An insight into the sialotranscriptome of the cat flea, Ctenocephalides felis.
Saliva of hematophagous arthropods contains a diverse mixture of compounds that counteracts host hemostasis. Immunomodulatory and antiinflammatory components are also found in these organisms' saliva. Blood feeding evolved at least ten times within arthropods, providing a scenario of convergent evolution for the solution of the salivary potion. Perhaps because of immune pressure from hosts, the salivary proteins of related organisms have considerable divergence, and new protein families are often found within different genera of the same family or even among subgenera. Fleas radiated with their vertebrate hosts, including within the mammal expansion initiated 65 million years ago. Currently, only one flea species-the rat flea Xenopsylla cheopis-has been investigated by means of salivary transcriptome analysis to reveal salivary constituents, or sialome. We present the analysis of the sialome of cat flea Ctenocephaides felis. A salivary gland cDNA library from adult fleas was randomly sequenced, assembled, and annotated. Sialomes of cat and rat fleas have in common the enzyme families of phosphatases (inactive), CD-39-type apyrase, adenosine deaminases, and esterases. Antigen-5 members are also common to both sialomes, as are defensins. FS-I/Cys7 and the 8-Cys families of peptides are also shared by both fleas and are unique to these organisms. The Gly-His-rich peptide similar to holotricin was found only in the cat flea, as were the abundantly expressed Cys-less peptide and a novel short peptide family. Fleas, in contrast to bloodsucking Nematocera (mosquitoes, sand flies, and black flies), appear to concentrate a good portion of their sialome in small polypeptides, none of which have a known function but could act as inhibitors of hemostasis or inflammation. They are also unique in expansion of a phosphatase family that appears to be deficient of enzyme activity and has an unknown function.


Effects of the Paratemnus elongatus pseudoscorpion venom in the uptake and binding of the L-glutamate and GABA from rat cerebral cortex.
L-Glu is the most important and widespread excitatory neurotransmitter of the vertebrates. Four types of receptors for L-glu have been described. This neurotransmitter modulates several neuronal processes, and its dysfunction causes chronic and acute diseases. L-Glu action is terminated by five distinct transporters. Antagonists for these receptors and modulators of these transporters have anticonvulsant and neuroprotective potentials, as observed with the acylpoliamines and peptides isolated from spiders, solitary and social wasp venoms. On the other hand, the major inhibitory neurotransmitter in mammalian nervous tissue is the GABA. Drugs that enhance GABA neurotransmission comprise effective approaches to protecting the brain against neuronal injury. Is this study, we demonstrate for the first time the inhibition of the [3H]L-glu binding to its specific sites in synaptosomal membranes from rat cerebral cortex, produced by 0.027 U of Paratemnus elongatus venom (EC50). The venom of P. elongatus changes Km and Vmax into the high affinity uptake of the L-glu and decreases Km and Vmax into the parameters of the GABA uptake from rat synaptosomes. This leads us to speculate on the possible presence of selective and specific compounds in this venom that act in L-glu and GABA dynamics, and therefore, that can serve as tools and new drug models for understanding these neurotransmissions.


Modeling Parental Influence on Food Consumption among Chinese Adolescents through Self-Efficacy: A Path Analysis.
This study aimed to investigate the associations between perceived parental control, perceived parental modeling and parent-teen co-decision making, and fruit and vegetable (F&V) and sugar-sweetened beverage and junk food (S&J) consumption among Chinese adolescents, and examine whether self-efficacy mediates the associations. Data were collected in a cross-sectional survey of Chinese adolescents carried out in the fall of 2019. The questionnaires were adapted from the Family Life, Activity, Sun, Health, and Eating (FLASHE) Study. Ordinary least-squares regressions and a path analysis were performed to evaluate the hypothesized associations. The final sample included 3595 Chinese adolescents (mean (SD) age, 14.67 (1.73) years; 52.82% (n = 1899) males). Perceived parental control was positively associated with adolescents' F&V consumption, and was negatively associated with adolescents' S&J consumption. Perceived parental modeling and parent-teen co-decision making were both positively associated with adolescents' F&V consumption and negatively associated with their S&J consumption. Adolescents' self-efficacy was positively associated with F&V consumption and negatively associated with S&J consumption. These results suggest that serving as a positive role model, having adolescents participate in the decision-making process, and increasing adolescents' self-efficacy can be feasible and efficacious strategies to improve the nutritional quality of Chinese adolescents' diets.


Serum IgG and IgM anticardiolipin antibodies in neurological diseases.
To determine whether anti-cardiolipin antibodies (ACA) are associated with multiple sclerosis (MS) or myasthenia gravis (MG), sera from 42 patients suffering from MS and from 21 patients with myasthenia were studied, using an enzyme-linked immunosorbent assay (ELISA). No significant difference in IgG or IgM immunoglobulin isotypes between the MS myasthenic patients and controls was found.


Correction: Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models.
[This corrects the article DOI: 10.1371/journal.pntd.0005568.].


How Valinomycin Ionophores Enter and Transport K+ across Model Lipid Bilayer Membranes.
Valinomycin, a cyclic peptide, was incorporated into a biomimetic lipid membrane tethered to the surface of a gold (111) electrode. Electrochemical impedance spectroscopy was used to study the ionophore properties of the peptide, and polarization modulation infrared reflection absorption spectroscopy was employed to determine the conformation and orientation of valinomycin in the membrane. The combination of these two techniques provided unique information about the ionophore mechanism where valinomycin transports ions across the membrane by creating a complex with potassium ions and forming an ion pair with a counter anion. The ion pair resides within the hydrophobic fragment of the membrane and adopts a small angle of ∼22° with respect to the surface normal. This novel study provides new insights explaining the valinomycin ion transport mechanism in model biological membranes.


Short-Term Psycho-Education for Caregivers to Reduce Overmedication of People with Intellectual Disabilities (SPECTROM): Development and Field Testing.
People with intellectual disabilities (PwID) are at a higher risk of developing challenging behaviours (CB). Despite the poor evidence for the effectiveness of medications in managing CB, they are used widely among PwID (50-63%). The aims of our study were to develop a training programme, SPECTROM for support staff to help reduce overmedication in PwID and carry out field testing of SPECTROM including a process evaluation. We developed SPECTROM using the Experience-based co-design method that included four focus groups and a one-day co-design event. Twenty trainees received SPECTROM training. We used the Management of Aggression and Violence Attitudes Scale-Revised-Intellectual Disabilities (MAVAS-R-ID) and the Psychotropic knowledge questionnaire. A semi-structured interview and a feasibility questionnaire were used for process evaluation. SPECTROM website contains 14 modules, resources, and face-to-face training. MAVAS-R-ID scores showed change in staff attitude to 'medication management' domain was statistically significant (p < 0.05). Psychotropic knowledge questionnaire showed statistically significant post-training improvement in correct responses (p < 0.05). Process evaluation data showed that SPECTROM was acceptable, applicable, practical, and relevant to staff practice, and helped to improve self-reflection, knowledge, and support to PwID. SPECTROM is a useful training that helps to change the support staff's attitude toward CB and improve their knowledge of psychotropic medications.


Loganin reduces neuroinflammation and promotes functional recovery after spinal cord injury through inhibiting NF-κB/NLRP3 signalling.
The highly disabling nature of spinal cord injuries (SCI) and high cost of treatment and rehabilitation impose a burden on families and society. Loganin has potential medicinal value in alleviating neuroinflammation. This study aimed to explore whether loganin can be used to reduce SCI-induced neuroinflammation and elucidate the molecular mechanisms underlying its action. An SCI rat model was developed to assess whether loganin promotes motor recovery after SCI. The anti-inflammatory effects of loganin on the dorsal horn of the spinal cord were identified by haematoxylin-eosin and immunohistochemical staining. The inflammatory effects of loganin were characterised using a lipopolysaccharide (LPS)-induced neuroinflammatory model in BV2 cells. For mechanistic exploration, the signalling pathways and target proteins of loganin action were predicted using bioinformatics and computational biology and then validated in cellular inflammation models. Loganin promoted animal motor recovery after SCI at the behavioural level, and it inhibited M1 differentiation of microglia and reduced NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated inflammatory responses at the tissue level. Loganin inhibited LPS-induced inflammation in BV2 cells, and bioinformatics and computational biology suggested that loganin acts on the p65 protein through the nuclear factor kappa-B (NF-κB)/NLRP3 signalling pathway. This was validated in a cellular model in which p65 trans-overexpression eliminated the downregulation of inflammatory factors by loganin. In conclusion, loganin reduces neuroinflammatory responses and promotes motor recovery after SCI. Loganin inhibits the NF-κB/NLRP3 signalling pathway by targeting the p65 protein to achieve repair.


Histologic characteristics of lichen planus transplanted onto nude mice and cultured in vitro.
Typical confluent lesions of lichen planus were transplanted onto nude mice and cultured in organ culture. The characteristic histologic appearance of lichen planus disappeared after grafting and became similar to normal skin within 6 weeks on nude mice; the dense lymphocyte infiltrate in dermis disappeared, the basal cell layer normalized, and the colloid bodies disappeared from epidermis, although some of them were found in dermis. The granular layer also normalized, but the stratum corneum remained hyperkeratotic 6 weeks after transplantation. In organ culture, characteristic histologic features of lichen planus disappeared in 3-5 days via a rapid necrosis of the upper part of the epidermis and formation of a new, normal-looking basal epidermis. These results suggest that lesions of lichen planus are primarily dependent on the influence of the host to maintain their typical histologic appearance.


Hearing loss and respiratory health symptoms among large-scale sawmill workers of the timber processing factories within the Gert Sibande District Municipality: a comparative cross-sectional study.
Occupational exposure to wood dust may cause respiratory illnesses, while prolonged exposure to loud noise may cause noise-induced hearing loss. The objective of the study was to assess the prevalence of hearing loss and respiratory symptoms among large-scale sawmill workers within the Gert Sibande Municipality in Mpumalanga Province, South Africa. A comparative cross-sectional study consisting of 137 exposed and 20 unexposed randomly selected workers was undertaken from January to March 2021. The respondents completed a semi-structured questionnaire on hearing loss and respiratory health symptoms. The data was analysed using Statistical Package for Social Sciences (SPSS) version 21 (Chicago II, USA). The statistical analysis of the difference between the two proportions was done using an independent student t-test. The level of significance was set at p < 0.05. There was a statistically significant difference between the exposed and unexposed workers on the prevalence of respiratory symptoms like phlegm (51.8 vs. 0.0%) and shortness of breath (chest pain) (48.2 vs. 50%). There was also a statistically significant difference between the exposed and unexposed workers on the signs and symptoms of hearing loss like tinnitus (ringing in the ears) (50 vs. 33.3%), ear infections (21.4 vs. 66.7%), ruptured ear drums (16.7 vs. 0.0%), and ear injuries (11.9 vs. 0.0%). The exposed workers reported always wearing personal protective equipment (PPE) (86.9%) compared to the unexposed workers (75%). The reason for not wearing PPE consistently by the exposed workers was due to not being available (48.5%), compared to the unexposed workers who reported other reasons (100%). The prevalence of respiratory symptoms among the exposed workers was higher than that of the unexposed workers, except for chest pains (shortness of breath). The prevalence of symptoms of hearing loss among the exposed workers was higher than the unexposed workers, except for ear infections. The results suggest that measures should be implemented at the sawmill to help protect workers' health.


