Experimental manipulation of testosterone and condition during molt affects activity and vocalizations of male blue tits.
Testosterone (T) is a key hormone regulating behavioral trade-offs in male birds, shifting investment towards sexual and competitive behaviors. However, the role of T in regulating male behavior during the molt has received very little attention, although this is a crucial life-history stage. Since the effect of T on behavior may be condition-dependent, particularly during the costly molt period, we studied the effects of T and condition in a two-way design. We manipulated T under two dietary regimes (standard and improved, resulting in an enhanced condition) in captive blue tits (Cyanistes caeruleus) undergoing the first pre-basic molt. T treatment increased song frequency, indicating that song is T-dependent also at this time of year. Males on the improved diet sang less than males in relatively worse condition, providing no support for song as an indicator of male condition. T-treated males exhibited greater locomotor activity than control males, but only when fed the standard diet. Neither T- nor diet-treatment affected plumage maintenance (preening). Although T treatment resulted in a delay in molt progress all birds completed the molt. Taken together our results show that during the molt male birds are sensitive to relatively small fluctuations in T. Similar to its commonly observed effects during the breeding season, T stimulated an increase in song and locomotion. While there might be some benefits associated with such T effects, these must be traded-off against costs associated with conspicuous behavior and increased molt duration.


Analysis of Notch1 signaling in mammalian sperm development.
A mammalian Delta-Notch signaling component, Notch1, has been suggested for its expression during the normal sperm development although its conditional deletion caused no apparent abnormalities. Since we established our original transgenic mouse system that enabled labeling of past and ongoing Notch1 signaling at a cellular level, we tried to validate that observation in vivo. Our transgenic mouse system used Cre/loxP system to induce tandem dsRed expression upon Notch1 signaling. To our surprise, we were unable to observe tandem dsRed expression in the seminiferous tubules where the sperms developed. In addition, tandem dsRed expression was lacking in the somatic cells of the next generation in our transgenic mouse system, suggesting that sperms received no Notch1 signaling during their development. To validate this result, we conducted re-analysis of four single-cell RNA-seq datasets from mouse and human testes and showed that Notch1 expression was little in the sperm cell lineage. Collectively, our results posed a question into the involvement of Notch1 in the normal sperm development although this observation may help the interpretation of the previous result that Notch1 conditional deletion caused no apparent abnormalities in murine spermatogenesis.


Effects of heterochronic, non-myeloablative bone marrow transplantation on age-related behavioural changes in mice.
Experiments using heterochronic parabionts, i.e. young and old animals connected surgically and hence developing a shared circulation, have shown that blood-borne factors, transferred from young to old mice and vice versa, play a role in influencing a range of health outcomes associated with advanced age. Previous work has explored the contributory role of plasma-derived factors in mediating such parabiotic effects, including those on aging-associated neural and behavioural impairments. Here, we wanted to identify possible influences that blood-borne cellular factors may have on age-related behavioural phenotypes. Towards this end, we subjected old BALB/c H-2d mice to repetitive non-myeloablative bone marrow transplants (BMT) from young donor animals and assessed effects on behaviour and cognition. We detected expected age-related alterations in our behavioural assays but did not discern any obvious differences between old BMT mice and old control animals. Our study represents the first to look at possible behavioural and cognitive effects of heterochronic, non-myeloablative BMT. Future work should extend this study by including additional behavioural tests in the analysis, addressing whether beneficial effects of BMT may be detectable on other genetic backgrounds and reconciling our findings with those achieved by myeloablative BMT.


Reliability of classification for post-traumatic ankle osteoarthritis.
The purpose of this study was to identify the most reliable classification system for clinical outcome studies to categorize post-traumatic-fracture-osteoarthritis. A total of 118 orthopaedic surgeons and residents-gathered in the Ankle Platform Study Collaborative Science of Variation Group-evaluated 128 anteroposterior and lateral radiographs of patients after a bi- or trimalleolar ankle fracture on a Web-based platform in order to rate post-traumatic osteoarthritis according to the classification systems coined by (1) van Dijk, (2) Kellgren, and (3) Takakura. Reliability was evaluated with the use of the Siegel and Castellan's multirater kappa measure. Differences between classification systems were compared using the two-sample Z-test. Interobserver agreement of surgeons who participated in the survey was fair for the van Dijk osteoarthritis scale (k = 0.24), and poor for the Takakura (k = 0.19) and the Kellgren systems (k = 0.18) according to the categorical rating of Landis and Koch. This difference in one categorical rating was found to be significant (p < 0.001, CI 0.046-0.053) with the high numbers of observers and cases available. This study documents fair interobserver agreement for the van Dijk osteoarthritis scale, and poor interobserver agreement for the Takakura and Kellgren osteoarthritis classification systems. Because of the low interobserver agreement for the van Dijk, Kellgren, and Takakura classification systems, those systems cannot be used for clinical decision-making. Development of diagnostic criteria on basis of consecutive patients, Level II.


Liquid chromatographic analysis of sebum lipids and other lipids of medical interest.
A technique is described for the high-pressure liquid chromatographic (HPLC) analysis of sebum lipid classes. The lipid present in sebum are separated by gradient elution HPLC from a microparticulate silica column and detected using a moving-wire detector. The system described can be linked to a computer. Quantitation can be carried out by comparing peak areas obtained with those of an internal standard. Peak trapping for further investigations of the separated components, for example by gas chromatography-mass spectrometry, is very easy. Sebum lipids are separated into the following lipid classes: hydrocarbons and squalene, cholesterol esters and wax esters, fatty acids as their methyl esters, triglycerides, 1,3-diglycerides, 1,2-diglycerides, free cholesterol, monoglycerides and other polar materials. Besides to sebum, the method has been successfully applied to other lipid mixtures, such as serum lipids. Examples of other applications are shown.


Stressed out? Healing Tips for Newly Reprogrammed Neurons.
How do astrocyte-derived neurons deal with the sudden loss of their glial identity? Exciting new findings from Gascón et al. (2016) single out metabolic conversion as a critical checkpoint for direct neuronal reprogramming.


Computational fluid dynamics analysis of upper airway reconstructed from magnetic resonance imaging data.
We performed flow computations on an accurate upper airway model in a patient with obstructive sleep apnea and computed the velocity, static pressure, and wall shear stress distribution in the model. Cartesian coordinates for airway boundaries were determined from cross-sectional magnetic resonance images, and a 3-dimensional computational model of the upper airway was constructed. Flow simulations were then performed within a FLUENT commercial software framework. Four different flow conditions were simulated during inspiration, assuming the steady-state condition. The results were analyzed from the perspectives of velocity, static pressure, and wall shear stress distribution. We observed that the highest axial velocity was at the site of minimum cross-sectional area (retropalatal pharynx) resulting in the lowest level of wall static pressure. The highest wall shear stresses were at the same location. The pressure drop was significantly larger for higher flow rates than for lower flow rates. Our results indicate that the presence of airway narrowing, through change in the flow characteristics that result in increased flow velocity and reduced static pressure, can itself increase airway collapsibility. Additionally, the effects of wall shear stress on airway walls may be an important factor in the progression over time of the severity of obstructive sleep apnea.


Paramacular temporal atrophy in sickle cell disease occurs early in childhood.
Initially reported in a few patients with homozygous sickle cell disease (SCD), atrophic areas of the retina temporal from the macula are now known to be present in about 48% of eyes of adult patients with SS-SCD and in 35% of eyes of adult patients with SC-SCD. The aim of this study is to describe this paramacular atrophy in children affected with SCD. In this retrospective series, spectral-domain optical coherence tomography images of 81 children with SCD, acquired with specific patterns including one evaluating the retina temporal to the macula, were reviewed, in order to look for retinal atrophy. Fundus examination status for SCD peripheral retinopathy was also reviewed. Mean age was 12.0 years (SD: 3.56). The genotype distribution was: 64 HbSS (79%), 10 HbSC (12%) and 7 HbS/β0 thalassaemia (9%). Using a usual fovea-centred programme, retinal atrophy was found in 38% of eyes (52% of children). Using a specific temporal pattern, retinal atrophy was found in 53% of eyes (64% of children), with no significant difference in the prevalence between HbSS and HbSC genotype (p=0.92), and no effect of age (mean 12.3 years (SD=3.61) vs11.9 (3.56), p=0.65). Peripheral retinopathy was found in 11% of children, with a significant relation between the HbSC genotype and the severity of the retinopathy (p=0.003). Paramacular temporal atrophy occurs early in the course of SCD, which suggests distinct mechanisms from those of peripheral retinopathy.


