < 0·001). After controlling for potential confounders, we found that the parenting pattern, annual household income and attitude of the primary caregiver towards vaccination significantly influenced the vaccination status of children. Moreover, we noted a relatively high prevalence of delayed vaccination among left-behind children. Hence, we believe that the age-appropriate immunisation coverage rate among left-behind children in rural areas should be further improved by delivering and sustaining primary care services.


Impact of Gender on Outcome in Octogenarians after Coronary Artery Bypass Grafting.
Background Increasing life expectancy makes cardiac surgery in octogenarians not very uncommon. In this study, the impact of gender on outcome of octogenarians after coronary artery bypass grafting (CABG) was assessed. Materials and Methods We retrospectively studied 485 octogenarians (176 females: mean age 82.4 ± 2.2 years vs. 306 males: mean age 82.2 ± 2.4 years) who underwent isolated CABG using extracorporeal circulation between January 2005 and December 2012. Results No significant differences were noted between both gender groups with regard to preoperative risk factors. At baseline, the groups differed significantly with respect to mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (women: 22.3 ± 17.4% vs. men: 17.5 ± 13.3%; p < 0.001). Likewise, EuroSCORE II differs significantly between women and men in our cohort (women: 16.7 ± 11.9% vs. men: 13.9 ± 10.7%; p = 0.008). Intraoperatively, the number of distal anastomoses (3.1 ± 0.9 vs. 3.2 ± 0.8), the mean extracorporeal circulation time (99 ± 31 vs. 102 ± 29 minutes), and the mean aortic cross-clamp time (63 ± 31 vs. 60 ± 19 minutes) were similar in both groups. Postoperatively, no significant differences in complications and major morbidity were observed between the groups. The 30-day mortality (women 8.0 vs. men 9.7%; p = 0.62) were without statistical significance between the groups. Conclusion Outcome of octogenarians after CABG resulted in acceptable mortality. Female gender was not associated with increased risks for morbidity and mortality after surgery. Satisfactory outcomes encourage the offering of surgery in octogenarians.


The MN RIDE pilot: feasibility of a synchronous, remotely delivered, aerobic exercise training program for rural-dwelling adults with subjective cognitive decline.
Out of all the modifiable risk factors for Alzheimer's disease and related dementias (ADRD), physical inactivity is the strongest. Rural residents have an increased risk for dementia and face significant barriers to accessing ADRD information, caregiving support, and memory-related services, which contributes to substandard care. Rural communities have greater barriers to participating in physical activity, and in particular exercise, due to lack of social support, travel/weather problems, and lack of facilities/equipment. The purpose of this pilot study was to implement and evaluate the feasibility and safety of a synchronous, remotely delivered, aerobic exercise (AEx) telerehabilitation program in persons with subjective cognitive decline (SCD) living in rural areas. The Minnesota Rehabilitation Intervention for Dementia Evasion for rural residents (MN RIDE) pilot study was one of five pilot studies conducted through the Center for Community Engaged Rural Dementia and Alzheimer's Research, conducted in collaboration with the Memory Keepers Medical Discovery Team. The Memory Keepers Medical Discovery Team employs a community-based participatory research model and uses a community advisory group, community-based researchers and a rural community engagement specialist to ensure research studies are aligned with rural community needs and to facilitate the recruitment of participants living in rural northern Minnesota. The MN RIDE study employed a single group, pretest-post-test design to test the feasibility and safety of an AEx-focused synchronous telerehabilitation program in rural-living middle-aged or older adults (>45 years) with SCD (indicated by answering yes to both, 'Do you perceive memory or cognitive difficulties?' and 'In the last two years, has your cognition or memory declined?'). All 36 AEx sessions (conducted over 12 weeks) were supervised remotely via smart devices and Zoom. The AEx program was classified as moderate intensity stationary cycling starting at a rating of perceived exertion (RPE) 11-12 or for 30-35 minutes in session 1, and was alternatively increased by 1-point RPE or 5-minute increments as tolerated up to RPE 12-14 for 50 minutes a session over time (by session 18). Secondarily, moderate intensity was defined as achieving an exercise heart rate of 64-76% of age-predicted maximum heart rate (HRmax). Feasibility and safety outcomes were assessed by session attendance, intensity adherence, presence of adverse events, and participant satisfaction. The average age of the study sample (n=9) was 57.44±7.16 years (average age of SCD onset 53.44±7.47 years) with 14.00±5.57 years of education and 88.9% female. All patients completed the study, resulting in a dropout rate of 0%. Out of the possible 324 sessions scheduled, 276 were attended (85% session adherence). Average intensity metrics achieved over the AEx sessions were RPE 13.2±0.5 and HRmax 72.0±7.9%, which both represent of moderate intensity AEx metrics. No adverse events were reported. This pilot study further provides the first evidence of preliminary feasibility of synchronous audiovisual, telerehabilitation programs delivered to rural residents at risk for ADRD. Thus, exercise telerehabilitation programs that focus on AEx could be viable and useful tools to overcome situations with limited access to healthcare services such as in rural communities. Further controlled studies with greater sample size could help further expand our results.


Approach to traumatic hand injuries for primary care physicians.
To review the initial management of common traumatic hand injuries seen by primary care physicians. Current clinical evidence and literature identified through MEDLINE electronic database searches was reviewed. Expert opinion was used to supplement recommendations for areas with little evidence. Primary care physicians must routinely manage patients with acute traumatic hand injuries. In the context of a clinical case, we review the assessment, diagnosis, and initial management of common traumatic hand injuries. The presentation and management of nail bed injuries, fingertip amputations, mallet fingers, hand fractures, tendon lacerations, bite injuries, and infectious tenosynovitis will also be discussed. The principles of managing traumatic hand injuries involve the reduction and immobilization of fractures, obtaining post-reduction x-ray scans, obtaining soft tissue coverage, preventing and treating infection, and ensuring tetanus prophylaxis. Proper assessment and management of traumatic hand injuries is essential to prevent substantial long-term morbidity in this generally otherwise healthy population. Early recognition of injuries that require urgent or emergent referral to a hand surgeon is critical.