E-1500: Survey on feeding practices in the first 1,500 days of life, recommended by healthcare professionals in Latin America.
Health-disease processes are established and programmed in the first 1500 days of life, a period in which nutrition and the microbiota play a fundamental role. Feeding practices vary, according to regional sociocultural characteristics. The Early Nutrition Group of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN) established the goal of identifying the main feeding practices in the first 1500 days that were recommended by health professionals in Latin America. A survey was conducted on the aspects of maternal-infant and young child nutrition during the first 1500 days of life. An open invitation was extended to Latin American healthcare professionals to anonymously answer the online survey. A total of 1284 surveys from participants in 18 Latin American countries were analyzed. The mean age of the participants was 37.14 ± 11.1 years, 75.7% were women, 64.7% were physicians, and the rest were nutritionists/nutriologists. A total of 71.4% were familiar with the concept of the first 1000 days of life, 95% answered that exclusive breastfeeding should be carried out up to 6 months of age, and 34.3% responded that complementary feeding should be begun between 4 and 6 months of age. There was scant knowledge regarding nutrition in the pregnant woman. Adherence to traditional complementary feeding practices was evident. In a group of Latin American healthcare professionals, knowledge about nutrition in the first 1000-1500 days of life of an individual is still incomplete and insufficient, showing the need for continued training of healthcare professionals, with respect to those themes.


Association between bleeding severity and long-term mortality in patients experiencing vascular complications after percutaneous coronary intervention.
Vascular complications (VCs) occur in 3% to 8% of percutaneous coronary interventions (PCIs). However, only a portion of patients who experience VCs bleed significantly. The aim of this study was to assess the covariates associated with the amount of blood loss in patients experiencing postprocedural VCs as well as the effect of the degree of blood loss on long-term mortality. Overall, 7,718 unselected patients who underwent PCI through femoral access were evaluated. Those experiencing VCs were identified and stratified with regard to the degree of hematocrit (HCT) decrease after the procedure. In total, 444 patients (5.8%) had VCs. Compared to those without VCs, patients with VCs were older and had more extensive co-morbidities. Severe blood loss was most frequent in those who had vascular perforation requiring surgical repair or in those who had retroperitoneal bleeding. Overall, <25% of patients with hematoma had severe blood loss. The raw 1-year mortality was doubled in patients with minimal or moderate HCT decrease and was tripled in those with severe decreases in HCT. Similarly, the rate of definite stent thrombosis was tripled in patients with VCs and moderate or severe decreases in HCT. After adjustment, only patients with VCs and the greater HCT decreases had an increased risk for death at 1 year (hazard ratio 1.80, 95% confidence interval 1.03 to 3.14). Independent predictors of severe HCT decrease included age, female gender, glycoprotein IIb/IIIa inhibitor use, and activated clotting time peak. Bivalirudin and closure devices were independently associated with less frequent severe HCT decrease. In conclusion, VCs do not entail an increased risk for death at 1 year unless associated with severe blood loss. The use of bivalirudin and closure devices seems to reduce the risk for such complications.


Transcriptome analysis reveals genes expression pattern of Spirodela polyrhiza response to heat stress.
With global warming, high-temperature stress has become an essential abiotic factor affecting plant growth and survival. However, little knowledge was available of the molecular mechanism that aquatic plants respond to this stress. In the present study, we explore the adaptation mechanism of Spirodela polyrhiza, a surface-water-grown duckweed species broadly distributed worldwide to high temperatures, and analyze its gene expression pattern of S. polyrhiza under heat stress. Three temperature stress treatments, including room temperature group (CK), middle high-temperature group (MTS), and high-temperature group (45 °C, HTS) were set. The results showed that the contents of SOD first increased and then decreased, and those of MDA showed an upward trend under elevated high-temperature stress. According to the transcriptome data, 3145, 3487, and 3089 differently expressed genes (DEGs) were identified between MTS and CK, HTS and CK, and HTS and MTS, respectively. The transcription factors (TFs) analysis showed that 14 deferentially expressed TFs, including HSF, ERF, WRKY, and GRAS family, were responsive to heat stress, suggesting they might play vital roles in improving resistance to heat stress. In conclusion, S. polyrhiza could resist high temperatures by increasing SOD activity and MDA at the physiological level. Several transcription factors, energy accumulation processes, and cell membranes were involved in high-temperature stress at the molecular level. Our findings are helpful in better grasping the adaptation rules of some aquatic plants to high temperatures.


Balneoclimatic prevention and treatment of vascular disorders due to vibration at the forestry workers.
A total of 824 chain-saw operators who were employed in felling trees in the forestry industry were exposed to local vibration, which produced peripheral blood-flow disorders and lesions in the joints and hand bones. In the last 10 years, they have undergone 24-day balneoclimatic treatment at the Kołobrzeg Health Resort. It was found that a stay in the spa and certain balneological treatments exert a favorable effect on the peripheral blood-flow disorders produced by the local vibration of chain saws. The symptoms (chills and numbing of the fingers, etc.) disappeared in nearly 40% of these workers. An improvement in the objective indices of the peripheral circulation (thermographic and plethysmographic tests) was observed in about 90% of patients treated with brine baths combined with underwater vibratory massage (rotatory) or brine baths alone. The brine bath and vibratory massage have a direct beneficial influence on the peripheral blood flow of pectoral limbs.


Characterization and crystal structure of lysine insensitive Corynebacterium glutamicum dihydrodipicolinate synthase (cDHDPS) protein.
The lysine insensitive Corynebacterium glutamicum dihydrodipicolinate synthase enzyme (cDHDPS) was recently successfully introduced into maize plants to enhance the level of lysine in the grain. To better understand lysine insensitivity of the cDHDPS, we expressed, purified, kinetically characterized the protein, and solved its X-ray crystal structure. The cDHDPS enzyme has a fold and overall structure that is highly similar to other DHDPS proteins. A noteworthy feature of the active site is the evidence that the catalytic lysine residue forms a Schiff base adduct with pyruvate. Analyses of the cDHDPS structure in the vicinity of the putative binding site for S-lysine revealed that the allosteric binding site in the Escherichia coli DHDPS protein does not exist in cDHDPS due to three non-conservative amino acids substitutions, and this is likely why cDHDPS is not feedback inhibited by lysine.


Real life practice of sweat testing in Europe.
Evidence based guidelines exist for sweat testing, which remains a key component of a diagnosis of cystic fibrosis (CF), especially following newborn bloodspot screening (NBS). There are emerging challenges with respect to maintaining a valid sweat test service, notably a smaller number of sweat tests ordered in regions with established NBS programmes where Pediatricians refer less children for sweat testing, younger patients and equipment becoming obsolete. The ECFS Diagnostic Network Working Group has undertaken a comprehensive survey to better define sweat test practice across Europe. The survey was completed by 136 European respondents representing a CF center or laboratory providing a sweat test service (65% from regions with NBS for CF). There was considerable variance in practice, often not consistent with guidelines. In particular collection of sweat from two sites was rarely reported in European centres in contrast to US guidelines. There was a range of different references quoted for cut-off for both a positive and intermediate test. Most responses suggest cost is becoming an increasing issue and is not sufficiently reimbursed. This work will inform best practice guidelines and resources to sustain and improve sweat testing in Europe.


Characteristics of Killian-Jamieson diverticula mimicking a thyroid nodule.
Killian-Jamieson (K-J) diverticula have been incidentally detected on neck ultrasonography and could be misdiagnosed as thyroid nodules. The purpose of this study was to define the clinical and ultrasonographic characteristics of K-J diverticula. We analyzed 13 patients with K-J diverticula mimicking thyroid nodules including 4 of our patients and 11 previously reported cases between 1984 and August 2009. Seven patients (54%) were women, and all patients were asymptomatic. The average lesion's diameter was 1.5 cm (range, 0.5-4.0). Most of the lesions (92%) were located in the left thyroid lobe. Ultrasonography showed heterogeneous echogenic masses with echogenic foci and hypoechoic rims. A connection with the adjacent esophageal wall was found in 7 diverticula (54%) at the time of initial diagnosis. The K-J diverticula had unique ultrasonographic findings. Awareness of the fact that K-J diverticula can be misdiagnosed as thyroid nodules is important to avoid unnecessary interventions.


Natural language processing and machine learning algorithm to identify brain MRI reports with acute ischemic stroke.
This project assessed performance of natural language processing (NLP) and machine learning (ML) algorithms for classification of brain MRI radiology reports into acute ischemic stroke (AIS) and non-AIS phenotypes. All brain MRI reports from a single academic institution over a two year period were randomly divided into 2 groups for ML: training (70%) and testing (30%). Using "quanteda" NLP package, all text data were parsed into tokens to create the data frequency matrix. Ten-fold cross-validation was applied for bias correction of the training set. Labeling for AIS was performed manually, identifying clinical notes. We applied binary logistic regression, naïve Bayesian classification, single decision tree, and support vector machine for the binary classifiers, and we assessed performance of the algorithms by F1-measure. We also assessed how n-grams or term frequency-inverse document frequency weighting affected the performance of the algorithms. Of all 3,204 brain MRI documents, 432 (14.3%) were labeled as AIS. AIS documents were longer in character length than those of non-AIS (median [interquartile range]; 551 [377-681] vs. 309 [164-396]). Of all ML algorithms, single decision tree had the highest F1-measure (93.2) and accuracy (98.0%). Adding bigrams to the ML model improved F1-mesaure of naïve Bayesian classification, but not in others, and term frequency-inverse document frequency weighting to data frequency matrix did not show any additional performance improvements. Supervised ML based NLP algorithms are useful for automatic classification of brain MRI reports for identification of AIS patients. Single decision tree was the best classifier to identify brain MRI reports with AIS.