Why does mutation of Gln61 in Ras by the nitro analog NGln maintain activity of Ras-GAP in hydrolysis of guanosine triphosphate?
Interpretation of the experiments showing that the Ras-GAP protein complex maintains activity in guanosine triphosphate (GTP) hydrolysis upon replacement of Glu61 in Ras with its unnatural nitro analog, NGln, is an important issue for understanding details of chemical transformations at the enzyme active site. By using molecular modeling we demonstrate that both glutamine and its nitro analog in the aci-nitro form participate in the reaction of GTP hydrolysis at the stages of proton transfer and formation of inorganic phosphate. The computed structures and the energy profiles for the complete pathway from the enzyme-substrate to enzyme-product complexes for the wild-type and mutated Ras suggest that the reaction mechanism is not affected by this mutation.


Partial quantum information.
Information--be it classical or quantum--is measured by the amount of communication needed to convey it. In the classical case, if the receiver has some prior information about the messages being conveyed, less communication is needed. Here we explore the concept of prior quantum information: given an unknown quantum state distributed over two systems, we determine how much quantum communication is needed to transfer the full state to one system. This communication measures the partial information one system needs, conditioned on its prior information. We find that it is given by the conditional entropy--a quantity that was known previously, but lacked an operational meaning. In the classical case, partial information must always be positive, but we find that in the quantum world this physical quantity can be negative. If the partial information is positive, its sender needs to communicate this number of quantum bits to the receiver; if it is negative, then sender and receiver instead gain the corresponding potential for future quantum communication. We introduce a protocol that we term 'quantum state merging' which optimally transfers partial information. We show how it enables a systematic understanding of quantum network theory, and discuss several important applications including distributed compression, noiseless coding with side information, multiple access channels and assisted entanglement distillation.


Validity and reliability of the on-road driving assessment with senior drivers.
The on-road driving assessment is widely regarded as the criterion measure for driving performance despite a paucity of evidence concerning its psychometric properties. The purpose of this study was 2-fold. First, we examined the psychometric properties of an on-road driving assessment with 100 senior drivers between 60 and 86 years (80 healthy volunteers and 20 with specific vision deficits) using Rasch modeling. Second, we compared the outcome of the gestalt decision made by trained professionals with that based on weighted error scores from the standardized assessment. Rasch analysis provided good evidence for construct validity and inter-rater reliability of the on-road assessment and some evidence for internal reliability. Goodness of fit statistics for all items were within an acceptable range and the item hierarchy was logical. The test had a moderate reliability index (0.67). The best cut off score yielded sensitivity of 81% and specificity of 95% compared with the gestalt decision. Further research is required with less competent drivers to more fully examine reliability. Healthy senior drivers failed to check blind spots when changing lanes and made errors when asked to report road markings and traffic signs as they drove. In addition unsafe drivers had difficulty negotiating intersections and lane changes.


Effects of amino acids on the formation of hematite particles in a forced hydrolysis reaction.
The influence of amino acids on the formation of hematite particles from a forced hydrolysis reaction of acidic FeCl3 solution was examined. The spherical particles were produced on the systems with L-phenylalanine (L-Phe), L-serine (L-Ser) and L-alanine (L-Ala), though L-glutamine (L-Gln) and L-glutamic acid (L-Glu) gave ellipsoidal hematite particles. This morphological change in hematite particles is consistent with the order of stability constant of amino acids against to Fe3+ ions (K). The hematite particles produced with L-Glu, L-Gln and L-Ser were highly porous because they are formed by aggregation of cluster particles. These particles exhibited microporous behavior by outgassing the particles below 200 degrees C while they changed to mesoporous after treating above 300 degrees C by elimination of amino acids molecules remained between the cluster particles within the hematite particles. The hematite particles strongly depended on the nature of amino acids such as alternation of solution pH and adsorption affinity to beta-FeOOH and/or polynuclear primary (PN) particles. The systems on L-Ala and L-Phe, showing very rapid phase transformation from beta-FeOOH to hematite, exhibited the Ostwald ripening. A rotational particle preparation procedure suggested that the morphology of hematite particle is governed by the mode and strength of amino acid adsorption onto beta-FeOOH and/or PN particles.


Application of concentrated growth factor to autotransplantation with inflammation in recipient area.
The purpose of this study was to apply concentrated growth factor (CGF) to the transplanted area with inflammation, to observe the clinical effects of CGF on the inflammation area assisted by 3D printing technology. A total of 52 compromised mandibular first or second molar with chronic periapical lesions were transplanted with mature third molars. The patients were divided into CGF group (n = 26) and control group (n = 26) and transplanted into fresh extraction sockets with or without CGF. All the patients underwent clinical and radiographic examinations during the follow-up. Average surgery and extra-oral time were 39 min (± 7.8) and 42 s (± 10.2). The success rates of CGF group and control group were 100% and 92.3% respectively. Most of the periapical lesions in CGF group healed completely within 3 months, which was significantly faster than control group. The initial stability of CGF group was better than control group immediately after operation, and the degree of pain in CGF group was lower than control group on the 1st and 3rd day after operation. The application of CGF in recipient site with chronic periapical lesions can accelerate the regeneration of alveolar bone and the healing of inflammation, greatly shorten the healing period. Meanwhile, CGF help to reduce postoperative pain and reaction at the early stage of healing and increase the success rate of autogenous tooth transplantation (ATT). Additionally, the use of 3D printing model can greatly reduce the extra-oral time of donor teeth.


Development of a simple method for the determination of lead in lipstick using alkaline solubilization and graphite furnace atomic absorption spectrometry.
A simple method was developed for determining the total lead content in lipstick samples by graphite furnace atomic absorption spectrometry (GFAAS) after treatment with tetramethylammonium hydroxide (TMAH). Multivariate optimization was used to establish the optimal conditions of sample preparation. The graphite furnace heating program was optimized through pyrolysis and atomization curves. An aliquot containing approximately 50mg of the sample was mixed with TMAH and heated in a water bath at 60°C for 60 min. Using Nb as the permanent modifier and Pd as the chemical modifier, the optimal temperatures were 900°C and 1800°C for pyrolysis and atomization, respectively. Under optimum conditions, the working range was from 1.73 to 50.0 μg L(-1), with detection and quantification limits of 0.20 and 0.34 μg g(-1), respectively. The precision was evaluated under conditions of repeatability and intermediate precision and showed standard deviations of 2.37%-4.61% and 4.93%-9.75%, respectively. The % recovery ranged from 96.2% to 109%, and no significant differences were found between the results obtained using the proposed method and the microwave decomposition method for real samples. Lead was detected in 21 tested lipstick samples; the lead content in these samples ranged from 0.27 to 4.54 μg g(-1).


Pulsus paradoxus: definition and relation to the severity of cardiac tamponade.
Based on 101 control patients, the 95% confidence limit for the inspiratory decrease in arterial systolic pressure (delta SYST, mm Hg) and the percentage decrease in arterial systolic pressure (% delta SYST = delta SYST/expiratory systolic pressure) were determined to be 12 mm Hg and 9%, respectively. In 65 patients with pericardial effusion, the severity of cardiac tamponade was estimated on the basis of the percentage increase in cardiac output resulting from pericardiocentesis: absent = less than 20% (n = 24), mild = 20% to 49% (n = 9), and moderate or severe = greater than or equal to 50% (n = 32). The accuracy of a delta SYST greater than 12 mm Hg and % delta SYST greater than 9% in the identification of tamponade was 92% and 97%, respectively. A % delta SYST greater than 15% with relative hypotension (expiratory systolic pressure less than or equal to 120 mm Hg) or a delta SYST greater than 25 mm Hg or inspiratory pulse obliteration was found in 31 of 32 patients with moderate or severe tamponade compared to 2 of the 33 remaining patients. We conclude that the inspiratory decline in arterial systolic pressure can be used to accurately estimate the level of hemodynamic embarrassment resulting from pericardial effusion.