[Life in their eyes, heart in their hands: conceptions and representations of women in the process of health and disease].
This social and historical investigation into the ways the health and sickness of mothers from Teixeiras municipality, Minas Gerais state, was represented is designed to comprehend behaviors in this sphere and help develop research in collective health. The semantics and indicators of a pluralistic view of disease and health, were built up from the most holistic to the most biomedical, from the most relational to the most individual. The quest for happiness was presented as a health concept by the mothers, which recalls Aristotelian and Spinozian philosophical concepts, but they put greater emphasis on the absence of illness. The prevailing welfare model still supplies useful references for interpreting such experiences. As the mother's status as care-taker helps one glean an understanding of other factors that affect the process of health and disease, it becomes possible to plan healthcare initiatives that are less alienating and more libertarian.


Digit somatotopy within cortical areas of the postcentral gyrus in humans.
Characterizing the cortical representation of the body surface is fundamental to understanding the neural basis of human somatic sensation. Monkey studies benefited from the detailed somatotopic maps obtained from electrophysiology methods. Advances in noninvasive neuroimaging techniques now permit such questions to be probed in humans. The present study characterizes the detailed somatotopic representation of individual digits within subregions of the postcentral gyrus in humans using high-spatial resolution functional magnetic resonance imaging and surface-based mapping. Four areas of consistent activation included area 3b, area 2, and 2 discrete foci within area 1. Area 3b and the superior area 1 foci demonstrated an orderly somatotopic distribution for all digits of the hand, whereby the thumb was represented most lateral, anterior, and inferior and the fifth digit was most medial, posterior, and superior. Compared with area 3b, somatotopic variability was greater in area 1 and the digits spanned less cortical territory. This study additionally identified the specific digit pairs that are separable in areas 3b and 1 using current imaging methods. Somatotopy was not resolved in area 2 or in the inferior area 1 foci.


Identifying human papillomavirus subtypes in cervical biopsies with in situ DNA hybridization with biotinylated probes.
To test the utility of biotinylated DNA probes against various subtypes of human papillomavirus (HPV), we performed in situ DNA hybridization on routinely processed archival material from 30 patients with serial cervical biopsies including conization (group I) and a prospective group of 35 patients whose cervical biopsies showed various degrees of koilocytotic atypia and/or dysplasia (group II). Commercially available biotinylated probe cocktails against HPV types 6 and 11, 16 and 18, and 31, 35 and 51 were detected via the avidin-biotin horseradish peroxidase technique. Virus was found in 87% (26/30) of group I and 57% (20/35) of group II. Almost exclusively, viral types 16, 18, 31, 35 and 51 were detected in group I; 54% (19/35) of group II stained for types 16, 18 or 31, 35 and 51; 2.9% (1/35) stained for types 6 and 11. Nine percent of group II (3/35) showed coinfection with types 16, 18 and 31, 35 and 51. Three of six vulvar condylomata (50%) stained for types 6 and 11. In general, weaker staining was associated with greater dysplasia. In situ hybridization using biotinylated DNA probes is useful in identifying patients infected with dysplasia/carcinoma-associated HPV subtypes and can be performed easily on routine surgical specimens.


Developmental venous anomalies (DVA): the so-called venous angioma.
Following a review of the literature it is possible to demonstrate the "normality" of the so called venous angiomas. They should be named Developmental Venous Anomaly (DVA). They illustrate in their two extreme types (superficial and deep) the hemodynamic equilibrium of the transcortical venous drainage in the periependymal zones. Venous ectasias and varices which can be encountered, associated with DVA constitute an acquired feature in relation to a venous outlet obstacle. The sinus pericranii represents an extracerebral DVA, but also corresponds to a normal variation. As any extreme anatomical variant, each DVA corresponds to a weak situation which may express itself clinically; only rare situations justify a radical treatment.


Bolstering the secretion and bioactivities of umbilical cord MSC-derived extracellular vesicles with 3D culture and priming in chemically defined media.
Human mesenchymal stem cells (hMSCs)-derived extracellular vesicles (EVs) have been known to possess the features of the origin cell with nano size and have shown therapeutic potentials for regenerative medicine in recent studies as alternatives for cell-based therapies. However, extremely low production yield, unknown effects derived from serum impurities, and relatively low bioactivities on doses must be overcome for translational applications. As several reports have demonstrated the tunability of secretion and bioactivities of EVs, herein, we introduced three-dimensional (3D) culture and cell priming approaches for MSCs in serum-free chemically defined media to exclude side effects from serum-derived impurities. Aggregates (spheroids) with 3D culture dramatically enhanced secretion of EVs about 6.7 times more than cells with two-dimensional (2D) culture, and altered surface compositions. Further modulation with cell priming with the combination of TNF-α and IFN-γ (TI) facilitated the production of EVs about 1.4 times more than cells without priming (9.4 times more than cells with 2D culture without priming), and bioactivities of EVs related to tissue regenerations. Interestingly, unlike changing 2D to 3D culture, TI priming altered internal cytokines of MSC-derived EVs. Through simulating characteristics of EVs with bioinformatics analysis, the regeneration-relative properties such as angiogenesis, wound healing, anti-inflammation, anti-apoptosis, and anti-fibrosis, for three different types of EVs were comparatively analyzed using cell-based assays. The present study demonstrated that a combinatory strategy, 3D cultures and priming MSCs in chemically defined media, provided the optimum environments to maximize secretion and regeneration-related bioactivities of MSC-derived EVs without impurities for future translational applications.