Dementia and Poor Continuity of Primary Care Delay Hospital Discharge in Older Adults: A Population-Based Study From 2001 to 2016.
Delayed discharge, remaining in acute care longer than medically necessary, reflects less than optimal use of hospital care resources and can have negative implications for patients. We studied (1) the change over time in delayed discharge in people with and without dementia, and (2) the association of delayed discharge with discharge destination and with the continuity of primary care prior to urgent admission. A retrospective population-based study. Delayed discharge after urgent admission and length of delayed discharge were studied in all hospital users aged ≥70 years with at least 1 urgent admission in British Columbia, Canada, in years 2001/02, 2005/06, 2010/11, and 2015/16 (N = 276,299). Linked administrative data provided by Population Data BC were analyzed using generalized estimating equations (GEE), logistic regression analysis, and negative binomial regression analyses. Delayed discharge increased among people with dementia and decreased among people without dementia, whereas the length of delay decreased among both. Dementia was the strongest predictor of delayed discharge [odds ratio 4.76; 95% confidence interval (CI) 4.59-4.93], whereas waiting for long-term care placement [incidence rate ratio (IRR) 1.56; 95% CI 1.50-1.62] and dementia (IRR 1.50; 95% CI 1.45-1.54) predicted a higher number of days of delay. Continuity and quantity of care with the same physician before urgent admission was associated with a decreased risk of delayed discharge, especially in people with dementia. This study demonstrates the need for better system integration and patient-centered care especially for people with dementia. Population aging will likely increase the number of patients at risk of delayed discharge. Delayed discharge is associated with both the patient's complex needs and the inability of the system to meet these needs during and after urgent care. Sufficient investments are needed in both primary care and long-term care resources to reduce delayed discharges.


Production and antibacterial activity of malforming C, a toxic metabolite of Aspergillus niger.
The production of the new mycotoxin malformin C by a solid substrate fermentation is described. Malformin C is highly toxic (mean lethal dose = 0.9 mg/kg) and exerts antibacterial activity against a variety of gram-positive and gram-negative organisms.


Phosphate ions functionalized spinel iron cobaltite derived from metal organic framework gel for high-performance asymmetric supercapacitors.
Spinel iron cobaltite (FeCo2O4) with high theoretical capacity is a promising positive electrode material for building high-performance supercapacitors. However, its inherent poor conductivity and deficient electrochemical active sites hinder the improvement of its electrochemical kinetics behavior. Herein, phosphate ions modified FeCo2O4 is obtained in the presence of oxygen vacancies (P-FeCo2O4-x) by a simple metal organic framework gel-derived strategy. Phosphate ions added on the surface of P-FeCo2O4-x greatly enhances its surface activity, thus prompting the faster charge storage kinetics of the electrode material. Due to its ample electrochemical active sites and rapid ion diffusion and electron mobility, the optimized P-FeCo2O4-x electrode delivers a superior specific capacity of 1568.8 F g-1 (784.4 C g-1) at a current density of 1 A/g and has an excellent cycling stability with 93.3 % initial capacity retention ratio after 5000 cycles. More impressively, the assembled asymmetric supercapacitor consisting of P-FeCo2O4-x and activated carbon which act as positive and negative electrode materials, respectively displays a favorable energy density of 60.2 Wh kg-1 at a power density of 800 W kg-1 and has a long cycling lifespan. These results demonstrate the potential importance of modifying the surface of spinel cobaltite with phosphate ions and incorporating oxygen defects in it as a facile strategy for enhancing the electrochemical kinetics of electrode materials.


Evolutionary relationships and polymorphisms among V kappa 10 genes from inbred and wild-derived inbred mice.
The V kappa 10 family in BALB/c mice is composed of three members, two of which are utilized in a variety of immune responses. We previously demonstrated that the product of the third gene, V kappa 10C, has never been detected as part of a functional antibody and productive rearrangements are selectively lost during B-cell development. Here we analyzed germline V kappa 10 genes from inbred and wild-derived mice by RFLP and sequencing in order to determine the origin of the V kappa 10C gene, as well as to examine the evolutionary relationships of V kappa 10 genes. Our results demonstrated that the V kappa 10 family is highly conserved across Mus species and subspecies, but that V kappa 10C is rare, being found in only inbred mice of V kappa 10 allelic group b and two of six M. m. domesticus isolates. It was not found in other M. musculus subspecies or M. spretus. V kappa 10A and V kappa 10B were found in all strains, with the exception of one M. m. domesticus isolate, which had only V kappa 10B genes. Overall, V kappa 10A sequences were more highly conserved than V kappa 10B, indicating that different selective pressures may be operating on these genes. The two V kappa 10C sequences from M. m. domesticus were 100% identical to that found in inbred mice. V kappa 10C is more closely related to V kappa 10B than to V kappa 10A and our data suggest that it is a recent duplication of the V kappa 10B gene.


Introducing unactivated acyclic internal aliphatic olefins into a cobalt catalyzed allylic selective dehydrogenative Heck reaction.
Unactivated acyclic internal aliphatic olefins are often found to be unreactive in conventional alkenylation reactions. To address this problem, a cobalt catalyzed allylic selective dehydrogenative Heck reaction with internal aliphatic olefins has been developed. The method is highly regio- and stereoselective, the conditions are mild and a wide variety of functional groups can be tolerated. Remarkably, both internal and terminal aliphatic olefins can be employed, thereby significantly expanding the scope of alkenylation chemistry with aliphatic olefins.


Nucleostemin promotes the proliferation of human glioma via Wnt/β-Catenin pathway.
Nucleostemin, nucleolar guanosine triphosphate (GTP)-binding protein 3, is a member of the MMR1/HSR1 GTP-binding protein family. The important roles of nucleostemin in self-renewal, cell cycle regulation, apoptosis, and cell proliferation of various cancer types as been shown. Nevertheless, its expression and potential functions in human glioma is still unclear. In the present study, we demonstrated that up-regulation of nucleostemin was tightly related to poor 5-year-survival ratios. In serum-starved and re-feeding models of U251 and U373MG, we observed the rising expression of nucleostemin and p-β-Catenin (p-Tyr645) were accompanied with cell proliferation markers (cyclin D1 and proliferating cell nuclear antigen (PCNA)). Employing nucleostemin-depletion models, we found down-regulated nucleostemin and p-β-Catenin. The flow cytometry analysis proved the weakened cell proliferation. Moreover, we detected the translocation of β-Catenin into the nucleus was impaired, meaning the inhibition of the Wnt/β-Catenin pathway. Taken together, we identified a positive correlation between up-regulation of nucleostemin and human glioma cell proliferation and that knocking-down nucleostemin alleviated glioma proliferation by reducing β-Catenin transportation into the nucleus. All results suggested that nucleostemin might accelerate human glioma proliferation via the Wnt/β-Catenin pathway.


The Synthesis of 2-Aminobenzoxazoles Using Reusable Ionic Liquid as a Green Catalyst under Mild Conditions.
A facile, green, and efficient method for the direct oxidative amination of benzoxazoles using heterocyclic ionic liquid as catalyst has been developed. The reaction proceeded smoothly at room temperature and gave the desirable 2-aminobenzoxazoles with good to excellent yields (up to 97%). The catalyst 1-butylpyridinium iodide can be easily recycled and reused with similar efficacies for at least four cycles.


The effects of carbohydrate supplementation during the second of two prolonged cycling bouts on immunoendocrine responses.
The purpose of this study was to examine the effect of carbohydrate (CHO) feeding during the second of two 90-min cycling bouts (EX1 started at 09:00 and EX2 started at 13:30) at 60% VO2max on leucocyte redistribution, neutrophil degranulation and oxidative burst and plasma IL-6 and stress hormone responses. This study consisted of two trials, which were completed in a counterbalanced order and separated by at least 4 days. Subjects (n=9) consumed a lemon flavoured 10% w/v CHO (glucose) or placebo (PLA) beverage during EX2: 500 ml just before exercise and 250 ml every 20 min during exercise. Venous blood samples were taken 5 min before exercise, immediately post-exercise, and 18-h post-EX2 for both trials. The main findings of this study were that ingestion of CHO compared with PLA during EX2 better maintained plasma glucose concentration, blunted the responses of plasma adrenaline, ACTH, cortisol, GH and IL-6, and attenuated the leukocytosis and monocytosis, but had no effect on neutrophil degranulation and oxidative burst activity. Furthermore, the immunoendocrine disturbances induced by two bouts of prolonged exercise returned to resting values within 18 h. These findings suggest that ingestion of CHO compared with PLA during the second of two bouts of 90-min cycling at 60% VO2max better maintains plasma glucose, blunts hypothalamic-pituitary-adrenal activation, and attenuates leucocyte trafficking, but does not affect neutrophil function. Furthermore, the disturbances of immunoendocrine responses induced by two bouts of prolonged exercise on the same day recover within 18 h.


Modified extraperitoneal approach to the abdominal aorta in exposure of the thoracoabdominal aorta.
A modified left transthoracic and retroperitoneal approach to the thoracoabdominal aorta without entering the peritoneal cavity is reported. The advantage of this modification is that the abdominal wall musculature is preserved intact except for the division of a small part of the transversus abdominis muscle.


Alzheimer's disease susceptibility locus in CD2AP is associated with increased cerebrospinal fluid tau levels in mild cognitive impairment.
Rs9296559 within CD2-associated protein (CD2AP) has been identified as a susceptibility locus for Alzheimer's disease (AD). Recent studies indicated that CD2AP functioned as a regulator of endocytic trafficking to modulate the β-amyloid (Aβ) generation in neurons. Moreover, knockdown of cindr, the Drosophila ortholog of CD2AP, enhanced tau-induced neurodegeneration, implying CD2AP also participated in tau pathology. However, the role of rs9296559 in regulating Aβ and tau metabolism in AD was still unclear. Here, the associations of rs9296559 with CSF Aβ1-42, p-tau, and t-tau were performed using a linear regression model in a total of 543 cognitive normal (CN), mild cognitive impairment (MCI), and AD subjects from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort. The results were replicated in an independent cohort consisting of 198 Chinese subjects recruited from our hospital. In the ADNI cohort, CC + TC genotypes significantly increased CSF t-tau and p-tau levels in MCI patients but did not alter CSF tau levels in AD. This association was also observed in the replication cohort. Moreover, there was no association between rs9296559 and CSF Aβ1-42 level at different disease statuses in the two cohorts. Our findings showed that rs9296559 was associated with higher CSF t-tau and p-tau levels in MCI, supporting that CD2AP modified AD risk by altering tau-related neurodegeneration in the early stage of the AD continuum. To the best of our knowledge, this is the first study to evaluate the association between CD2AP genotypes and AD CSF biomarkers.