Subnuclear organization of the dorsal motor nucleus of the vagus nerve in the pigeon, Columbia livia.
The present study is the first of two papers describing the cytoarchitectural and functional organization of the dorsal motor nucleus of the vagus nerve (DMN complex) in the pigeon. This paper describes the distribution of vagal motoneurons within the pigeon brainstem, and the cytoarchitectural organization of the DMN complex. Our description is based on studies of Nissl-stained tissue from normal animals and on experimental studies using retrograde tracing techniques. Cells within the DMN complex were classified according to size, morphology, location, and staining characteristics. These studies demonstrate that vagal motoneurons are localized to (1) the DMN complex, (2) the region of the nucleus ambiguus, and (3) the region of the reticular formation extending between the dorsal motor nucleus and the nucleus ambiguus. Our cytoarchitectural indicate that the DMN complex is composed of at least 11 cytoarchitecturally distinct subnuclei. These subnuclei are evident in normal tissue and are especially prominent in cases where HRP backfilling produces a Golgi-like staining of the motoneurons. The subnuclei can be distinguished by their positions within the DMN complex and by the size, shape, and staining characteristics of their constituent neurons. Comparison of these data with studies in other species indicates similar patterns of cytoarchitectural organization in the DMN complex of some mammals. The diversity of nuclear subgroups within the DMN complex may be related to the heterogeneity of target organs innervated by these cells.


Acute illnesses associated with exposure to fipronil--surveillance data from 11 states in the United States, 2001-2007.
Fipronil is a broad-spectrum phenylpyrazole insecticide widely used to control residential pests and is also commonly used for flea and tick treatment on pets. It is a relatively new insecticide and few human toxicity data exist on fipronil. This paper describes the magnitude and characteristics of acute illnesses associated with fipronil exposure. Illness cases associated with exposure to fipronil-containing products from 2001 to 2007 were identified from the Sentinel Event Notification System for Occupational Risks (SENSOR)-Pesticides Program and the California Department of Pesticide Regulation. A total of 103 cases were identified in 11 states. Annual case counts increased from 5 in 2001 to 30 in 2007. Of the cases, 55% were female, the median age was 37 years, and 11% were <15 years old. The majority (76%) had exposure in a private residence, 37% involved the use of pet-care products, and 26% had work-related exposures. Most cases (89%) had mild, temporary health effects. Neurological symptoms (50%) such as headache, dizziness, and paresthesia were the most common, followed by ocular (44%), gastrointestinal (28%), respiratory (27%), and dermal (21%) symptoms/signs. Exposures usually occurred from inadvertent spray/splash/spill of products or inadequate ventilation of the treated area before re-entry. Our findings indicate that exposure to fipronil can pose a risk for mild, temporary health effects in various body systems. Precautionary actions should be reinforced to prevent fipronil exposure to product users.


[Study on the dynamic model with supercritical CO2 fluid extracting the lipophilic components in Panax notoginseng].
To establish a dynamics model for extracting the lipophilic components in Panax notoginseng with supercritical carbon dioxide (CO2). Based on the theory of counter-flow mass transfer and the molecular mass transfer between the material and the supercritical CO2 fluid under differential mass-conservation equation, a dynamics model was established and computed to compare forecasting result with the experiment process. A dynamics model has been established for supercritical CO2 to extract the lipophilic components in Panax notoginseng, the computed result of this model was consistent with the experiment process basically. The supercritical fluid extract dynamics model established in this research can expound the mechanism in the extract process of which lipophilic components of Panax notoginseng dissolve the mass transfer and is tallied with the actual extract process. This provides certain instruction for the supercritical CO2 fluid extract' s industrialization enlargement.


Mitochondrial DNA Haplogroup R Confers a Genetic Risk Factor for Intrauterine Adhesion in Han Women Population.
To determine whether a specific mitochondrial DNA (mtDNA) haplogroup is implicated in the pathogenesis of intrauterine adhesion (IUA). Peripheral blood samples were collected from 486 women with (case group, n = 154) and without IUA (control group, n = 332) at the Women's Hospital, Zhejiang University School of Medicine. Genomic DNA was extracted from the blood, and the mtDNA haplogroups of Han women M, N and R were determined by sequencing hypervariable mtDNA segments and testing diagnostic polymorphisms in the mtDNA coding region. Women with mtDNA haplogroup R had an independently increased genetic risk factor for IUA with an OR 1.77 (95% CI 1.16-2.70, p = 0.009) compared with women without. Moreover, repeated intrauterine surgery within 1 month and number of intrauterine operations were both significantly associated with IUA (p < 0.001). These results suggest that mtDNA haplogroup R, one of the main mtDNA haplogroups in Han population, is a strong independent genetic risk factor for women with IUA.


Synthesis and biological activity of some pyrrole derivatives. I.
The synthesis of some 5-substituted 2-amino-3-cyano (and 3-carboethoxy)pyrroles is described starting from the cyano- and carboethoxyacetomidines and the alpha-halogeno ketones. The compounds tested in vitro as antimicrobial agents did not show any significative activity.


Alternative splicing in neurodegenerative disease and the promise of RNA therapies.
Alternative splicing generates a myriad of RNA products and protein isoforms of different functions from a single gene. Dysregulated alternative splicing has emerged as a new mechanism broadly implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson disease and repeat expansion diseases. Understanding the mechanisms and functional outcomes of abnormal splicing in neurological disorders is vital in developing effective therapies to treat mis-splicing pathology. In this Review, we discuss emerging research and evidence of the roles of alternative splicing defects in major neurodegenerative diseases and summarize the latest advances in RNA-based therapeutic strategies to target these disorders.


Concentration and distribution of hyaluronic acid in mouse uterus throughout the estrous cycle.
To quantify and study the immunoexpression of hyaluronic acid (HA) in the uterine horns of the mouse throughout the estrous cycle phases. Experimental study using an ELISA-like fluorometric assay to quantify HA and an avidin-biotin immunoperoxidase method using biotinylated hyaluronan-binding protein for histochemical studies. University-based laboratory. Forty regularly cycling adult female mice were divided into four groups according to the diagnosed phase of the cycle: proestrus, estrus, metaestrus, and diestrus. None. Histologic samples of the uterine horns. Immunohistochemical reaction was evaluated by detection of HA and CD44 distribution within the uterine horn. Tissue HA content was determined through an ELISA-like fluorometric assay with the same hyaluronan-binding protein and with europium-labeled streptavidin. The immunohistochemical HA and CD44 reactions were most intense during diestrus, mainly below the luminal epithelium. HA was strongly stained in the connective tissue near the myometrium layer during metaestrus. The biochemical data showed that the highest concentration of HA in uterine horns occurred during diestrus (4053.0 +/- 651.4 ng/g dry tissue) compared with other phases. Our data show that the expression of HA in mouse uterine horns is highest during the diestrous phase. The fluctuations of HA in the mouse uterus during the estrous phase may be related to the varying estrogen and P levels during the cycle and may be important as far as embryo implantation is concerned.


Tctex-1 augments G protein-coupled receptor-mediated Gs signaling by activating adenylyl cyclase.
Proteins interacting with G protein-coupled receptors (GPCRs) can modulate signal transduction of these receptors. However, the regulatory mechanisms of the interacting proteins are diverse and largely unknown. We have previously shown that Tctex-1 (or DYNLT1) can interact with the parathyroid hormone receptor (PTHR). In the present study, we investigated the role of Tctex-1 in the PTHR signaling and found that Tctex-1 augmented the PTHR-mediated Gs/adenylyl cyclase (AC) pathway by activating AC regardless of the binding to PTHR. Furthermore, Tctex-1 directly bound to AC type 6. These data demonstrate a novel mechanism underlying GPCR/Gs signaling regulated by Tctex-1.