Anomalous phase transition behavior in hydrothermal grown layered tellurene.
Recent studies have demonstrated that tellurene is a van der Waals (vdW) two-dimensional material with potential optoelectronic and thermoelectric applications as a result of its pseudo-one-dimensional structure and properties. Here, we report on the pressure induced anomalous phase transition of tellurium nanoribbons. The observation of clean phase transitions was made possible with high quality single crystalline Te nanoribbons that are synthesized by hydrothermal reaction growth. The results show that phase transition has a large pressure hysteresis and multiple competing phases: during compression, the phase transition is sudden and takes place from trigonal to orthorhombic phase at 6.5 GPa. Orthorhombic phase remains stable up to higher pressures (15 GPa). In contrast, phase transition is not sudden during decompression, but orthorhombic and trigonal phases co-exist between 6.9 to 3.4 GPa. Grüneisen parameter calculations further confirm the presence of co-existing phases and suggest hysteretic phase change behavior. Finally, orthorhombic to trigonal phase transition occurs at 3.4 GPa which means overall pressure hysteresis is around 3.1 GPa.


Reduced satellite cell density and myogenesis in Wagyu compared with Angus cattle as a possible explanation of its high marbling.
Mechanisms responsible for excellent marbling in Japanese black cattle, Wagyu, remain to be established. Because both muscle cells and intramuscular adipocytes are developed from mesenchymal progenitor cells during early muscle development, we hypothesized that intramuscular progenitor cells in Wagyu cattle have attenuated myogenic capacity in favor of adipogenesis, leading to high marbling but reduced muscle growth. Biceps femoris muscle biopsy samples were obtained from both Angus (n=3) and Wagyu (n=3) cattle at 12 months of age. Compared with Angus, the density of satellite cells was much lower in Wagyu muscle (by 45.8±10%, P<0.05). Consistently, the formation of myotubes from muscle-derived progenitor cells was also lower (by 64.2±12.9%, P<0.05), but adipogenic capacity was greater in Wagyu. The average muscle fiber diameter was larger in Wagyu (by 23.9±6.8%, P=0.089) despite less muscle mass, suggesting less muscle fiber formation in Wagyu compared with Angus cattle. Because satellite cells are derived from fetal myogenic cells, the reduction in satellite cell density together with lower muscle fiber formation suggests that myogenesis was attenuated during early muscle development in Wagyu cattle. Given the shared pool of mesenchymal progenitor cells, the attenuated myogenesis likely shifts progenitor cells to adipogenesis during early development, which may contribute to high intramuscular adipocyte formation in Wagyu cattle.


Safety outcomes of salbutamol: A systematic review and meta-analysis.
Salbutamol has been used to alleviate bronchospasm in airway disease for decades, while its potential risks have not been systematically investigated yet. The risk of any potential adverse events (AEs) in patients treated with salbutamol was assessed through systematic review and meta-analysis. A systematic search of the literature was conducted, using EMBASE, PubMed and Cochrane library, until 3 April 2023. Once the AE incidence was evaluated, randomized controlled trials (RCTs) were eligible for review. The endpoints included the incidence of total AEs, severe AEs, treatment discontinuation and specific AEs. The pooled AEs incidence was analysed via random-effects model in a single-arm meta-analysis. A subgroup study was carried out to examine whether the pooled incidence of AE differed by indications or formulations. Of the 8912 studies that were identified, 58 RCTs met the inclusion criteria and involved 12 961 participants. The analysis showed the pooled incidences of total AEs, severe AEs and treatment discontinuation in patients treated with salbutamol were 34%, 2% and 3%, respectively. Subgroup analysis indicated that premature labour users and intravenous salbutamol users were more likely associated with total AEs. The most frequently observed specific AEs were palpitations or tachycardia. This meta-analysis indicated that salbutamol was associated with a very common risk of palpitations or tachycardia. Clinical vigilance and research efforts are needed to optimize the safe use of salbutamol.


[Role of grandaxin in the treatment of functional gastrointestinal diseases].
To assess efficacy of grandaxine in correction of anxiety syndrome and vegetative dysfunction in patients with gastrointestinal diseases. The trial included 59 patients with functional gastrointestinal, emotional and vegetative disorders who failed standard therapy. 43 patients of the test group received standard therapy in combination with grandaxine. Anxiety (Spilberg-Khanin scale), vegetative dysfunction (Vein scale) reduced in 90% of the patients of the test group more significantly than in the control group. Intestinal passage in patients with irritable colon syndrome improved also. A pronounced role of psychovegetative disorders was confirmed in development of functional gastrointestinal disorders. Grandaxine proved efficient in correction of such disorders irrespective of location of the pathology and prevalent tonicity of the autonomic nervous system.


Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0.
Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.


Spine MR angiography.
The use of MR angiography to evaluate spinal vessels is in an early stage of development. Both time-of-flight (3D) and phase-contrast (2D and 3D) techniques have been applied, and for both types of techniques, the vessels are best visualized following intravenous gadolinium administration. The vessels of interest are the millimeter-sized intradural arteries and veins, which are located on the cord surface and travel from the cord to the epidural space. Only the post gadolinium 3D TOF technique has been shown to display normal intradural vessels (thoracolumbar region), principally veins. Both TOF and PC techniques provide better delineation of enlarged intradural vessels associated with spinal vascular malformations than standard MR imaging alone. PC techniques are much less sensitive in detecting the arterial supply to dural arteriovenous fistula than intramedullary arteriovenous malformation. The TOF technique can predict the foraminal level of a dural fistula when an enlarged medullary vein, resulting from retrograde drainage, is present. MR angiography, in conjunction with MR imaging, is now suggested for screening of suspected spinal vascular malformation. Other applications such as vascular tumors and arterial or venous occlusive disease are under investigation.