White matter pathology isolates the hippocampal formation in Alzheimer's disease.
Prior work has demonstrated that the memory dysfunction of Alzheimer's disease (AD) is accompanied by marked cortical pathology in medial temporal lobe (MTL) gray matter. In contrast, changes in white matter (WM) of pathways associated with the MTL have rarely been studied. We used diffusion tensor imaging (DTI) to examine regional patterns of WM tissue changes in individuals with AD. Alterations of diffusion properties with AD were found in several regions including parahippocampal WM, and in regions with direct and secondary connections to the MTL. A portion of the changes measured, including effects in the parahippocampal WM, were independent of gray matter degeneration as measured by hippocampal volume. Examination of regional changes in unique diffusion parameters including anisotropy and axial and radial diffusivity demonstrated distinct zones of alterations, potentially stemming from differences in underlying pathology, with a potential myelin specific pathology in the parahippocampal WM. These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways.


Fire Needle Combined Topical Mupirocin for the Treatment of Simple Skin Abscesses in Pediatric Patients: A Case Series.
Skin abscesses are a common skin condition usually caused by bacterial infections and their incidence is increasing in children. Its current management strategy is still mainly incision and drainage, sometimes with antibiotics. In pediatric patients, surgical incision and drainage of skin abscesses is challenging compared to in adults because of their specific age and psychological characteristics and high aesthetic requirements. Therefore, it is important to seek better treatment options. We reported 17 cases of skin abscesses in pediatric patients aged 1 to 9 years. Ten cases had lesions on the face and neck and 7 cases on the trunk and limbs. They all received treatment based on fire needle combined with topical mupirocin. The lesions of all 17 pediatric patients healed within 4 to 14 days, with a median time of 6 days, and all achieved satisfactory results with no scarring left behind. No adverse events were observed in all patients, and no recurrence occurred within 4 weeks. For skin abscesses in pediatric patients, early application of a combination therapy based on fire needle is convenient, aesthetic, economical, safe and clinically important as an alternative to incision and drainage, and deserves further clinical promotion.


[Adrenocorticotropic hormone (ACTH): antagonistic effect on opioid analgesia in central nervous system of the rat and its possible mechanisms of action].
Using the behavioral pharmacological approach, we have studied the influence of ACTH on the analgesia mediated by three types of opioid receptors (mu, delta, kappa). The mechanisms by which ACTH antagonizes opioid analgesia were explored at receptor level and post-receptor second messenger level. The expression of Fos protein induced by ACTH was also observed in rat brain. The main results show that ACTH selectively antagonizes spinal opioid analgesia mediated by mu and delta, but not kappa receptors. The proposed mechanisms of the anti-opioid effect of ACTH are that ACTH can modulate opioid-induced decrease of intracellular cAMP content and the suppression of calcium influx. ACTH has been shown to induce Fos protein expression in selected brain areas including the nuclei involved in pain modulation. These brain areas may serve as sites of action for ACTH to exert its anti-opioid effect.


Red blood cell distribution width and cardiovascular diseases.
The red blood cell distribution width (RDW) is a rather simple measure of red blood cell (RBC) size heterogeneity (i.e., anisocytosis), which is easily calculated by dividing the standard deviation (SD) of erythrocyte volumes for the mean corpuscular volume (MCV). Emerging evidence suggests that, besides RBC abnormalities, many human disorders may be frequently associated with a high degree of anisocytosis. In this narrative review, we analyzed the current scientific literature about the putative role and the potential epidemiologic association between RDW and cardiovascular diseases. The findings of the most representative epidemiological studies were summarized and discussed. Overall, considerable and convincing evidence has been brought that an increased RDW value is associated with acute coronary syndrome (ACS) [including acute myocardial infarction (AMI)], ischemic cerebrovascular disease (including stroke), peripheral artery disease (PAD), as well as with atrial fibrillation (AF), heart failure (HF) and hypertension. Higher anisocytosis also significantly and independently predicts adverse outcomes in patients with these conditions. Although the role of anisocytosis in the pathogenesis of cardiovascular diseases remains uncertain, the considerable evidence available so far suggests that the clinical use of RDW may be broadened beyond the conventional boundaries of erythrocyte disorders, in particular for assisting the diagnosis and prognostication of patients with ACS, ischemic cerebrovascular disease, PAD, HF and AF.


γ-Glutamyl transferase: a marker of nonalcoholic fatty liver disease in patients with the metabolic syndrome.
The incidence of metabolic syndrome has increased in Mexico and nonalcoholic fatty liver disease (NAFLD) is a common complication. The authors aimed to evaluate the role of hepatic enzymes as biomarkers for NAFLD in patients presenting metabolic syndrome. We studied 193 nondiabetic individuals with metabolic syndrome identified from a population-based cross-sectional survey. To identify NAFLD, real-time gray-scale abdominal ultrasound was performed, and the right, left, and caudate hepatic lobules were observed to assess the size, echogenicity, and borders of the liver. All individuals answered a questionnaire for risk factors, and anthropometric measures and blood pressure were obtained. The concentration of hepatic enzymes and insulin in blood was measured and the Homeostatic Model Assessment index was calculated. A total of 160 individuals were identified as presenting NAFLD (82.9%). Body weight, BMI, and the waist-hip ratio increased as a direct result of the presence and severity of fatty liver. A similar situation was observed in the levels of triglyceride and hepatic enzymes aspartate aminotransferase and γ-glutamyltransferase (GGT), basal insulin level, and the Homeostatic Model Assessment index. In a multivariate model, the variables associated with the occurrence of NAFLD were sex, triglyceride and GGT levels, and obesity. The main factors that predict the occurrence of NAFLD are levels of triglyceride and GGT in the blood, as well as obesity. The accumulation of fat in the liver, in addition to increased oxidation and oxidative stress at the hepatic level, may be the mechanisms through which these factors increase the risk of NAFLD.


Separation of active and inactive forms of the third component of human complement, C3, by fast protein liquid chromatography (FPLC).
C3(H2O), an inactive form of C3 present to a variable extent in most C3 preparations, has been isolated in 40 min from previously purified C3 using FPLC ion exchange chromatography on a Mono Q column. As many as six peaks were obtained from some C3 preparations, corresponding to different molecular forms of the protein. One of these peaks consisted of a molecular form of C3 with intact alpha and beta chains, a free sulfhydryl group but no hemolytic activity and was identified as C3(H2O). C3(H2O) eluted as a homogeneous peak well resolved from native C3, C3b, high molecular weight aggregates and small degradation fragments. The same C3(H2O) peak was generated from native C3 by repeated freeze-thaw cycles or NH2OH treatment. C3(H2O) alpha chain appeared as a doublet about 2 kDa heavier than native C3 alpha chain in low cross-linked gels. Two forms of C3b could be separated on the Mono S column, both able to form the C3 convertase. The present report describes a very fast method to resolve and isolate to homogeneity C3(H2O) and native C3 from C3 preparations. Both molecular forms of C3 are very suitable for studies of the initial and amplification C3 convertases of the alternative pathway of complement.


Using metaphor to read the organisation of the NHS. National Health Service.
The paper is concerned with the complexity of the British National Health Service (NHS) as an organisation and with different ways of seeing this. Morgan proposes that explanations of organisational life are based on metaphors which highlight particular interpretations (Morgan, G., 1986, Images of Organisation. London, Sage). The ability to "read" a complex phenomenon depends on being able to see how these different aspects co-exist. The study applies metaphoric thinking to the organisation of the NHS. Utilising documentary data sources, a diagnostic reading is made examining different metaphors to highlight key aspects of the situation. The metaphors of machine and organism are drawn from Morgan's conceptual scheme, those of religion and marketplace are proposed as of particular relevance to the NHS. In the religious metaphor the focus is on the mission of the NHS in terms of its founding principles of universality, comprehensiveness, equality and collectivism. Perceived as a machine the NHS is characterised as an organisation originally based on technocratic rationality and its subsequent history interpreted as moving towards increasingly centralised control. An alternative perspective on the same events is considered in terms of the organic metaphor. In this view the NHS is examined as an open system, which is devolved, decentralised, participative and responsive to its environment. The image of the marketplace focuses on the impact on the organisation of the introduction of competition and incentives in the post-reform period. Other images are sketched briefly. In the critical evaluation the insights generated by the different images are assessed and the different interpretations linked together. It is concluded that metaphoric thinking enables us to appreciate and interpret the ambiguities and paradoxes in NHS organisational life.


Role of clostridial toxin in the pathogenesis of clindamycin colitis in rabbits.
The pathophysiology of antibiotic-associated colitis was studied in rabbits with severe ileocolitis induced by oral administration of clindamycin. Cell-free, sterile filtrates of cecal contents of rabbits with clindamycin colitis contained a toxin that was lethal for mice and cytotoxic for HeLa-cell monolayers. The toxin was heat labile, was inactivated by pronase but not trypsin, and had a mol wt by gel filtration on Sephadex G-100 of 45,000. The toxin was neutralized by antiserum to Clostridium perfringens type E, but not by other clostridial antisera. The toxin also caused severe necrosis of rabbit rectal epithelium during 18-hr organ culture, which could be completely reversed by neutralization with C. perfringens type E antiserum. These studies indicate that clindamycin colitis in rabbits is caused by overgrowth of a clostridial species, which releases a heat-labile toxic protein of mol wt of 45,000 capable of necrosing colonic epithelial cells.