Closing wards during summer time and its effects on patients' outcomes.
Closure of wards (units) during the summer is a management practice introduced in some Italian hospitals to deal with the national nursing shortage and seasonal staffing patterns. The authors discuss a cross-sectional comparative study that they conducted to assess the effects of this management practice on patient outcomes.


Realization in biology?
It is widely assumed that functional and dispositional properties are not identical to their physical base, but that there is some kind of asymmetrical ontological dependence between them. In this regard, a popular idea is that the former are realized by the latter, which, under the non-identity assumption, is generally understood to be a non-causal, constitutive relation. In this paper we examine two of the most widely accepted approaches to realization, the so-called 'flat view' and the 'dimensioned view', and we analyze their explanatory relevance in the light of a number of examples from the life sciences, paying special attention to developmental phenomena. Our conclusion is that the emphasis placed by modern-day biology on such properties as variability, evolvability, and a whole collection of phenomena like modularity, robustness, and developmental constraint or developmental bias requires the adoption of a much more dynamic perspective than traditional realization frameworks are able to capture.


Antinuclear antibodies in follicular fluid may reduce efficacy of in vitro fertilization and embryo transfer by invading endometrium and granular cells.
The mechanism(s) by which antinuclear antibodies (ANA) induce implantation failure are not clear, and little information regarding the function of autoantibodies in reproductive tissues is available. A total of 380 patients who underwent in vitro fertilization and embryo transfer (IVF-ET) were divided into control, serum positive, and follicular fluid (FF) positive groups based on the results of indirect immunofluorescence assay for ANA in the serum and FF. Immunofluorescence assay was performed to evaluate the existence of ANA in granular cells and endometrial tissues. Presence in FF of soluble apoptotic markers, including Bcl-2, Caspase-3, cleaved PARP, Cytochrome C, GAPDH, and p53, was assessed using magnetic bead based assays. The patients in the FF positive group had the lowest numbers of retrieved oocytes, fertilizations, and high-quality embryos. The fertilization rate, and the proportion of two pronuclear (2PN) embryos in patients in the FF positive group were significantly lower than those in the other two groups. The FF positive group also had the lowest clinical pregnancy rate, and the highest early miscarriage rate. Granulosa cells and endometrial tissues in patients in the FF positive group were ANA positive. High levels of BCL-2, Caspase-3, Cytochrome C, GAPDH, and p53 were found in the FF of patients in the FF positive group. Antinuclear antibodies in FF and endometrial tissues may cause imbalanced apoptosis, resulting in poor IVF-ET treatment outcomes. Local autoimmunity and cell apoptosis in reproductive tissues could be considered new therapeutic targets for improving IVF-ET treatment efficacy.


Establishment of a pancreatic β cell proliferation model in vitro and a platform for diabetes drug screening.
Diabetes, a disease resulting from loss of functional β cells, is globally an increasingly important condition. Based on the islet-differentiation ability of ductal epithelial cells and stimulating β cell proliferation ability of the Reg Iα gene, we aimed to establish an in vitro pancreatic β cell proliferation model for screening therapeutic drugs of diabetes in the future. Pancreatic ductal epithelial cells were isolated from male Wistar rats, and induced to differentiate into pancreatic β cells. Immunofluorescence staining assay, western blot, RT-PCR analysis, and dithizone staining were used to characterize the cells. Rat Reg Iα protein was transiently expressed in vitro by transfection of HEK 293 cells with the PCMV6-entry-REG Ia plasmid, and expression was verified by RT-PCR analysis, proliferation assay, and apoptosis assay. The pancreatic β cell proliferation model was further validated by a proliferation assay using differentiated pancreatic β cells treated with transfection supernatant. Finally, we have successfully established an in vitro pancreatic β cells proliferation model using transiently expressed rat Reg Iα protein and differentiated pancreatic β cells from pancreatic ductal epithelial cells. This model could be used as a platform to screen new drugs for islet neogenesis to cure diabetes, especially Chinese herbal drugs in the future.


Suction thrombectomy of thrombotic occlusion of the subclavian artery in a case of Takayasu's arteritis.
Takayasu's arteritis, also known as pulseless disease, is a chronic inflammatory arteritis affecting large vessels, predominantly the aorta and its main branches. Vessel inflammation leads to wall thickening, fibrosis, stenosis, and thrombus formation. Percutaneous removal of arterial thrombus with the use of several devices has been reported, with mixed results. We present a case of Takayasu's arteritis with thrombotic occlusion of the subclavian artery in which pulsed urokinase injection and suction thrombectomy were used to revascularize a threatened limb and to establish the sole arterial supply to the brain.


Identification of luteolin -7-glucoside and epicatechin gallate from Vernoniacinerea, as novel EGFR L858R kinase inhibitors against lung cancer: Docking and simulation-based study.
Lung cancer ranks number one among the all cancer types in the world, out of which 85% are non-small cell lung cancer (NSCLC). In case of NSCLC, a substitution mutation of Leu 858 Arg (L858R) in the gene of Epidermal Growth Factor Receptor (EGFR) has been reported. Hence, targeting EGFR containing L858R mutation using inhibitors is well reported strategy to discover potential drugs against NSCLC. The present work aims to identify the potent inhibitors against EGFR L858R from Vernonia cinerea plant. A library of 45 phytochemicals was subjected to virtual screening using rigid and flexible docking. 12 potential phytochemicals were screened by molecular docking with high binding energy (between -8.0 and -9.7 kcal mol-1). Two compounds viz., luteolin -7-glucoside and epicatechin gallate showed interaction with Met793 of EGFR-L858R which was similar to the reference inhibitor PD168393. To analyze the stability of the luteolin -7-glucoside and epicatechin gallate with EGFR L858R, molecular dynamics simulations were conducted in explicit water conditions using 60 nanosecond. The results of hydrogen bonding patterns, radius of gyration, deviations in conformational elements, fluctuations in the residual components, and solvent accessible surface area revealed better stability of luteolin -7-glucoside and epicatechin gallate with EGFR-L858R as compared to PD168393. Therefore, we conclude that luteolin -7-glucoside and epicatechin gallate have excellent inhibition properties thus they can be used further to develop effective drugs against lung cancer having EGFR-L858R mutation.Communicated by Ramaswamy H. Sarma.


Divergent coordination mode of magnesium and zinc alkyls supported by the bifunctional pyrrolylaldiminato ligand.
The first magnesium and zinc alkyls derived from N-(iso-propyl)-pyrrolylaldimine have been synthesised and structurally characterised: both tBuM(N,N')-type compounds exist as three-coordinate monomers in benzene solution, but in the solid state the magnesium complex is a centrosymmetric dimer with Mg2(mu-N)2 bridges, whereas the zinc complex is a Zn...pi bonded dimer with a pi-coordinated pyrrole unit.


Insulin-like growth factor-1 levels in children with Beta-thalassemia minor.
Growth retardation in children with b-thalassemia major is multifactorial. Some etiologies described for this condition are hemochromatosis, disturbed growth hormone (GH) / insulin growth factor-1 (IGF-1) axis, undernutrition and hypermetabolism. It has also been proven that growth retardation is present in b-thalassemia major children despite regular transfusion and chelation. Our aim was to evaluate the level of IGF-1 in b-thalassemia minor subjects and compare it with that in healthy children. Fifty children aged 6 months to 15 years with b-thalassemia minor (32 males, 18 females) and 50 age- and sex-matched normal healthy children were selected. Medical history was taken and complete physical examination was done in each case; IGF-1 level was checked in all cases. This study was done in Shiraz, southern Iran, during 2005. IGF-1 levels were significantly lower in b-thalassemia minor children than normal children (P = 0.015). This result demonstrates that some etiologies of growth failure in b-thalassemia major other than those described to date can exist, which may be shared with b-thalassemia minor in feature or may be transformed by genes that are either expressed or not. We conclude that in addition to that observed in b-thalassemia major, IGF-1 level is also decreased in b-thalassemia minor, and these two may have similar etiologies.