Is renal dysfunction associated with adverse stroke outcome after thrombolytic therapy?
Renal dysfunction is a prevalent comorbidity in acute stroke patients requiring thrombolytic therapy. Reports studying the relationship between renal dysfunction and risk of postthrombolytic symptomatic intracerebral hemorrhage (SICH) are contradictory. We aimed to compare the safety and effectiveness of thrombolytic therapy in acute stroke patients with and without renal dysfunction. Based on the prospective stroke registries of 4 hospitals in Taiwan from 2007-2012, we identified acute stroke patients who received thrombolytic therapy. Clinically significant renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Renal dysfunction was further defined as stage 3 (30 ≤ eGFR < 60 ml/min/ 1.73 m(2)), stage 4 (15 ≤ eGFR < 30 ml/min/1.73 m(2)) and stage 5 (<15 ml/min/1.73 m(2)). The rates of SICH and poor outcome (defined as modified Rankin scale score ≥4) at 3 months after thrombolytic therapy were compared in patients with and without renal dysfunction. SICH was determined according to the definition of the National Institute of Neurological Disorders and Stroke. Multivariable logistic regression was used to determine the effect of renal dysfunction on outcome. Patients with different stages of renal dysfunction were further analyzed to determine the effect of disease severity on outcome. Of the 657 stroke patients with thrombolysis, 239 (36%) had renal dysfunction, including 212 patients in stage 3, 17 patients in stage 4 and 10 patients in stage 5 of renal dysfunction. Patients with renal dysfunction were older and more likely to have hypertension, ischemic heart disease, congestive heart failure and prior antiplatelet use than those without. There were no differences in SICH (8 vs. 7%, p = 0.580) and poor outcome (41 vs. 39%, p = 0.758) between patients with and without renal dysfunction. After multivariable analysis, renal dysfunction was not associated with SICH (odds ratio: 1.03, 95% confidence interval: 0.55-1.92) and poor outcome. Pretreatment stroke severity was the only factor significantly associated with both SICH and poor outcome at 3 months. When stratifying renal dysfunction into stage 3 and stage ≥4, there was no significant increase in SICH as the severity of renal dysfunction increased after multivariable adjustment. Renal dysfunction did not increase the risk of SICH and poor outcome at 3 months after stroke thrombolysis. Further study comparing directly the risk and benefit of thrombolytic therapy versus no therapy in stroke patients with renal dysfunction is warranted.


Recent insights into the role of Toll-like receptors in viral infection.
Toll-like receptors (TLRs) have a central role in innate immunity as they detect conserved pathogen-associated molecular patterns (PAMPs) on a range of microbes, including viruses, leading to innate immune activation and orchestration of the adaptive immune response. To date, a large number of viruses have been shown to trigger innate immunity via TLRs, suggesting that these receptors are likely to be important in the outcome to viral infection. This suggestion is supported by the observation that many viruses have evolved mechanisms not only to evade the innate immune system, but also to subvert it for the benefit of the virus. In this review we will discuss earlier evidence, mainly from knock-out mice studies, implicating TLRs in the innate immune response to viruses, in light of more recent clinical data demonstrating that TLRs are important for anti-viral immunity in humans.


Infectious Complications Following Kidney Transplantation-A Focus on Hepatitis C Infection, Cytomegalovirus Infection and Novel Developments in the Gut Microbiota.
The incidence of infectious complications, compared with the general population and the pre-transplant status of the recipient, increases substantially following kidney transplantation, causing significant morbidity and mortality. The potent immunosuppressive therapy given to prevent graft rejection in kidney transplant recipients results in an increased susceptibility to a wide range of opportunistic infections including bacterial, viral and fungal infections. Over the last five years, several advances have occurred that may have changed the burden of infectious complications in kidney transplant recipients. Due to the availability of direct-acting antivirals to manage donor-derived hepatitis C infection, this has opened the way for donors with hepatitis C infection to be considered in the donation process. In addition, there have been the development of medications targeting the growing burden of resistant cytomegalovirus, as well as the discovery of the potentially important role of the gastrointestinal microbiota in the pathogenesis of post-transplant infection. In this narrative review, we will discuss these three advances and their potential implications for clinical practice.