Implementation of Guidelines for Healthier Canteens in Dutch Secondary Schools: A Process Evaluation.
The Netherlands Nutrition Centre has developed 'Guidelines for Healthier Canteens'. To facilitate their implementation, implementation tools were developed: stakeholders' questionnaires, the 'Canteen Scan' (an online tool to assess product availability/accessibility), a tailored advisory meeting/report, communication materials, establishment of an online community, newsletters, and a fact sheet with students' wishes/needs. In this quasi-experimental study, we investigated the effect of these tools in secondary schools on (a) factors perceived by stakeholders as affecting implementation; (b) the quality of implementation. For six months, ten intervention schools implemented the guidelines, supported by the developed implementation tools. Ten control schools received the guidelines without support. School managers, caterers, and canteen employees (n = 33) reported on individual and environmental factors affecting implementation. Implementation quality was determined by dose delivered, dose received, and satisfaction. Stakeholders (n = 24) in intervention schools scored higher on the determinants' knowledge and motivation and lower on need for support (p < 0.05). Dose received (received and read) and satisfaction was highest for the advisory meeting/report (67.9%, 64.3%, 4.17), communication materials (60.7%, 50.0%, 3.98), and fact sheet (80%, 60%, 4.31). Qualitative analyses confirmed these quantitative results. In conclusion, a combination of implementation tools that includes students' wishes, tailored information/feedback, reminders and examples of healthier products/accessibility supports stakeholders in creating a healthier school canteen.


Clinical syndromes and management of intracerebral hemorrhage.
Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality. Acutely, ICH is associated with a sudden surge in intracranial pressure (ICP), as the volume of hematoma increases the pressure in the closed head, leading to non-specific symptoms of ICP: headache, nausea, vomiting, and alterations in consciousness. In the early phase, damage to the brain tissues surrounding the hematoma causes progression of neurologic symptoms. Expansion of supratentorial ICHs may result in transtentorial herniation, causing mental status deterioration and loss of pupillary light reflex. Compared to ischemic stroke, seizure is more common in ICH.


Timeliness of childhood vaccinations in Kampala Uganda: a community-based cross-sectional study.
Child survival is dependent on several factors including high vaccination coverage. Timely receipt of vaccines ensures optimal immune response to the vaccines. Yet timeliness is not usually emphasized in estimating population immunity. In addition to examining timeliness of the recommended Expanded Programme for Immunisation (EPI) vaccines, this paper identifies predictors of untimely vaccination among children aged 10 to 23 months in Kampala. In addition to the household survey interview questions, additional data sources for variables included data collection of child's weight and length. Vaccination dates were obtained from child health cards. Timeliness of vaccinations were assessed with Kaplan-Meier time-to-event analysis for each vaccine based on the following time ranges (lowest-highest target age): BCG (birth-8 weeks), polio 0 (birth-4 weeks), three polio and three pentavalent vaccines (4 weeks-2 months; 8 weeks-4 months; 12 weeks-6 months) and measles vaccine (38 weeks-12 months). Cox regression analysis was used to identify factors associated with vaccination timeliness. About half of 821 children received all vaccines within the recommended time ranges (45.6%; 95% CI 39.8-51.2). Timely receipt of vaccinations was lowest for measles (67.5%; 95% CI 60.5-73.8) and highest for BCG vaccine (92.7%: 95% CI 88.1-95.6). For measles, 10.7% (95% CI 6.8-16.4) of the vaccinations were administered earlier than the recommended time. Vaccinations that were not received within the recommended age ranges were associated with increasing number of children per woman (adjusted hazard ratio (AHR); 1.84, 95% CI 1.29-2.64), non-delivery at health facilities (AHR 1.58, 95% CI 1.02-2.46), being unmarried (AHR 1.49, 95% CI 1.15-1.94) or being in the lowest wealth quintile (AHR 1.38, 95% CI 1.11-1.72). Strategies to improve vaccination practices among the poorest, single, multiparous women and among mothers who do not deliver at health facilities are necessary to improve timeliness of vaccinations.


Reappraisal of therapeutic vancomycin trough concentrations with empirical dosing in neonatal infections.
Vancomycin is commonly used for neonatal sepsis. However, consensus on an empirical neonatal vancomycin regimen remains uncertain. We aimed to reappraise the therapeutic optimum concerning vancomycin trough concentrations with empirical dosing and to evaluate the relationship between trough concentrations and predicted 24-h area under the curve (AUC24). This was a 3-year retrospective study. Neonates who were admitted to the neonatal intensive care unit with available vancomycin trough concentrations were enrolled. Trough levels were obtained before the fourth dose. Achievement of goal trough after implementing the vancomycin dosing regimen was based on the Practical Neonatology Medical Manual, published by the National Taiwan University College of Medicine. A total of 46 neonates were included for analysis. Coagulase-negative staphylococci were the most commonly identified pathogens of sepsis. Among these patients, 22 achieved goal trough levels of 10-20 mcg/mL. Trough levels of 5-10 or >20 mcg/mL occurred in 13 and 11 patients, respectively. A moderately positive correlation between trough and predicted AUC24 was found in all patients (Spearman's rho = 0.676, p < 0.001). In patients with body weight 1200-2000 g and postnatal age >7 days, the serum creatinine of those with trough levels >20 mcg/mL was significantly higher than those with goal trough levels (0.61 vs. 0.45 mg/dL, p = 0.01). Among those with trough levels >20 mcg/mL, 5 patients received ibuprofen for patent ductus arteriosus closing prior to vancomycin treatment (45%, 5/11), compared to only 3 patients with trough levels <20 mcg/mL (9%, 3/35) (p = 0.013). Only half of the neonates receiving empirical vancomycin regimen achieved goal trough levels of 10-20 mcg/mL. Higher serum creatinine or ibuprofen treatment may increase the risk of overly high trough levels. The vancomycin regimen needs further validation and modification to provide adequate dosing for optimal use in neonates.


In vitro susceptibility to thrombin-induced platelet microbicidal protein is associated with reduced disease progression and complication rates in experimental Staphylococcus aureus endocarditis: microbiological, histopathologic, and echocardiographic analyses.
Mammalian platelets contain small, cationic, staphylocidal peptides, termed thrombin-induced platelet-microbicidal proteins (tPMPs). Evidence suggests that tPMPs play a key role in host defense against endovascular infections, such as infective endocarditis (IE). In the present study, we evaluated the influence of differences in staphylococcal tPMP-susceptibility profiles in vitro on disease severity in experimental IE. Experimental IE was induced in rabbits with either a tPMP-susceptible or an isogenic tPMP-resistant Staphylococcus aureus strain. Vegetation size, left ventricular fractional shortening, and onset of aortic valvular regurgitation were serially assessed by echocardiography over an 11-day postinfection period. In addition, blood cultures were performed daily. Parameters delineated at autopsy included vegetation weights; bacterial densities in vegetations, myocardium, and kidneys; extent of valvular and perivalvular tissue damage; and renal embolization. The following significant differences were observed in animals infected with the tPMP-susceptible versus the tPMP-resistant S aureus strain: substantially lower bacteremia rates (P=0.02); reduced vegetation growth (P<0.001) and weight (P<0.001); a later onset of aortic valvular regurgitation (P=0.0039); increased preservation of left ventricular function (P<0.001); reduced valvular tissue damage (P=0.01) and perivalvular inflammation (P=0.015); and reduced bacterial densities in vegetations (P<0.001) and kidneys (P<0.01). The in vitro tPMP-susceptibility profile in S aureus substantially affects a number of well-defined cardiac and microbiological parameters related to disease severity and prognosis in IE. These findings underscore the likelihood that platelets mitigate the pathogenesis of endovascular infections via local secretion of antimicrobial peptides.


Electrical tissue impedance spectroscopy: a novel device to measure esophageal mucosal integrity changes during endoscopy.
Patients with gastroesophageal reflux disease (GERD) have impaired esophageal mucosal integrity. Measurement of the mucosal integrity is complex and time-consuming. Electrical tissue impedance spectroscopy (ETIS) is a device that measures impedance of tissue in vivo during endoscopy. In this study, we aimed to validate ETIS as a measure of esophageal mucosal integrity. Electrical tissue impedance spectroscopy measurements were performed during upper endoscopy in 12 GERD patients and 11 healthy controls after cessation of proton pump inhibition. During endoscopy biopsies of the distal esophagus were obtained for transmission electron microscopy to determine dilation of intercellular spaces (DIS) and for Ussing chamber experiments to determine transepithelial permeability and transepithelial electrical resistance. Extracellular impedance measured in vivo by ETIS was significantly lower in GERD patients compared to controls [mean (SD) 5621 (3299) Ω.m and 8834 (2542) Ω.m, respectively, P < 0.05]. We found a strong inverse relation between extracellular impedance determined by ETIS and DIS (r = -0.76, P < 0.05), and between extracellular resistance in vivo and transepithelial permeability of esophageal biopsies (r = -0.65, P < 0.01). Electrical tissue impedance spectroscopy is a new tool that can be used to evaluate esophageal mucosal integrity changes during endoscopy.


Left ventricular failure in calves produced by supravalvular aortic stenosis.
A stable model of left ventricular failure is required to test left ventricular assist devices. Supravalvular aortic constriction will cause left atrial pressure to rise to new levels which are stable for several days. When left atrial pressure becomes unstable, an automatically actuated left ventricular assist device will increase its output and prevent pulmonary edema.


High prevalence of genetic abnormalities in Middle Eastern patients with idiopathic non-obstructive azoospermia.
Our objective is to detect the frequency and types of major genetic abnormalities of idiopathic non-obstructive azoospermia (NOA) to give appropriate genetic counseling before assisted reproductive techniques (ART) in Middle East and to compare the frequencies with other regions of the world. A total of 880 Middle Eastern patients with NOA were recruited in this multicenter study for genetic evaluation prior to use of ART. Karyotyping was performed on peripheral blood lymphocytes according to standard G-banding methods, polymerase chain reaction (PCR) was performed to screen the microdeletions in the AZF region of the Y chromosome. The present study shows that the total prevalence of genetic abnormalities is 28.41 %, including 184 patients (20.91 %) with chromosome disorder and 66 patients (7.5 %) with Y chromosome microdeletions. The most prevalent chromosome abnormality is Klinefelter's syndrome, which includes 161 patients (18.3 %), 7 patients had XX reversal male sex (0.8 %), 2 patients had 47XYY (0.23 %) and 2 patients had 45XO/46XY (0.23 %). Structural abnormalities occurred in 12 patients (1.36 %). The high prevalence of genetic abnormalities (28.41 %) in our study strongly suggests the need for routine genetic testing and counseling prior to assisted reproduction in such population with idiopathic infertility, as a result may help determine the prognosis, as well as the choice of ART. Moreover it allows specific pre-implantation genetic testing to minimize the risk of transmitting genetic defects to offspring.