Segregation of habitat and prey in two sympatric carnivorous plant species, Drosera rotundifolia and Drosera intermedia.
In 1984 a quantitative field study was made on two sympatric species of sundew, Drosera rotundifolia and Drosera intermedia, growing in a small silting-up bog in southern Germany. Both species differ in individual size and abundance but have nearly the same total biomass. Their association along a transect was strongly negative and also the vertical distribution was quite different. D. rotundifolia grows in significantly higher parts of the bog than D. intermedia. The composition of arthropod prey fauna proved to be markedly different in both species. For instance, Collembola were found more frequently on D. rotundifolia, winged insects on D. intermedia. The reasons for these differences are probably different microhabitats and different shapes of the plants. Seasonal dynamics of the arthropod populations affect their share in the composition of prey.


Diversifying Science: Underrepresented Student Experiences in Structured Research Programs.
Targeting four institutions with structured science research programs for undergraduates, this study focuses on how underrepresented students experience science. Several key themes emerged from focus group discussions: learning to become research scientists, experiences with the culture of science, and views on racial and social stigma. Participants spoke of essential factors for becoming a scientist, but their experiences also raised complex issues about the role of race and social stigma in scientific training. Students experienced the collaborative and empowering culture of science, exhibited strong science identities and high self-efficacy, while developing directed career goals as a result of "doing science" in these programs.


Systemic and renal pharmacokinetics of adefovir and tenofovir upon coadministration.
Adefovir and tenofovir are nucleotide analogs that undergo renal secretion by the human renal organic anion transporter. The pharmacokinetics of tenofovir and adefovir following the administration of tenofovir disoproxil fumarate and adefovir dipivoxil alone and together were determined in 24 healthy subjects in an 8-day, open-label, fixed-sequence study. Subjects received oral doses of adefovir dipivoxil on days 1 and 8 and oral doses of tenofovir disoproxil fumarate on days 2 to 8. Pharmacokinetic sampling was performed on days 1, 7, and 8. The plasma pharmacokinetics of tenofovir and adefovir were unaltered upon coadministration. Furthermore, the renal clearances (CLrenal) of tenofovir and adefovir were unaffected by their coadministration. The plasma Cmax values of tenofovir and adefovir were 33-fold and 340-fold lower than their Km values for the human renal organic anion transporter. These results demonstrate that coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil does not result in substantial changes to their individual pharmacokinetic profiles.


Direct comparison of myocardial perfusion cardiovascular magnetic resonance sequences with parallel acquisition.
To directly compare the three main myocardial perfusion cardiovascular magnetic resonance (CMR) sequences incorporating parallel acquisition methods. In 15 subjects (12 men, 57 +/- 15.7 years) referred for diagnostic coronary angiography, we acquired first-pass perfusion images (0.1 mmol/kg gadolinium-DTPA) at rest and during adenosine (140 microg/kg/min) on three separate occasions using three sequences incorporating parallel acquisition methods and approximately equivalent spatiotemporal resolution: hybrid echo planar imaging (hEPI), steady-state free precession (SSFP), and gradient echo imaging (GRE). We calculated the contrast-to-noise ratio (CNR) of each scan and blinded observers scored the presence and severity of artifacts (1, worst to 4, best), diagnostic confidence (0, low to 2, high), transmurality, area, and epicardial vessel territory of perfusion defects. CNR was greatest with SSFP and least with hEPI (13.15 vs 7.85 P < 0.001). The most artifacts were recorded with SSFP and least with hEPI (2.00 vs 3.03 P < 0.001). Observers were significantly more confident in reporting hEPI images (1.6 hEPI vs 0.9 SSFP, P < 0.001). Results for GRE were intermediate for all assessments. The hEPI sequence scored best for diagnostic performance despite the SSFP sequence having greater CNR. This trial favors hEPI for clinical myocardial perfusion CMR and suggests CNR should not be the sole criterion used to gauge the best candidate sequence.


Current status of percutaneous valvular procedures.
During the past few decades, percutaneous valvular procedures have been used in mitral and aortic stenosis. Percutaneous mitral commissurotomy, which has virtually replaced surgical commissurotomy in the treatment of mitral stenosis, has been performed since the mid-1980s and has provided good results in thousands of patients worldwide. Percutaneous balloon aortic valvuloplasty has largely been abandoned due to its limited efficacy and the risks involved. New percutaneous procedures are currently being developed in mitral regurgitation and aortic stenosis, which represent the two most frequent valve diseases in industrialized countries. They are in the early stages of development but have opened a very exciting field of investigation. Two percutaneous mitral valve treatment techniques have been used: the edge-to-edge technique and the prosthetic ring annuloplasty. Preliminary series show that they are feasible; however, they need to be further evaluated in comparison with contemporary treatment to accurately assess their effectiveness and the risks involved. Since 2003, percutaneous aortic valve replacement has been performed in approximately 100 compassionate cases with end-stage aortic stenosis, formally declined for surgery. It results in hemodynamic and clinical improvement, with an acceptable risk in this highly selected population. The evaluation of these new percutaneous procedures requires a close collaboration between interventionalists, echocardiographers, engineers, and surgeons. It is probable that they will play an important role in the treatment of valve disease in the future.


Anti-Glycolipid Antibody Examination in Five EAE Models and Theiler's Virus Model of Multiple Sclerosis: Detection of Anti-GM1, GM3, GM4, and Sulfatide Antibodies in Relapsing-Remitting EAE.
Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain-Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)35-55, MOG92-106, or myelin proteolipid protein (PLP)139-151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler's murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP139-151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies.


A population-based epidemiology of Wilson's disease in South Korea between 2010 and 2016.
Very few population-based studies have examined the epidemiology of Wilson's disease (WD). We investigated the epidemiology of WD using the National Health Insurance Service (NHIS) database in South Korea. We analyzed not only the statistical variables of WD, but also those of WD-related diseases. WD patients were identified with the relevant International Classification of Diseases-10 code out of 50.5 million people. We used the NHIS database from 2009 to 2016 and analyzed the incidence rate, prevalence, and clinical symptoms of WD. A total of 1,333 patients were identified. The average annual incidence rate was 3.8 per million person-years. The prevalence was 38.7 per million people. The mean diagnostic age was 26.1 ± 17.2 with earlier diagnosis in men (P = 0.0003). Among the patients, 988 (74.1%) had hepatic symptoms, 510 (38.3%) had neurologic symptoms, and 601 (45.1%) had psychiatric symptoms. Before the diagnosis of WD, 350 (26.3%) had neurologic symptoms, and 427 (32%) had psychiatric symptoms. The annual mortality rate was 0.7%. Age, liver cirrhosis, and liver failure correlated with a fatal prognosis (P < 0.05). Many patients showed neurologic and psychiatric symptoms before they were diagnosed with WD. Prognosis correlated with age, liver cirrhosis, and liver failure.


Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues.
A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9-12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19-21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA(A) receptor agonists, with ED(50) values of 252, 380, 251 mg/kg; TD(50) values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD(50) values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.


Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.
Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.


Characteristics Associated With Depression, Anxiety, and Social Isolation in Adults With Spina Bifida.
To identify demographic and clinical characteristics associated with depression, anxiety, and social isolation among adults with spina bifida. We hypothesize that lower urinary tract dysfunction is associated with poor psychosocial outcomes. An anonymous survey was distributed via Facebook advertising to individuals with congenital urologic conditions. Adults with spina bifida were included in our analysis. Lower urinary tract dysfunction was assessed with the Neurogenic Bladder Symptom Score. Depression, anxiety, and social isolation T-scores were measured using Patient-Reported Outcome Measures Information System instruments. A composite depression-anxiety score was calculated. Separate adjusted linear models assessed the association between lower urinary tract dysfunction and depression, anxiety, composite depression-anxiety, and social isolation. Around 195 participants were included. Rates of depression, anxiety, and social isolation were 48%, 47%, and 43%, respectively. Comorbid depression and anxiety occurred in 39% of subjects. On adjusted regression analysis, lower urinary tract dysfunction was associated with depression (P < 001), anxiety (P <.001), composite depression-anxiety (P <.001), and social isolation (P = .010). Depression, anxiety, and social isolation are common in individuals with spina bifida relative to the general population, and associated with lower urinary tract dysfunction. Interventions focused on optimizing lower urinary tract symptoms and function, transition-age adults, group psychotherapy, and comorbid depression and anxiety may be of particular value in this population.