Evaluation of autoimmune phenomena in patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).
The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are basically characterized by obsessive-compulsive symptoms and/or tics triggered by group-A beta-hemolytic Streptococcus infections. Poor data are available about the clear definition of PANDAS's autoimmune origin. The aim of our study was to evaluate the prevalence of autoimmune phenomena, including thyroid function abnormalities, specific celiac disease antibodies, and positivity of organ- or nonorgan-specific autoantibodies in a large cohort of Caucasian children and adolescents with PANDAS. Seventy-seven consecutive patients (59 males, 18 females; mean age 6.3±2.5 years, range 2.0-14.5 years) strictly fulfilling the clinical criteria for PANDAS diagnosis were recruited. In all subjects we evaluated serum concentrations of free-T3, free-T4, thyrotropin, and the following auto-antibodies: anti-thyroperoxidase, anti-thyroglobulin, anti-thyrotropin receptor, anti-gliadin, anti-endomysium, anti-tissue transglutaminase, anti-nuclear, anti-smooth muscle, anti-extractable nuclear antigens, anti-phospholipid, plus lupus-like anticoagulant. The results were compared with those obtained from 197 age- and sex-matched healthy controls (130 males, 67 females; mean age 6.8±2.9 years, range 2.3-14.8 years). The frequencies of subclinical (3.8% vs 3.6%) and overt hypothyroidism (1.2% vs 0%), autoimmune thyroiditis (2.46% vs 1.14%), celiac disease (1.2% vs 0.05%), and positivity of organ- and nonorgan-specific autoantibodies (5.1% vs 4.8%) were not statistically significant between patients with PANDAS and controls. Evaluating the overall disease duration, we did not observe any significant difference between patients with (3.4±2.15 years) and without (3.4±2.89 years) autoimmune abnormalities. However, PANDAS patients with autoimmune diseases or positivity for any organ- and nonorgan-specific antibodies showed significantly higher anti-streptolysin O and anti-DNAse B titers, as well as a history of more frequent throat infections than controls (p<0.0001). Abnormalities of thyroid function and thyroid autoimmune diseases, as well as the association with celiac disease or organ- and nonorgan-specific autoimmunity seem not more frequent in children and adolescents with PANDAS than in healthy controls. A potential relationship between autoimmunity and PANDAS should be assessed further in larger studies. Children and adolescents with PANDAS should not be actually screened for thyroid function, celiac disease and/or autoimmune diseases.


Capsaicin sensitizes malignant glioma cells to TRAIL-mediated apoptosis via DR5 upregulation and survivin downregulation.
Capsaicin, a pungent ingredient of red chili peppers, has been reported to possess antitumor activities. Here, we show that subtoxic doses of capsaicin effectively sensitize multiple malignant glioma cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Although TRAIL alone mediated partial proteolytic processing of procaspase-3 in glioma cells, cotreatment with capsaicin and TRAIL efficiently restored complete activation of caspases. We found that treatment of various gliomas with capsaicin significantly upregulated DR5, a death receptor of TRAIL, and downregulated the caspase inhibitor survivin. The induction of DR5 was mediated by CHOP/GADD153. The reduction in survivin protein level was associated with downregulation of cyclin B and Cdc2 expression, suggesting that inhibition of Cdc2 activity might contribute to capsaicin-induced survivin downregulation. Taken together, these results indicate that the activity of capsaicin toward DR5 and survivin contributes to the amplification of caspase cascades, thereby restoring TRAIL sensitivity in malignant glioma cells. Interestingly, normal astrocytes were resistant to combined treatment with capsaicin and TRAIL. Neither capsaicin-induced DR5 upregulation/survivin downregulation nor the partial processing of procaspase-3 by TRAIL was induced in astrocytes. Thus, a combined regimen using capsaicin and TRAIL may provide a safe and effective strategy for treating malignant gliomas.


Application of multiple intake temporal check all that apply: A case study of strawberry yoghurt formulated with alternative sweeteners.
It is crucial to reduce the high sugar content of fruit yoghurts in response to the excessive weight gain epidemic. The use of alternative sweeteners in yoghurts is often associated with the negative sensory attributes that can have an impact on yoghurt liking. The main objective of this research was to investigate the effect of alternative sweeteners and strawberry puree addition on the temporal sensory profile of yoghurt using multiple-intake temporal check all that apply (TCATA). A novel approach to the statical analysis of the temporal sensory data was employed by using Aligned Rank Transformation (ART)-ANOVA to investigate the differences between sensory attributes within different product and within different intakes. Results showed that attributes sweet and fruity decreased when the concentration of fruit puree was increased at low concentration of sucrose. Interestingly, when the concentration of fruit puree was increased fruitiness increased and mouthcoating decreased at low concentration of stevia. With successive intakes, attributes sweet, sour, creamy and fruity significantly decreased in yoghurts sweetened with sucrose, xylitol and stevia. Yoghurts containing low concentration of sucrose or xylitol and fruit puree were liked the most. However, stevia-sweetened yoghurts varying in sweetener and puree concentration were not significantly different in liking. In order to investigate the consumer acceptance of yoghurts, a novel approach was used i.e., utilising TCATA temporal data to investigate temporal drivers of liking for each yoghurt type. The use of multiple statistical analysis to analyse temporal data suggested that both sweetener and puree concentration need to be considered when developing products using alternative sweeteners. This article is protected by copyright. All rights reserved.


Surgery of the nasal septum and turbinates.
The following article presents nasal septum and turbinate surgery. First an overview with special consideration of the anatomical and physiological background is given followed by indications for surgical procedures. Key steps of the gold standard procedure first described by Cottle and common variations are presented. Furthermore, some techniques dealing with special problems of the septumplasty are discussed followed by an overview on complications and long term results. However, it should be mentioned that studies on surgical procedures of the nasal septum are still not sufficient as higher evidence levels are very rare. Within a separated chapter techniques for closure of septum perforations are presented and indications particularly in the background of the standard procedure of bridge flaps forwarded by Schultz-Coulon are discussed. The second part focusses on turbinate surgery. Accordingly, anatomical and physiological basics are presented followed by indications for surgical procedures and the surgical steps of different procedures as well as postsurgical treatment and long term results.