Stall-Feeding of Sheep on Restricted Grazing: Effects on Performance and Serum Metabolites, Ruminal Fermentation, and Fecal Microbiota.
This study investigated the effects of three feeding systems, indoor feeding (CONT), indoor feeding with time-restricted grazing artificial pasture (4 h/day, G4H), and indoor feeding with an eight-hour daily grazing artificial pasture (G8H), on the growth performance, serum metabolites, ruminal fermentation, and fecal microbiota composition of lambs. Average daily gain showed a tendency (p = 0.081) to be higher for the G4H group compared with the CONT group. Moreover, feeding systems did not have a significant effect on most of the serum biochemical indicators in lambs. Concentrations of serum glutathione peroxidase and immunoglobulins (IgA, gG, and IgM) were significantly lower (p < 0.01) in the CONT group. Additionally, a tendency towards higher levels of volatile fatty acids, acetate, and butyrate was found in animals of the G4H group compared to the CONT group. Furthermore, fecal microbiota composition was altered in G4H and G8H groups, resulting in the increased relative abundance of Firmicutes and Ruminococcaceae UCG-005, as well as the decreased relative abundance of Ruminobacter compared with the CONT group. Overall, these results suggest that indoor feeding with restricted grazing time does not significantly affect fattening performance or rumen fermentation but enhances antioxidation and immune function activity and also alters fecal microbiota composition.


MITF::CREM-rearranged tumor: a novel group of cutaneous tumors with melanocytic differentiation.
Cutaneous tumors with melanocytic differentiation represent a broad group of neoplasms of both melanocytic and non-melanocytic origin. Besides traditional members such as clear-cell sarcoma (CCS) and PEComa, the latter group has recently expanded to also include MITF::CREM fusion-associated tumors, but the available data are limited. Herein, we present a third case of this rare neoplasm which occurred in the temporal region in a 1-year-old girl. It was an infiltratively growing polypoid dermal-based lesion lacking an intraepidermal component. It consisted of cellular solid sheets or small nests of epithelioid to spindled cells with a predominantly eosinophilic and much less commonly clear cytoplasm. The nuclei had round to ovoid shape and exhibited moderate to high-grade atypia and prominent nucleoli. The mitotic activity was 11 mitoses per 10 high-power fields, and atypical mitotic figures were present. Immunohistochemically, the tumor was strongly positive with S100 protein, SOX10, and MITF, while HMB45, tyrosinase, and Melan A were negative. Extensive molecular analysis revealed only MITF::CREM gene fusion. There had no evidence of disease 9 months after the diagnosis. These tumors need to be distinguished from malignant tumors with melanocytic differentiation, primarily from melanoma. However, additional cases still need to be studied to precisely define their biological potential and establish their nosologic status.


Profit inefficiency of goat farming in Malawi: A Bayesian approach.
Goat farms located in villages constitute an important sub-sector to buffer household livelihoods against climate shocks in absence of insurance markets, and thus the need to intensify production to meet the growing goat meat demand. There has been little attempt to quantify the efficiency of goat farms and the associated drivers. Potential initiatives to bolster goat farm incomes have not gone beyond production. Using the Bayesian Stochastic Frontier Approach and Malawi's national Integrated Household Panel Survey data from 2010 to 2019, we analyze the profit efficiency of goat farming and the priority drivers that influence inefficiencies across production plants. The findings reveal that farmers are operating below the profit frontier and 71% of the profit-loss is influenced by farm characteristics. The results further suggest that policies involving stirring commercializing and specialization are key to closing the efficiency gap. Finally, the study proposes new policy directions, namely, government provision of livestock extension services to farmers, incorporating goat farming into women's empowerment programs, and provision of access to tailor-made livestock microfinance loans.


[Fusaria and their mycotoxins in hay and grass silage from grassland with different intensities of management].
Conservation forage (17 hay and 18 grass silage samples) from 15 farms with different intensities of grassland management in the Federal State of Brandenburg were examined for contamination with fusaria and their mycotoxins. The numbers of culturable filamentous fungi in hay were determined by plate counting andFusarium isolates were classified taxonomically. The mycotoxins Zearalenone (ZEA) and Deoxynivalenol (DON) were extracted from hay as well as silage by different procedures and detected chromatographically (HPLC). The numbers of filamentous fungi in the hay samples were 10(2) and 10(6) CFU/g FM independently of intensive or extensive management. Only fourFusarium species were identified.Fusarium culmorum, a potential toxin producing species, was most frequently detected (52% of all isolates). ZEA was found in two hay and four silage samples (6-66 μg/kg), DON in three hay and seven silage samples (63-1290 μg/kg). There were no differences between forage samples of extensive and intensive cultivated grassland of the year 2003 regarding numbers of fusaria and the content of their mycotoxins.


Clinical utility of exercise, pacing, and pharmacologic stress testing for the noninvasive determination of myocardial contractility and reserve.
The ability of the left ventricle to modulate its performance is an important and integral component in the cardiovascular system's adaptive response to increased workload. Abnormalities in ventricular contractility can blunt this response and thus significantly limit the patient's functional capacity. The accurate determination and quantitation of cardiac contractility and reserve is a difficult task in the symmetrically contracting ventricle and more so when regional contraction abnormalities are present. Moreover, derangements in other physiologic variables, such as ventricular loading conditions, heart rate, systemic vascular tone, cardiac autonomic function, and pulmonary gas exchange, can diminish cardiopulmonary reserve. This report relates the determinants of myocardial oxygen demand and efficiency to the currently available forms of exercise, pacing, and pharmacologic stress testing. Within this framework, commonly used as well as newer approaches to the noninvasive assessment of stress-induced changes in left ventricular performance and contractility are addressed. In addition, several examples are presented in which noninvasive techniques for assessing intracardiac structures, pressures, and flows (eg, echo/Doppler, radionuclide angiography, rapid acquisition computed tomography, and magnetic resonance imaging) are combined with various cardiovascular stress tests to achieve more reliable measures of myocardial contractility and reserve.


Ultrasonographic diagnosis of massive periretinal proliferation in eyes with opaque media (triangular retinal detachment).
A triangular pattern of retinal detachment, as seen by B-scan ultrasonography in eyes with opaque media has been correlated with advanced massive periretinal proliferation (MPP). The ultrasonographic triangular configuration was created by a proliferative membrane that united detached retina anteriorly. Thirteen eyes with opaque media and a triangular retinal detachment by ultrasound had severe MPP at vitrectomy or enucleation. Twelve eyes with clear media with advanced MPP were also studies by B-scan ultrasonography and a triangular detachment could be demonstrated in each case. The finding of a triangular retinal detachment by B-scan ultrasonography in eyes with opaque media is diagnostic of advanced MPP. Eyes with this type of retinal detachment have a poor surgical prognosis even with modern vitrectomy techniques.


Transverse location of new fluorene based depth dependent fluorescent probes in membranes--quenching studies with 9,10-dibromostearic acid.
Fluorescence quenching technique has been used to determine the transverse location of the fluorescent fluorenyl fatty acids in single bilayer vesicles prepared from phosphatidylcholine. The fluorenyl fatty acids used here are 2-fluorenyl acetic, butyric, hexanoic and octanoic acid. In addition a new type of fluorescent probe, 7-n-butyl-fluorene-2-butyric acid, wherein a hydrophobic tail is attached to 2-fluorenyl-butyric acid has also been used to study its effect on alignment of these probes in the membrane. The association properties of the quencher 9,10-dibromostearic acid have been analysed. It is observed that the quencher association involves partitioning into the vesicles and does not involve any binding to the vesicles. The absolute partition coefficient of the 9,10-dibromostearic acid which partitions between the aqueous and the lipid phases of the phospholipid dispersion has been evaluated. Using this information the corrected Stern-Volmer plots were drawn and the bimolecular quenching constant evaluated.


[Gastric polyps: endoscopic and surgical treatment].
A personal series of gastric polyps is reported. The therapeutic approach is described together with the results obtained. Comparison are made with literature.


Giant inguinoscrotal hernia containing intestinal segments and urinary bladder successfully repaired by simple hernioplasty technique: a case report.
Giant inguinoscrotal hernias are extremely rare nowadays, but they may still be encountered after years or even decades of neglect. Such hernias containing both bowel loops and urinary bladder have not been reported in the medical literature to date, to the best of our knowledge. We report a case of a 65-year-old Moroccan man who presented with giant right-sided and long-standing inguinoscrotal hernia with compromised quality of life due to walking difficulties and sexual discomfort. Computed tomography revealed a voluminous hernia sac containing small and large bowel loops, greater omentum, and urinary bladder. Surgical repair was done through the classical inguinal incision using the Lichtenstein tension-free hernioplasty technique. No debulking or abdominal enlargement procedure had to be performed, apart from a partial omentectomy. Giant inguinoscrotal hernia containing intestinal segments and urinary bladder is a challenging surgical disease. A Lichtenstein tension-free technique seems to be the best surgical procedure for both the patient and the operating surgeon. It should be used whenever possible in such cases.


Hepatitis B surface antigen and antibody positivity among women of childbearing age after three decades of universal vaccination in South Korea.
We estimated the impact of universal hepatitis B immunization using 18-year data of women who are of childbearing age in South Korea. We used hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) data of 145,993 women aged 20-49 years during 2001-2018 at the Gangnam CHA Medical Center. Annual prevalences of HBsAg and anti-HBs positivity were calculated and tested for linear trend. We conducted age-period-cohort (APC) analysis to obtain period and cohort effect. Overall proportion of HBsAg positivity was 3.5% (n = 5050) and anti-HBs positivity was 75.3% (n = 109,907) during the study period. HBsAg positivity percentage decreased from 5.1% in 2001 to 2.5% in 2018 (P < 0.001) while anti-HBs positivity increased from 59.9% to 75.8% (P = 0.002). Average annual percent change of HBsAg positivity was -5.9% (95% confidence interval (CI): -6.9%, -4.8%). The period and cohort RR curve identified a consistent decrease in HBsAg positivity over time and across generations. We observed a concurrent decrease in HBsAg and an increase in anti-HBs seropositivity among Korean women of childbearing age, implicating success in preventing vertical transmission.