Systemic lupus erythematosus-associated diffuse alveolar hemorrhage: A case report and review of the literature.
Systemic lupus erythematosus is associated with numerous pleuropulmonary complications. Although uncommon, diffuse alveolar hemorrhage represents a life-threatening cause of acute respiratory failure among patients with lupus. Here, we present a 24-year-old woman with a history of lupus who developed hemoptysis and respiratory failure associated with diffuse radiographic infiltrates and anemia. Bronchoscopy confirmed diffuse alveolar hemorrhage. She was managed with supportive care, plasmapheresis, and immunosuppressive pharmacotherapy leading to sustained resolution of her pulmonary hemorrhage and respiratory failure. We then review the available literature on the pathophysiology and management of lupus-associated diffuse alveolar hemorrhage, which centers on supportive care, reversal of coagulopathy, and immunosuppressive measures.


Calcaneus fractures: a review article.
Calcaneus fractures are a significant burden to society. Assessment and treatment of these injuries has improved significantly. The use of CT scanning has allowed a greater understanding of the pathologic anatomy of these fractures, and has provided for prognostic classification systems with respect to outcome. The treatment options are diverse and are reviewed.


Dynamic regulation of gut Clostridium-derived short-chain fatty acids.
Short-chain fatty acids (SCFAs) are major products of intestinal microbial fermentation with beneficial effects for human health. The dynamic balance and real-time monitoring of endogenous SCFA biosynthesis are important for understanding their physiological functions. We discuss the promising future of applying CRISPRi genetic systems and biosensors for targeted SCFA improvement.


Molecular epidemiology of dengue virus serotype 2 in the Taiwan 2002 outbreak with envelope gene and nonstructural protein 1 gene analysis.
The genetic relationships among dengue virus serotype 2 (DEN-2) isolates from the Taiwan 2002 epidemic were studied by sequence analysis of the envelope (E) and nonstructural protein 1 (NS1) genes. A 0-0.4% divergence among 10 isolates revealed an epidemic strain in the outbreak. Phylogenetic study demonstrated that the 2002 Taiwan isolates were of the Cosmopolitan genotype, which is different from the Asian 1 and Asian 2 genotypes of Taiwan DEN-2 isolates from 1981 to 1998 and the American/Asian genotype of 2005 Taiwan isolates. Although grouping results from both E and NS1 gene sequence analyses were the same, the usage of the NS1 gene as a sequence analysis target has not been validated for the lower bootstrap support values of branches in the phylogenetic tree. Our result showing the same genotype changes in Taiwan and Philippines isolates suggests strain transfer of DEN-2 to nearby countries resulting in the same trend of genotype change.


Particle size, resource concentration, and the distribution of net-spinning caddisflies.
The dimensions of net meshes constructed by hydropsychid Trichoptera vary both within and between species. Despite these catchnet differences, the diets of most Hydropsychidae studied in Utah streams were statistically indistinguishable. There was no relationship between the size of available resources and catchnet construction among species assemblages inhabiting 10 different localities. A particle-size model of caddis communities, suggesting that taxa feed selectively on particle sizes corresponding to the dimension of catchnet meshes, is not supported by these data.Diatom concentration increased regularly with downstream passage in two different drainages. The identity and number of coexisting hydropsychid species and the size of their catchnets were strongly correlated with diatom concentration. Taxa with large catchnet mesh were the only residents at sites where diatom concentration was very low; as resource concentration increased downstream, species with successively smaller mesh joined the coexisting guild. Together, the broad dietary similarities and distributional pattern from Utah streams suggest that resource concentration, rather than particle size, is the basis of community organization among the hydropsychid Trichoptera.


Making Advocacy Part of Your Job: Working for Children in Any Practice Setting.
Effective child health advocacy is an essential strategy to improve child health, and can improve access to equitable care. It can also be professionally rewarding and improve career satisfaction. However, while advocacy has been a part of pediatrics since its origins as a specialty, many barriers to engaging in health advocacy exist which can be challenging to navigate. There are a wide range of organizational practice settings, which are each accompanied by unique strengths and limitations. No matter the practice setting, pediatricians can be effective advocates for child health through leveraging organizational, professional, and community resources and partnerships.


A case-driven hypothesis for multi-stage crack growth mechanism in fourth-generation ceramic head fracture.
Ceramic bearings are used in total hip arthroplasty due to their excellent wear behaviour and biocompatibility. The major concern related to their use is material brittleness, which significantly impacts on the risk of fracture of ceramic components. Fracture toughness improvement has contributed to the decrease in fracture rate, at least of the prosthetic head. However, the root cause behind these rare events is not fully understood. This study evaluated head fracture occurrence in a sizeable cohort of patients with fourth-generation ceramic-on-ceramic implants and described the circumstances reported by patients in the rare cases of head fracture. The clinical survivorship of 29,495 hip prostheses, with fourth-generation ceramic bearings, was determined using data from a joint replacement registry. The average follow-up period was 5.2 years (range 0.1-15.6). Retrieval analysis was performed in one case for which the ceramic components were available. Clinical outcomes confirmed the extremely low fracture rate of fourth-generation ceramic heads: only two out of 29,495 heads fractured. The two fractures, both involving 36 mm heads, occurred without a concurrent or previous remarkable trauma. Considering the feature of the fractured head, a multi-stage crack growth mechanism has been hypothesized to occur following damage at the head-neck taper interface. Surgeons must continue to pay attention to the assembly of the femoral head: achieving a proper head seating on a clean taper is a prerequisite to decrease the risk of occurrence of any damage process within head-neck junction, which may cause high stress concentration at the contact surface, promoting crack nucleation and propagation even in toughened ceramics.


Sex and age differences of neurons expressing GABA-immunoreactivity in the rat bed nucleus of the stria terminalis.
Neurons, containing GABA were visualised immunohistochemically in the bed nucleus of the stria terminalis. Young prepubertal (20 days of age) and postpubertal (3 months and 1 year of age) Sprague-Dawley rats were used. Quantitative studies revealed greater density of GABA-immunoreactive perikarya in female than in male bed nucleus of the stria terminalis. This difference was not due to distribution in different volumes, since the volumes of the bed nucleus of the stria terminalis in the three ages studied did not differ by gender. Castration of new-born male rats caused elevation of the density of GABA-immunoreactive neurons in the bed nucleus of the stria terminalis to female levels on the third month of life. The percentage of nerve cells, expressing detectable amounts of GABA increased with age in the rat bed nucleus of the stria terminalis. The sexual dimorphism of GABA-immunoreactive neurons in the bed nucleus of the stria terminalis may contribute to the formation of reproductive behavior. The elevation of GABA expression with age might reflect change of the cellular activity in this part of the limbic circuitry.