Post-radiation intramedullary malignant peripheral nerve sheath tumor.
We report the intramedullary growth of a malignant peripheral nerve sheath tumour (MPNST). A 50year-old man developed a severe tetraparesis over a 4-month period. Following irradiation of a chronic tonsillitis during his childhood, the patient had later experienced a number of post-radiation diseases, including a laryngeal cancer that required permanent tracheotomy. Before admission, a magnetic resonance imaging (MRI) study had disclosed a C4-C5 intramedullary lesion. On admission to our Department, the patient had a nearly complete tetraparesis. At surgery, the lesion was exposed through a posterior midline myelotomy. A friable neoplasm, with no clear plane of cleavage, was found. The tumour was subtotally resected. Histological examination, which intraoperatively had not yielded a specific diagnosis, eventually revealed a MPNST, grade intermediate, with ultrastructural and immunohistochemical features consistent with a schwannian differentiation. No postoperative radiotherapy was undertaken. The patient died 9 months later from pneumonial complications. MPNSTs may develop within the spinal cord similarly to their benign schwannian counterpart. The reported sequence of events might support a possible relation between irradiation of the spinal cord and induction, followed by malignant transformation, of intramedullary schwannosis. This unique case must be added to the growing list of radiation-induced spinal cord tumours.


[Examination of myocardial perfusion with positron emission tomography: a clinically useful and valid method?].
Positron emission tomography (PET) of the heart has gained widespread scientific and clinical acceptance with regard to 2 indications: 1. the detection of perfusion abnormalities by qualitative and semiquantitative analyses of perfusion images at rest and during physical or pharmacological stress using well validated perfusion tracers such as N-13 ammonia, Rb-82 rubidiumchloride, or O-15 labeled water, 2. Viability imaging of myocardial regions with reduced contractility by combining perfusion measurements with substrate metabolism as assessed from F-18 deoxyglucose utilization. This overview summarizes the use of PET as a perfusion imaging method. With a sensitivity > 90% in combination with a high specificity, PET is today the best available nuclear imaging technique for the diagnosis of coronary artery disease (CAD). The short half-life of the perfusion tracers in combination with highly sophisticated hard- and software enables rapid PET studies with high patient throughput. The high diagnostic accuracy and the methological advantages as compared to conventional scintigraphy allows to use PET perfusion imaging for detection of subtle changes of the perfusion reserve for detection of CAD in high risk but asymptomatic patients as well as in patients with proven CAD undergoing various treatment forms such as risk factor reduction or coronary revascularization. In patients following orthotopic heart transplantation, evolving transplant vasculopathy can be detected at an early stage. Quantitative PET imaging at rest allows for detection of myocardial viability since cellular survival is based on maintenance of a minimal perfusion and structural changes correlate to the degree of perfusion reduction. Furthermore, quantitative assessment of the myocardial perfusion reserve detects the magnitude and competence of collaterals in regions with occluded epicardial arteries and thus, imaging of several coronary distribution territories in one noninvasive study. The cost of PET in combination with the cost of a cyclotron facility together with the demanding methological problems have limited the availability of PET to a few but sophisticated centers. Therefore, quantitative PET investigations have been performed predominantly for scientific purposes and the cost-effectiveness of PET in the everyday clinical setting is not yet finally proven. However, the unique possibilities of PET to study noninvasively and quantitatively myocardial perfusion and metabolism as well as cardiac innervation and pharmacokinetics of cardiac drugs have established cardiac PET as a scientific tool of highest quality for the future.


Structure of two developmentally regulated Dictyostelium discoideum ubiquitin genes.
A previously isolated cDNA clone, pLK229, that is specific for mRNA developmentally expressed during Dictyostelium discoideum spore germination and multicellular development, was used to screen two genomic libraries. Two genomic sequences homologous to pLK229 were isolated and sequenced. Genomic clone p229 is identical to the cDNA clone pLK229 and codes for a polypeptide of 381 amino acids. This polypeptide is composed of five tandem repeats of the same 76-amino-acid sequence. Clone lambda 229 codes for a protein of 229 amino acids, containing three tandem repeats of the identical 76-amino-acid sequence. A computer search for homology to known proteins revealed that the 76-amino-acid repeat was identical to human and bovine ubiquitin except for two amino acid differences.


Fast polygonal approximation of digital curves using relaxed straightness properties.
Several existing DSS (digital straight line segment) recognition algorithms can be used to determine the digital straightness of a given one-pixel-thick digital curve. Because of the inherent geometric constraints of digital straightness, these algorithms often produce a large number of segments to cover a given digital curve representing a real-life object=image. Thus, a curve segment, which is not exactly digitally straight, but appears to be visually straight, is fragmented into multiple DSS when these algorithms are run. In this paper, a new concept of approximate straightness is introduced by relaxing certain conditions of DSS, and an algorithm is described to extract those segments from a digital curve. The number of such segments required to cover the curve is found to be significantly fewer than that of the exact DSS-cover. As a result, the data set required for representing a curve also reduces to a large extent. The extracted set of segments can further be combined to determine a compact polygonal approximation of a digital curve based on certain approximation criteria and a specified error tolerance. The proposed algorithm involves only primitive integer operations and thus runs very fast compared to those based on exact DSS. The overall time complexity becomes linear in the number of points present in the representative set. Experimental results on several digital curves demonstrate the speed, elegance and efficacy of the proposed method.