Expression of thymidylate synthase and thymidine phosphorylase in recurrence and survival rates of advanced gastric cancer.
BACKGROUND: The immunohistochemical expression of thymidylate synthase (TS) and thymidine phosphorylase (TP) was examined in a comparative study of the recurrence rates and prognoses of patients with advanced gastric cancer at the same stage.METHODS: We examined the resected specimens of 67 patients with stage IIIB gastric cancer (pT3, pN2, M0) under 70 years of age who had undergone curative gastrectomy followed by adjuvant chemotherapy with 5-fluoropyrimidines. Paraffin sections of the resected specimens were stained with human anti-TS polyclonal and anti-TP monoclonal antibodies by the avidin-biotin-peroxidase complex (ABC) method.RESULTS: The overall expression of TS and TP was 45.4% and 43.4%, respectively. The postoperative survival curve for the TS-positive group was significantly depressed compared with that for the TS-negative group ( P = 0.0480). The survival curves for TP-positive and TP-negative groups did not show any difference. In regard to the combination of TS and TP expression, the best survival curve was obtained for the TS(-)/TP(+) group, followed by those for the TS(-)/TP(-), TS(+)/TP(-), and TS(+)/TP(+) groups in descending order. With regard to the recurrence site, there was no significant difference in peritoneal recurrence in relation to positivity for TS or TP. Lymph node recurrence, however, was significantly higher in the TS-positive and TP-positive groups, with P-values being 0.0466 and 0.0058, respectively, versus the corresponding negative groups. The incidence of hepatic recurrence was higher in the TP-positive group than in the TP-negative group ( P = 0.0910). As for the total doses of 5-fluoropyrimidines given, more favorable survival curves were obtained for the high dose of negative TS and TP groups, but no significant differences were observed in their positivities.CONCLUSION: The expressions of TS and TP showed different characteristics in overall survival and recurrence rate or site. They should be used for predicting prognosis in comprehension on their properties.


Attachment theory: a framework for understanding symptoms and interpersonal relationships in psychosis.
We investigated associations between adult attachment, symptoms and interpersonal functioning, including therapeutic relationships in 96 patients with psychosis. Using a prospective design, we also assessed changes in attachment in both psychiatrically unstable and stable groups. We measured attachment using the Psychosis Attachment Measure (PAM) and interpersonal problems and therapeutic relationships were assessed from both psychiatric staff and patient perspectives. Avoidant attachment was associated with positive symptoms, negative symptoms and paranoia. Attachment ratings were relatively stable over time, although changes in attachment anxiety were positively correlated with changes in symptoms. Predicted associations between high levels of attachment anxiety and avoidance and interpersonal problems were supported, and attachment avoidance was associated with difficulties in therapeutic relationships. Findings suggest that adult attachment style is a meaningful individual difference variable in people with psychosis and may be an important predictor of symptoms, interpersonal problems and difficulties in therapeutic relationships over and above severity of illness.


MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest.
Mitogen-activated protein (MAP) kinase pathways are three-kinase modules that mediate diverse cellular processes and have been highly conserved among eukaryotes. By using a functional complementation screen in yeast, we have identified a human MAP kinase kinase kinase (MAPKKK) that shares homology with members of the mixed lineage kinase (MLK) family and therefore was called MRK (MLK-related kinase). We report the structure of the MRK gene, from which are generated two splice forms of MRK, MRK-alpha and MRK-beta, encoding for proteins of 800 and 456 amino acids, respectively. By using a combination of solid phase protein kinase assays, transient transfections in cells, and analysis of endogenous proteins in stably transfected Madin-Darby canine kidney cells, we found that MRK-beta preferentially activates ERK6/p38gamma via MKK3/MKK6 and JNK through MKK4/MKK7. We also show that expression of wild type MRK increases the cell population in the G(2)/M phase of the cell cycle, whereas dominant negative MRK attenuates the G(2) arrest caused by gamma-radiation. In addition, exposure of cells to gamma-radiation induces MRK activity. These data suggest that MRK may mediate gamma-radiation signaling leading to cell cycle arrest and that MRK activity is necessary for the cell cycle checkpoint regulation in cells.


A case of pheochromocytoma in pregnancy: A syndromic association.
Pheochromocytoma in association with pregnancy is a very rare, without specific symptoms. Concurrent pheochromocytoma in pregnant women can lead to severe complications and death due to associated catecholamine excess. A 37-year-old pregnant woman, without medical or surgical history, gravida 1 para 0, was diagnosed with pheochromocytoma through biochemical and imaging tests at 20 weeks of gestation. Perioperative management included a multidisciplinary approach, symptom stabilization with medical treatment. An open right adrenalectomy was than performed at 23 weeks of gestation. Pheochromocytoma is a rare but important cause of hypertension in pregnancy. It should be included and investigated as a differential diagnosis in cases of labile hypertension in pregnant women with or without associated symptoms. A correct diagnosis in all pregnant women with severe hypertension and a multidisciplinary management are mandatory to obtain optimal results and avoid deleterious effects at delivery.


Reproducibility of peak oxygen consumption and the impact of test variability on classification of individual training responses in young recreationally active adults.
This study investigated whether VO2 peak is reproducible across repeated tests before (PRE) and after (POST) training, and whether variability across tests impacts how individual responses are classified following 3 weeks of aerobic exercise training (cycle ergometry). Data from 45 young healthy adults (age: 20·1 ± 0·9 years; VO2 peak, 42·0 ± 6·7 ml·min-1 ) from two previously published studies were utilized in the current analysis. Non-responders were classified as individuals who failed to demonstrate an increase or decrease in VO2 peak that was greater than 2·0 times the typical error of measurement (107 ml·min-1 ) away from zero, while responders and adverse responders were above and below this cut-off, respectively. VO2 peak tests at PRE (three total) and POST (three total) were highly reproducible (PRE and POST average and single measures ICCs: range 0·938-0·992), with low coefficients of variation (PRE:4·9 ± 3·1%, POST: 4·8 ± 2·7%). However, a potential learning effect was observed in the VO2 peak tests prior to training, as the initial pretraining test was significantly lower than the third (p = 0·010, PRE 1: 2 946 ± 924 ml·min-1 , PRE 3: 3 042 ± 919 ml·min-1 ). This resulted in fewer individuals classified as adverse responders for Test 3 compared to any combination of tests that included Test 1, suggesting that a single ramp test at baseline may not be sufficient to accurately classify the VO2 peak response in young recreationally active individuals. Thus, it is our recommendation that the initial VO2 peak test be used as a familiarization visit and not included for analysis.


Performance of two commercial blood IFN-gamma release assays for the detection of Mycobacterium tuberculosis infection in patient candidates for anti-TNF-alpha treatment.
The reactivation of latent tuberculosis (TB) is a major complication of tumor necrosis factor (TNF)-alpha inhibitors. Screening for TB infection is recommended before anti-TNF therapy is initiated; however, the use of tuberculin skin testing (TST) is controversial, due to the high rate of false-negative results in patients receiving immunosuppressive treatment. To compare the performance of two commercial interferon (IFN)-gamma release assays (IGRA), T-SPOT.TB (TS-TB) and QuantiFERON-TB Gold "In-tube" (QFT-GIT), with TST for the detection of TB infection in patients due to start anti-TNF therapy, 69 human immunodeficiency virus (HIV)-negative Italian patients (mean age: 45.2 +/- 12.6 years; male=39) were enrolled between September 2005 to August 2006. Patients affected by rheumatoid arthritis (n = 18), psoriatic arthritis (n = 26), ulcerous rectocolitis (n = 6), and Crohn's disease (n = 19) were tested simultaneously with TST, TS-TB, and QFT-GIT. Overall, 26% of patients were positive by TST, 30.4% by TS-TB, and 31.8% by QFT-GIT. Agreement with TST was similar (kappa = 0.21, p = 0.0002 and kappa = 0.26, p < 0.001, respectively). In 11 TST-negative cases, IFN-gamma release assays were positive. In addition, in seven Mantoux-positive cases with no TB risk factors, TST result agreement was achieved with at least one blood test. Indeterminate results were detected in 5.8% and 2.8% of cases, respectively, with TS-TB and with QFT-GIT (p = not significant [ns]). In conclusion, our results suggest that IGRAs may be helpful for screening purposes in patient candidates for anti-TNF therapy to confirm positive TST results and in selected cases when false-negative results are suspected. The utility of blood tests in patients with low or no TB risk remains to be assessed.


Electroneurography during facial nerve expansion.
With the use of tissue-expansion techniques, it is possible to elongate the facial nerve without impairing its function. The rate of expansion is limited by ischemic events imposed by stretching of the nerve and by anatomic characteristics of the nerve segment. In this study, we used various electroneurography techniques to determine the first sign of facial dysfunction during expansion. The main objective of the study was to ascertain test-retest variability of electroneurography techniques. Facial nerves were expanded in 16 cats with the use of a tissue expander secured more deeply to the main trunk. We conducted electroneurography measurements with the use of surface electrodes, temporary needle electrodes, and permanently implanted electrodes. Technique-dependent variations encountered with the surface electrodes made this method unreliable. Using implanted electrodes, we noted gradual worsening of the compound-action potential amplitude with increasing expansion. During acute expansion, reduction in compound-action potential amplitude was correlated with clinically observed deterioration of facial-nerve function. In this study, electroneurography with implanted electrodes was found to be the most reliable predictor of the rate of successful facial nerve expansion.


ASSOCIATION OF ORAL MONTELUKAST WITH REDUCED ODDS OF DEVELOPING EXUDATIVE AGE-RELATED MACULAR DEGENERATION.
This study was conducted to evaluate the association of oral montelukast, selective antagonism for cysteinyl leukotriene receptor 1, with reduced odds of exudative age-related macular degeneration (exAMD) development. This case-control study was conducted using institutional cohort finder tool, and included 1913 patients with exAMD (ICD: H35.32 and 362.52) and 1913 age- and gender-matched control subjects without exAMD. Subanalysis among 1913 exAMD and 324 nonexudative AMD was also conducted. A total of 47 (2.5%) exAMD cases were identified to have a history of oral montelukast use before exAMD diagnosis, compared with 84 (4.4%) controls. Montelukast usage was significantly associated with reduced odds of exAMD in the multivariable analysis (adjusted odds ratio [OR]: 0.50, 95% confidence interval: 0.31-0.80) and nonsteroidal anti-inflammatory drug usage (adjusted OR: 0.69). Caucasian race, history of smoking, and nonexudative macular degeneration in either eye were also found to have a significant relationship with increased odds of exAMD. In the subanalysis, montelukast usage showed significant association with reduced odds of developing exAMD from nonexudative AMD (adjusted OR: 0.53, 95% confidence interval: 0.29-0.97) and the presence of atopic disease (adjusted OR: 0.60). The study results suggested that oral montelukast is linked to reduced odds of exAMD development.