Long-distance migration law of radon in overburden of abandoned goaf during coal spontaneous combustion.
The surface isotope radon measurement method (SIRMM) is widely used in fire source detection in abandoned mines. However, studies on the long-distance migration of radon during coal spontaneous combustion are lacking, which hinders the further popularization of this technology in coal fire prevention and control. For this reason, the migration law of radon in overlying strata in fire areas was studied through experiments and numerical simulation. The radon exhalation concentration of coal was found to increase at first and then decrease in the range of 30-350 °C through experiments. The radon concentration reaches the maximum value (557.1 Bq/m3) at 150 °C, which is 6.3 times higher than that at 30 °C. Based on the radon source term obtained by fitting the experimental data, the radon migration model of coal spontaneous combustion in abandoned goaf was constructed, and the dynamic distribution characteristics of the airflow, temperature, and radon concentration fields in the overlying strata area were analyzed. The internal relationship between surface radon and underground fire source was discussed. The simulation results revealed the sharp change in the porosity of the overlying rock causes radon concentration at the interface between the caving and fissure zones to increase continually with the process of spontaneous combustion, providing material and energy support for the long-distance radon migration. When the maximum temperature of the coal pile reaches 70 °C, the concentration of radon released from the coal pile increases rapidly to 13696 Bq/m3, and the radon from the underground space appears on the surface at this temperature. In the range of 70-150 °C, with rapid increase in radon released from coal piles, the surface concentration of radon also increased rapidly to 225 Bq/m3. At the high-temperature stage exceeding 150 °C, the concentration of radon released from coal piles exhibited a downward trend, resulting in a decrease in the rate of increase of radon concentration on the surface. A close relationship between the surface radon concentration and underground fire source temperature in the process of coal spontaneous combustion was observed. In the spatial position, the peak position of radon on the surface was highly consistent with that of the fire source longitudinally, which ensures the accuracy of the SIRMM to determine the location of the hidden fire source. This suggests that the SIRMM can accurately evaluate the fire source's temperature and fire area's development trend.


Perception of Mattering and Suicide Ideation in the Australian Working Population: Evidence from a Cross-Sectional Survey.
Thoughts about suicide are a risk factor for suicide deaths and attempts and are associated with a range of mental health outcomes. While there is considerable knowledge about risk factors for suicide ideation, there is little known about protective factors. The current study sought to understand the role of perceived mattering to others as a protective factor for suicide in a working sample of Australians using a cross-sectional research design. Logistic regression analysis indicated that people with a higher perception that they mattered had lower odds of suicide ideation than those with lower reported mattering, after controlling for psychological distress, demographic and relationship variables. These results indicate the importance of further research and intervention studies on mattering as a lever for reducing suicidality. Understanding more about protective factors for suicide ideation is important as this may prevent future adverse mental health and behavioural outcomes.


Plasmonic/magnetic nanoarchitectures: From controllable design to biosensing and bioelectronic interfaces.
Controllable design of the nanocrystal-assembled plasmonic/magnetic nanoarchitectures (P/MNAs) inspires abundant methodologies to enhance light-matter interactions and control magnetic-induced effects by means of fine-tuning the morphology and ordered packing of noble metallic or magnetic building blocks. The burgeoning development of multifunctional nanoarchitectures has opened up broad range of interdisciplinary applications including biosensing, in vitro diagnostic devices, point-of-care (POC) platforms, and soft bioelectronics. By taking advantage of their customizability and efficient conjugation with capping biomolecules, various nanoarchitectures have been integrated into high-performance biosensors with remarkable sensitivity and versatility, enabling key features that combined multiplexed detection, ease-of-use and miniaturization. In this review, we provide an overview of the representative developments of nanoarchitectures that being built by plasmonic and magnetic nanoparticles over recent decades. The design principles and key mechanisms for signal amplification and quantitative sensitivity have been explored. We highlight the structure-function programmability and prospects of addressing the main limitations for conventional biosensing strategies in terms of accurate selectivity, sensitivity, throughput, and optoelectronic integration. State-of-the-art strategies to achieve affordable and field-deployable POC devices for early multiplexed detection of infectious diseases such as COVID-19 has been covered in this review. Finally, we discuss the urgent yet challenging issues in nanoarchitectures design and related biosensing application, such as large-scale fabrication and integration with portable devices, and provide perspectives and suggestions on developing smart biosensors that connecting the materials science and biomedical engineering for personal health monitoring.


Novel perspectives on the transcytotic route in osteoclasts.
We analyzed the characteristics of degraded bone matrix-delivering vesicles along the transcytotic route from the ruffled border to the functional secretory domain (FSD) in bone-penetrating osteoclasts. Cells of rat or human origin were cultured on bovine bone slices and analyzed via confocal microscopy. Helix pomatia lectin binding indicated that transcytotic vesicles expose aberrant N-acetylgalactosamine glycoconjugates, which is associated with a poor prognosis for a range of metastasizing human adenocarcinomas. Transcytotic vesicles fuse with the autophagosomal compartments and represent raft concentrates. Furthermore, the results of a vertical vesicle analysis suggest that multiple vesicle populations arise from the ruffled border and that some of these vesicles undergo a maturation process along the transcytotic route. Finally, our data suggest that the targeting of these membrane pathways may be determined by a novel F-actin-containing and FSD-circumscribing molecular barrier.


Bridged repair of large ventral hernia defects using an ovine reinforced biologic: A case series.
Of all hernia types, large ventral hernias have the most impact on patient quality of life, however they are also the most difficult type of hernia to repair and are associated with high rates of complications. This case series describes repair of large ventral hernias with an ovine reinforced biologic in a complex patient cohort with comorbidities and concomitant procedures. The author performed bridged repair with an ovine reinforced biologic in 19 consecutive high-risk patients over a 5-year period. In all cases the reinforced biologic was used as an underlay. Of the 19 patients, six (32%) experienced a surgical site occurrence including infection, seroma, abscess, fistula, bioloma, or bowel obstruction. Three patients (16%) had recurrences with two out of three of the recurrences occurring within 6 months of surgery. Rates of SSO's and recurrences using ovine reinforced tissue matrix (RTM) were in line with or better than other published studies of bridged repair utilizing biologic or synthetic mesh reinforcement. Ovine RTM's should therefore be considered in complex large ventral hernia repairs.


Compartment-Specific Differences in the Activation of Monocyte Subpopulations Are Not Affected by Nitric Oxide and Glucocorticoid Treatment in a Model of Resuscitated Porcine Endotoxemic Shock.
Inhaled nitric oxide (iNO) remains one of the treatment modalities in shock, and in addition to its vasoactive properties, iNO exerts immunomodulatory effects. We used a porcine model of endotoxemia with shock resuscitation (control) and additional treatment with iNO and a steroid (treatment group). After 20 h, bone marrow (BM), peripheral blood (PB), and bronchoalveolar lavage fluid (BALF) were collected to analyze the immunophenotype and mitochondrial membrane potential (Δφ) in three subsets of monocytes. In both groups, SLA-DR expression decreased twofold on the circulating CD14+CD163+ and CD14−CD163+ monocytes, while it did not change on the CD14+CD163+. Δφ increased only in the CD14−CD163+ subpopulation (0.8 vs. 2.0, p < 0.001). The analysis of compartment-specific alterations showed that nearly 100% of BALF CD14+CD163+ and CD14−CD163+ monocytes expressed SLA-DR, and it was higher compared to PB (32% and 20%, p < 0.0001) and BM (93% and 67%, p < 0.001, respectively) counterparts. BALF CD14+CD163+ had a threefold higher Δφ than PB and BM monocytes, while the Δφ of the other subsets was highest in PB monocytes. We confirmed the compartmentalization of the monocyte response during endotoxemic shock, which highlights the importance of studying tissue-resident cells in addition to their circulating counterparts. The iNO/steroid treatment did not further impair monocyte fitness.


STARD4 abundance regulates sterol transport and sensing.
Nonvesicular transport of cholesterol plays an essential role in the distribution and regulation of cholesterol within cells, but it has been difficult to identify the key intracellular cholesterol transporters. The steroidogenic acute regulatory-related lipid-transfer (START) family of proteins is involved in several pathways of nonvesicular trafficking of sterols. Among them, STARD4 has been shown to increase intracellular cholesteryl ester formation and is controlled at the transcriptional level by sterol levels in cells. We found that STARD4 is very efficient in transporting sterol between membranes in vitro. Cholesterol levels are increased in STARD4-silenced cells, while sterol transport to the endocytic recycling compartment (ERC) and to the endoplasmic reticulum (ER) are enhanced upon STARD4 overexpression. STARD4 silencing attenuates cholesterol-mediated regulation of SREBP-2 activation, while its overexpression amplifies sterol sensing by SCAP/SREBP-2. To analyze STARD4's mode of action, we compared sterol transport mediated by STARD4 with that of a simple sterol carrier, methyl-β-cyclodextrin (MCD), when STARD4 and MCD were overexpressed or injected into cells. Interestingly, STARD4 and cytosolic MCD act similarly by increasing the rate of transfer of sterol to the ERC and to the ER. Our results suggest that cholesterol transport mediated by STARD4 is an important component of the cholesterol homeostasis regulatory machinery.