Uncovering genes with divergent mRNA-protein dynamics in Streptomyces coelicolor.
Many biological processes are intrinsically dynamic, incurring profound changes at both molecular and physiological levels. Systems analyses of such processes incorporating large-scale transcriptome or proteome profiling can be quite revealing. Although consistency between mRNA and proteins is often implicitly assumed in many studies, examples of divergent trends are frequently observed. Here, we present a comparative transcriptome and proteome analysis of growth and stationary phase adaptation in Streptomyces coelicolor, taking the time-dynamics of process into consideration. These processes are of immense interest in microbiology as they pertain to the physiological transformations eliciting biosynthesis of many naturally occurring therapeutic agents. A shotgun proteomics approach based on mass spectrometric analysis of isobaric stable isotope labeled peptides (iTRAQ) enabled identification and rapid quantification of approximately 14% of the theoretical proteome of S. coelicolor. Independent principal component analyses of this and DNA microarray-derived transcriptome data revealed that the prominent patterns in both protein and mRNA domains are surprisingly well correlated. Despite this overall correlation, by employing a systematic concordance analysis, we estimated that over 30% of the analyzed genes likely exhibited significantly divergent patterns, of which nearly one-third displayed even opposing trends. Integrating this data with biological information, we discovered that certain groups of functionally related genes exhibit mRNA-protein discordance in a similar fashion. Our observations suggest that differences between mRNA and protein synthesis/degradation mechanisms are prominent in microbes while reaffirming the plausibility of such mechanisms acting in a concerted fashion at a protein complex or sub-pathway level.


Knowledge translation efforts in child and youth mental health: a systematic review.
The availability of knowledge translation strategies that have been empirically studied and proven useful is a critical prerequisite to narrowing the research-to-practice gap in child and youth mental health. Through this review the authors sought to determine the current state of scientific knowledge of the effectiveness of knowledge translation approaches in child and youth mental health by conducting a systematic review of the research evidence. The findings and quality of the 12 included studies are discussed. Future work of high methodological quality that explores a broader range of knowledge translation strategies and practitioners to which they are applied and that also attends to implementation process is recommended.


Quantitation of Candida albicans ergosterol content improves the correlation between in vitro antifungal susceptibility test results and in vivo outcome after fluconazole treatment in a murine model of invasive candidiasis.
MIC end point determination for the most commonly prescribed azole antifungal drug, fluconazole, can be complicated by "trailing" growth of the organism during susceptibility testing by the National Committee for Clinical Laboratory Standards approved M27-A broth macrodilution method and its modified broth microdilution format. To address this problem, we previously developed the sterol quantitation method (SQM) for in vitro determination of fluconazole susceptibility, which measures cellular ergosterol content rather than growth inhibition after exposure to fluconazole. To determine if SQM MICs of fluconazole correlated better with in vivo outcome than M27-A MICs, we used a murine model of invasive candidiasis and analyzed the capacity of fluconazole to treat infections caused by C. albicans isolates which were trailers (M27-A MICs at 24 and 48 h, </=1.0 and >/=64 microg/ml, respectively; SQM MIC, </=1.0 microg/ml), as well as those which were fluconazole sensitive (M27-A and SQM MIC, </=1.0 microg/ml) and fluconazole resistant (M27-A MIC, >/=64 microg/ml; SQM MIC, 54 microg/ml). Compared with the untreated controls, fluconazole therapy increased the survival of mice infected with a sensitive isolate and both trailing isolates but did not increase the survival of mice infected with a resistant isolate. These results indicate that the SQM is more predictive of in vivo outcome than the M27-A method for isolates that give unclear MIC end points due to trailing growth in fluconazole.


Maltreatment, competency deficits, and risk for academic and behavioral maladjustment.
Maltreatment was predicted to negatively affect children's academic and behavioral adjustment through the creation of deficits in academic engagement, social competencies, ego resiliency, and ego control. Teachers' comprehensive evaluations, school records, and camp counselors' ratings were obtained for 229 socioeconomically disadvantaged children (ages 5-12 years), 146 of whom had been maltreated. Maltreated children showed less academic engagement, more social skills deficits, and lower ego resiliency than nonmaltreated comparison children. Maltreated children manifested multiple forms of academic risk and showed more externalizing and internalizing behavior problems. The effects of maltreatment on academic maladjustment were partially mediated by academic engagement, whereas maltreatment's effects on behavior problems were mediated fully by social competencies and ego resiliency.


Social skill and social cognition in adolescents at genetic risk for psychosis.
Adolescents at genetic high risk (GHR) for schizophrenia have shown social skill impairments and there is some evidence to suggest they have Theory of Mind (ToM) deficits; however no research has used a standardized, performance-based behavioral measure to assess social functioning in this population nor evaluated ToM with a well-validated measure. We evaluated the psychometric properties of a new, theoretically-derived assessment of social functioning in GHR adolescents: the "High-Risk Social Challenge" task (HiSoC). The second aim was to explore whether GHR adolescents would show social skill and ToM deficits as compared to a non-psychiatric control (NPC) group. The present study evaluated social functioning with the HiSoC and ToM with the Eyes Test in 23 GHR adolescents and 31 NPCs. The HiSoC demonstrated high levels of reliability and validity. The GHR adolescents showed social skill impairments, but not ToM deficits. The results suggest that the HiSoC is a potentially useful new measure of social functioning in GHR adolescents. Furthermore, the findings add to the current body of literature that indicates that social skill impairments are related to schizophrenia vulnerability.


Driving with a Congestion Assistant; mental workload and acceptance.
New driver support systems are developed and introduced to the market at increasing speed. In conditions of traffic congestion drivers may be supported by a "Congestion Assistant", a system that combines the features of a Congestion Warning System (acoustic warning and gas pedal counterforce) and a Stop & Go system (automatic gas and brake pedal during congestion). To gain understanding of the effects of driving with a Congestion Assistant on drivers, mental workload of drivers was registered under different conditions as well as acceptance of the system. Mental workload was measured by means of physiological registrations, i.e. heart rate, a secondary task and with the aid of subjective scaling techniques. Acceptance was measured with an acceptance scale. The study was carried out in an advanced driving simulator. Driving with the Congestion Assistant while in congestion potentially leads to decreased driver mental workload, whereas just before congestion starts, i.e. developing just noticeable, the system may add to the workload of the driver. Acceptance is generally high after experiencing the system, though not in all respects.