Anomalous perception in synaesthesia: a cognitive neuroscience perspective.
An enduring question in cognitive neuroscience is how the physical properties of the world are represented in the brain to yield conscious perception. In most people, a particular physical stimulus gives rise to a unitary, unimodal perceptual experience. So, light energy leads to the sensation of seeing, whereas sound waves produce the experience of hearing. However, for individuals with the rare phenomenon of synaesthesia, specific physical stimuli consistently induce more than one perceptual experience. For example, hearing particular sounds might induce vivid experiences of colour, taste or odour, as might the sight of visual symbols, such as letters or digits. Here we review the latest findings on synaesthesia, and consider its possible genetic, neural and cognitive bases. We also propose a neurocognitive framework for understanding such anomalous perceptual experiences.


Severe fever with thrombocytopenia syndrome (SFTS) treated with a novel antiviral medication, favipiravir (T-705).
Severe fever and thrombocytopenia syndrome (SFTS) is an acute illness with a high mortality (16.2-29.1%). Unfortunately, there is no specific cure or vaccine for SFTS. In this open-label study, two patients with SFTS were treated with favipiravir, a new antiviral drug. Patients had a sustainable virologic, immunologic and symptomatic recovery. Favipiravir may be a prosiming drug for the treatment of SFTS.


In silico design, synthesis and evaluation of a less toxic octinoxate alternative with suitable photoprotection properties.
Excessive UV exposure leads to several skin pathologies such as sunburns, photoaging and carcinogenesis. Currently, sunscreen use is the most important factor in protecting skin from photoinduced damage. Octinoxate is a commonly used UV filter, but its use has become controversial because it acts as an endocrine disruptor in both humans, and marine animals. Research has relied on biotechnology, structure activity relationship (SAR) studies and combinatorial chemistry to find new and less toxic UV filters. However, there are no current examples that describe the possible applications of in silico techniques for obtaining these compounds. Thus, this project sought to design an octinoxate analog that could be used as a less toxic, but equally effective, photoprotective alternative through ligand based virtual screening (LBVS). We designed 213 novel molecules based on the (E)-cinnamoyl moiety of octinoxate, but only 23 were found to be less toxic than the parent compound. Then, an artificial neural network (ANN) based model was built to predict the molar absorptivity of those 23 molecules, and the molecule that presented a similar molar absorptivity to that of octinoxate was chosen for synthesis (analog 4, 3-phenylpropyl (E)-3-(4-methoxyphenyl)acrylate). Synthesis for analog 4 resulted in a 90% yield, and its photoprotective properties, lipophilicity and cytotoxicity were then evaluated. Analog 4 absorbed UV radiation in the range of 250-340 nm, and it presented a molar absorptivity of 36,155 M - 1cm-1. Its lipophilicity was evaluated with RP-HPLC resulting in a logkw of 2.49 and its LC50 was greater than octinoxate's (67.41 nM vs. 45.67 nM). Therefore, results showed that ligand based virtual screening is an effective strategy for the development of new organic UV filters, because it guided the design of less toxic analogs and pinpointed the most likely analog to exhibit UV properties similar to those of octinoxate. In this case, analog 4 is a promising alternative to its parent compound since it proved to be more effective and less toxic.


Regulation of Inflammation by IRAK-M Pathway Can Be Associated with nAchRalpha7 Activation and COVID-19.
In spite of the vaccine development and its importance, the SARS-CoV-2 pandemic is still impacting the world. It is known that the COVID-19 severity is related to the cytokine storm phenomenon, being inflammation a common disease feature. The nicotinic cholinergic system has been widely associated with COVID-19 since it plays a protective role in inflammation via nicotinic receptor alpha 7 (nAchRalpha7). In addition, SARS-CoV-2 spike protein (Spro) subunits can interact with nAchRalpha7. Moreover, Spro causes toll-like receptor (TLR) activation, leading to pro- and anti-inflammatory pathways. The increase and maturation of the IL-1 receptor-associated kinase (IRAK) family are mediated by activation of membrane receptors, such as TLRs. IRAK-M, a member of this family, is responsible for negatively regulating the activity of other active IRAKs. In addition, IRAK-M can regulate microglia phenotype by specific protein expression. Furthermore, there exists an antagonist influence of SARS-CoV-2 Spro and the cholinergic system action on the IRAK-M pathway and microglia phenotype. We discuss the overexpression and suppression of IRAK-M in inflammatory cell response to inflammation in SARS-CoV-2 infection when the cholinergic system is constantly activated via nAchRalpha7.


Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): clinicopathologic study in 20 adults.
Renal biopsies obtained from 20 adult patients within 30 days after onset of acute renal failure with microangiopathic hemolytic anemia ("the hemolytic-uremic syndrome") were studied. Lesions were graded independently by two observers without knowledge of the clinical history. All patients who did not have refractory hypertension were treated with heparin. Ten of the patients died, and four developed end-stage renal failure requiring chronic dialysis. Six patients, however, had a relatively good outcome: two recovered completely and four developed mild-to-moderate chronic renal failure not requiring dialysis. The six patients with a good outcome had significantly less severe arterial intimal thickening on biopsy compared with the remaining patients with a poor outcome. The patients with a good outcome and those with a poor outcome did not differ in the severity of glomerular lesions. The clinical features did not allow a prediction of late outcome. These results suggest that early renal biopsies may be helpful in predicting prognosis in the "hemolytic-uremic syndrome." This clinical syndrome may occur either in apparently healthy people, or may complicate the course of a chronic essential hypertension.


A protocol and guide for the in vivo rat hepatocyte DNA-repair assay.
The in vivo rat hepatocyte DNA-repair assay is a valuable tool in assessing the genotoxic activity of chemical agents. An advantage of the system is that it reflects the complex patterns of uptake, distribution, metabolism, detoxification and excretion that actually occur in the whole animal. This article provides a typical procedure and guidelines for conducting the rat in vivo hepatocyte DNA-repair assay.


The sanctity of the upper lid in lower eyelid reconstruction questioned. A modification of a lid sharing procedure with a long-term follow-up.
Sharing techniques using the upper eyelid to reconstruct the lower one have been criticised for causing distortion of the normal upper lid leading to corneal exposure and possible visual disturbance, and for creating second-rate lids. A modification of previously described tarsoconjunctival flap techniques is described which minimises the known complications of earlier methods. A flap of conjunctiva alone is mobilised from the upper eyelid and covered with a full thickness skin graft. A second minor procedure to divide the flap from its donor site is necessary 2 weeks later. Forty-three patients over a 25-year period have undergone total lower eyelid reconstruction with this modified technique and are reviewed with some illustrative cases. Total or subtotal lower eyelid reconstruction is most commonly performed following tumour resection and only occasionally to correct congenital or traumatic defects. The surgical techniques available still cause controversy (Byrd, 1983). An upper lid sharing technique has been criticised for possibly causing a shortened or distorted normal lid (Mustardé, 1981). A modification of this method is described which has been used for over 25 years and has reduced the morbidity of the procedure, leading to acceptable cosmetic and functional long-term results.


An Understated Comorbidity: The Impact of Homelessness on Traumatic Brain Injury.
Traumatic brain injury (TBI), a neurovascular injury caused by external force, is a common diagnosis among veterans and those experiencing homelessness (HL). There is a significant overlap in the veteran and homeless population, possibly accounting for the two to seven times greater incidence of TBI among those experiencing HL than the general population. Despite these statistics, individuals experiencing HL are often underdiagnosed and ineffectively treated for TBI. We introduced a novel model of HL. Over 5 weeks, adult Sprague-Dawley rats were randomly assigned to one of the following conditions: TBI only, HL only, TBI + HL, or control (n = 9 per group). To emulate HL, animals (2 animals per cage) were exposed to soiled beddings for 5 weeks. Subsequently, animals were introduced to TBI by using the moderate controlled cortical impact model, then underwent 4 consecutive days of behavioral testing (beam walk (BW), elevated body swing test (EBST), forelimb akinesia (FA), paw grasp (PG), Rotorod, and elevated T-maze). Nissl staining was performed to determine the peri-impact cell survival and the integrity of corpus callosum area. Motor function was significantly impaired by TBI, regardless of housing (beam walk or BW 85.0%, forelimb akinesia or FA 104.7%, and paw grasp or PG 100% greater deficit compared to control). Deficits were worsened by HL in TBI rats (BW 93.3%, FA 40.5%, and PG 50% greater deficit). Two-way ANOVA revealed BW (F(4, 160) = 31.69, p < 0.0001), FA (F(4, 160) = 13.71, p < 0.0001), PG (F(4, 160) = 3.873, p = 0.005), Rotorod (F(4, 160), p = 1.116), and EBST (F(4, 160) = 6.929, p < 0.0001) showed significant differences between groups. The Rotorod and EBST tests showed TBI-induced functional deficits when analyzed by day, but these deficits were not exacerbated by HL. TBI only and TBI + HL rats exhibited typical cortical impact damage (F(3,95) = 51.75, p < 0.0001) and peri-impact cell loss compared to control group (F(3,238) = 47.34, p < 0.0001). Most notably, TBI + HL rats showed significant alterations in WM area measured via the corpus callosum (F(3, 95) = 3.764, p = 0.0133). Worsened behavioral outcomes displayed by TBI + HL rats compared to TBI alone suggest HL contributes to TBI functional deficits. While an intact white matter, such as the corpus callosum, may lessen the consequent functional deficits associated with TBI by enhancing hemispheric communications, there are likely alternative cellular and molecular pathways mitigating TBI-associated inflammatory or oxidative stress responses. Here, we showed that the environmental condition of the patient, i.e., HL, participates in white matter integrity and behavioral outcomes, suggesting its key role in the disease diagnosis to aptly treat TBI patients.


Imaging the coupling between itinerant electrons and localised moments in the centrosymmetric skyrmion magnet GdRu2Si2.
Magnetic skyrmions were thought to be stabilised only in inversion-symmetry breaking structures, but skyrmion lattices were recently discovered in inversion symmetric Gd-based compounds, spurring questions of the stabilisation mechanism. A natural consequence of a recent theoretical proposal, a coupling between itinerant electrons and localised magnetic moments, is that the skyrmions are amenable to detection using even non-magnetic probes such as spectroscopic-imaging scanning tunnelling microscopy (SI-STM). Here SI-STM observations of GdRu2Si2 reveal patterns in the local density of states that indeed vary with the underlying magnetic structures. These patterns are qualitatively reproduced by model calculations which assume exchange coupling between itinerant electrons and localised moments. These findings provide a clue to understand the skyrmion formation mechanism in GdRu2Si2.