Shuttling of the herpes simplex virus type 1 regulatory protein ICP27 between the nucleus and cytoplasm mediates the expression of late proteins.
The herpes simplex virus type 1 (HSV-1) immediate-early protein ICP27 is required posttranscriptionally for the expression of HSV-1 late genes during a productive infection. ICP27 also inhibits host cell pre-mRNA splicing, effectively shutting off host cell protein synthesis. Here we describe intragenic suppressors of LG4, a virus with a conditional lethal mutation in the gene encoding ICP27. At the restrictive temperature, tsICP27 from LG4 fails to inhibit host cell pre-mRNA splicing and to activate the expression of HSV-1 late-gene products. Although the suppressors of LG4 restore virus growth, they still fail to inhibit host cell pre-mRNA splicing. Thus, the role of ICP27 in the synthesis of late proteins is independent of host shutoff. In HSV-1-infected cells, ICP27 shuttles between the nucleus and the cytoplasm. Shuttling of ICP27 occurs only at late times during infection. In transfected cells, ICP27 shuttling was dependent on coexpression of RNA from a late HSV-1 gene. While shuttling does not occur in cells infected with LG4 at 39.5 degrees C, the suppressors of LG4 restore shuttling. Temperature shift experiments correlate the defect in shuttling with the temperature-sensitive phenotype of LG4. These data provide a correlation between shuttling of ICP27 and the expression of HSV-1 late-gene products. We propose that ICP27 regulates late-gene protein synthesis by facilitating the export of late RNAs.


Drugs of abuse in wastewater and suspended particulate matter--further developments in sewage epidemiology.
This manuscript reports, for the first time, a monitoring study analysing wastewater and associated suspended particulate matter (SPM) to determine the concentration of drugs of abuse and metabolites in wastewater influent. The monitoring of SPM is crucial for target analytes because, depending on their physico-chemical properties, they may partition to particulates; thus, analysis of wastewater only will result in under-reporting of the concentration of target analytes in the sample. A daily one week monitoring study was carried out at a WWTP serving one of the largest cities in the Czech Republic; representing the first comprehensive application of the sewage epidemiology approach in the Czech Republic. In total, 60 analytes were targeted in the monitoring programme including stimulants, opioid and morphine derivatives, benzodiazepines, antidepressants, dissociative anaesthetics, drug precursors and their metabolites. Analysis of SPM determined that significant proportions of some compounds were present on the solids. For example, 21.0-49.8% of the total concentration of EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) in the sample was determined on SPM and 11.2-19.6% of methadone. The highest proportion on SPM was determined for fluoxetine in the range 68.1-79.6%, norfluoxetine 46.6-61.9% and amitriptyline 21.8-51.2%. In contrast, some compounds presented very little partitioning to SPM. Less than 5% was determined partitioned to SPM over the week period for analytes including cocaine, benzoylecgonine, cocaethylene, amphetamine, methamphetamine, MDMA (3,4-methylenedioxymethamphetamine), codeine, dihydrocodeine, tramadol, nortramadol, oxazepam and ephedrine. Determined concentrations in wastewater influent were subsequently utilised in the sewage epidemiology approach to estimate drug consumption, in the community from which the wastewater was derived. This back-calculation was updated for the first time to include the concentration of analytes present on SPM. The consumption of methamphetamine and MDMA was determined to be especially high in the studied community in relation to other European countries, while cocaine and methadone consumption was relatively low. This manuscript shows that in order to apply the sewage epidemiology approach, SPM analysis is required for some compounds; whereas for others the partitioning is small and one may regard this as negligible.


Collagen/gold nanoparticle nanocomposites: A potential skin wound healing biomaterial.
In this study, nanocomposite collagen scaffolds incorporating gold nanoparticles (AuNPs) were prepared for wound healing applications. Initially, dose (<20 ppm) and size (>20 nm) of AuNPs that were not cytotoxic on HaCat keratinocytes and 3T3 fibroblasts were determined. Both collagen sponges and AuNP-incorporated nanocomposites (CS-Au) were cross-linked with glutaraldehyde (CS-X and CS-AuX). Incorporation of AuNPs into cross-linked scaffolds enhanced their stability against enzymatic degradation and increased the tensile strength. Hydrolytic degradation of CS-Au group was also less than CS after seven days. Upon confirming in vitro biocompatibility of the scaffolds with cytotoxicity assays, cell attachment and proliferation tests and the in vivo efficacy for healing of full-thickness skin wounds were investigated by applying CS-X, CS-AuX or a commercial product (Matriderm®) onto defect sites and covering with Ioban® drapes. Defects were covered only with drapes for untreated control group. The wound areas were examined with histopathological and biomechanical tests after 14 days of operation. CS-AuX group was superior to untreated control and Matriderm®; it suppressed the inflammation while significantly promoting granulation tissue formation. Inflammatory reaction against CS-AuX was milder than CS-X. Neovascularization was also higher in CS-AuX than other groups, though the result was not significant. Wound closure in CS-X (76%), CS-AuX (69%), and Matriderm® (65%) were better than untreated control (45%). CS-AuX group had the highest tensile strength (significantly higher than Matriderm®) and modulus (significantly higher than Matriderm® and CS-X), indicating a faster course of dermal healing. Further studies are also needed to investigate whether higher loading of AuNPs affects these results positively in a statistically meaningful manner. Overall, their contribution to the enhancement of degradation profiles and mechanical properties, their excellent in vitro biocompatibility, and tendency to accelerate wound healing are encouraging the use of AuNPs in collagen sponges as potent skin substitutes in the future.