Competing endogenous RNAs and cancer: How coding and non-coding molecules cross-talk can impinge on disease.
Cancers are characterized by several dramatic biological changes. Among the many post-transcriptional regulatory mechanisms, microRNAs are known as fine-tune regulators for their transcript silencing ability. Competing endogenous RNAs (ceRNAs) are transcripts that share microRNA binding elements and can compete for them, thus regulating each other indirectly. ceRNA networks interconnect the regulatory control of different transcript classes of the coding and non-coding space and co-operate with other cellular and molecular regulatory mechanisms. Altered ceRNA networks are involved in tumor formation and progression as well as in chemoresistance, in invasion and in the onset of metastases. The analysis of changes in the balance between ceRNA transcripts could offer hints to identify novel pathways for diagnosis, prognosis and therapies in precision medicine interventions. Moreover, the possibility to query highly specific tumor databases, such as TCGA, and to combine clinical data, transcript expression and sequence information is allowing to develop specific predictive tools for precision medicine.


A 23-year-old man with left lung atelectasis treated with a targeted segmental recruitment maneuver: a case report.
Lung atelectasis are nonventilated parts of lung tissue and occur as a result of the collapse of the pulmonary parenchyma (alveoli). Various therapeutic procedures for inflating the collapsed pulmonary parenchyma, such as bronchial aspiration and/or standard recruitment maneuvers, are not always successful. We report a case of a 23-year-old Croatian man with a parapharyngeal abscess on the left side of the neck with spreading of infection in the mediastinum and left side of the thorax and consequent major atelectasis of the left lung. The patient was mechanically ventilated. We decided to apply a new method in which a pulmonary artery catheter was placed (guided by bronchoscope) on the entrance to the lower left bronchus. The pulmonary artery catheter balloon was inflated to achieve bronchial closure. Using another respirator, we ventilated the affected lobe separately with continuously high pressure of 30 cmH2O. After 30 minutes, we removed the pulmonary artery catheter from the lower left bronchus and placed it in the upper left bronchus and repeated the procedure. Our method allowed a significantly longer duration (30 minutes) of continuously high pressure of 30 cmH2O separately to only one of the total of five lobes of the lungs while the other four lobes were simultaneously ventilated continuously with protective ventilation mode. Use of a pulmonary artery catheter and two respirators in our patient's case proved to be a successful method for recruiting the atelectatic lung while maintaining protective ventilation of the lung segments without atelectasis.


Management of electrothermal injury of common bile duct with a degradable biliary stent: an experimental study in a porcine model.
Electrothermal injury of common bile duct is a frequent type of biliary injury. A long-term postoperative course and biliary leakage after removing T-tube are associated with external drainage. A method was developed to repair the injury with a degradable biliary stent instead of T-tube insertion. Pigs were divided into a stent repair (SR) group (n = 18), a T-tube repair (TR) group (n = 4), and a suturing repair (SUR) group (n = 4). An electrothermal injury model was made by electric coagulation. Pigs in the SR group were further divided into five subgroups according to the observation time (2 weeks and 1, 3, 6, and 18 months). Pigs in the TR group and SUR group were observed for 6 months. Cholangiography was repeated and bilirubin level was monitored. Pigs were reoperated for further evaluation at the end of observation. No biliary stricture, bile leakage, or bile duct necrosis occurred in the SR group. The stent could be detected in the first 2 months. No stent migration or stent-related obstruction was observed. Three pigs in the SUR group had biliary stricture with elevated bilirubin levels. These results suggested that the developed method for repairing electrothermal injury of common bile duct is feasible and safe.


Contrasting patterns of body size for Daphnia species that segregate by habitat.
We investigate how body size of two coexisting Daphnia species varies among 7 lakes that represent a gradient of predation risk. The two species segregate vertically in stratified lakes; D. galeata mendotae is typically smaller and more eplimnetic than D. pulicaria. The extent of vertical habitat partitioning, however, varies seasonally within and among lakes in apparent response to predation intensity by epilimnetic planktivorous fishes. Daphnia pulicaria uses the epilimnion at low levels of fish predation but is restricted to the hypolimnion under high fish predation, whereas D. galaeta mendotae always utilizes the epilimnion. The species display contrasting patterns of genetic variation in neonate size and size at maturity. D. pulicaria is larger in lakes with higher fish and Chaoborus densities whereas D. galeata mendotae is smaller. This contrast in body size in lakes with high predation is associated with greater habitat segregation in those lakes. In lakes with low predation risk, the two species are similar in body size at birth and maturity.


"See and Treat": spreading like wildfire? A qualitative study into factors affecting its introduction and spread.
The aim of this paper was to explore key factors that influenced the spread of "See and Treat" in a range of accident and emergency (A&E) departments. The study adopted a qualitative approach, and semi-structured interviews were undertaken with 21 key individuals working across 10 A&E departments operating See and Treat. Participants included clinicians, managers, and chief executives. Many factors influenced the spread of See and Treat. The initiative was well supported and monitored by external agencies, patients benefited and no staff groups lost out, waiting times were reduced, and Department of Health targets were achieved. However, this study indicates there were also a range of factors that limited the spread of See and Treat, including lack of additional resources and suitably experienced staff, impact upon quality of care, and no prior evaluation of its benefits. An interesting additional factor that may be both facilitating and limiting is the complexity of the A&E culture, in particular staff perspectives about working with minor injuries. See and Treat was promoted as a solution to waiting times problems in A&E, without evidence from any national evaluation. However, many staff members referred to its usefulness as a tool to reduce waiting times and enhance the patient journey, although resource, quality, and staffing issues may mean such an initiative may be difficult to sustain in its present form.


Stretchable Active Matrix Temperature Sensor Array of Polyaniline Nanofibers for Electronic Skin.
A stretchable polyaniline nanofiber temperature sensor array with an active matrix consisting of single-walled carbon nanotube thin-film transistors is demonstrated. The integrated temperature sensor array gives mechanical stability under biaxial stretching of 30%, and the resultant spatial temperature mapping does not show any mechanical or electrical degradation.


Vedolizumab Levels in Breast Milk of Nursing Mothers With Inflammatory Bowel Disease.
There are no data on the transfer of vedolizumab in breast milk of nursing mothers. We aimed to assess the presence of vedolizumab in breast milk of nursing inflammatory bowel disease [IBD] patients. This was a prospective observational study of vedolizumab-treated breastfeeding patients with IBD. Serum and breast milk samples were obtained at pre-defined tim -points. The in-house developed enzyme-linked immunosorbent assay [ELISA] for measuring vedolizumab in blood was adapted and validated for measurement of the drug in breast milk. The level of vedolizumab was also measured in breast milk of a control group of nursing healthy mothers. Vedolizumab was undetectable in breast milk in IBD patients before the first infusion of vedolizumab [n = 3] and in all of the healthy controls [n = 5]. Vedolizumab was measurable in all lactating women who received vedolizumab [n = 5]. However, on serial measurements in breast milk after an infusion, drug levels did not surpass 480 ng/ml, which was roughly 1/100 of the comparable serum levels. Vedolizumab can be detected in the breast milk of nursing mothers. Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant.


Retreatment of chronic hepatitis C virus genotype-4 patients after non-structural protein 5A inhibitors' failure: efficacy and safety of different regimens.
Nonstructural protein 5A (NS5A) is an important regimen for the treatment of chronic hepatitis C virus (HCV) genotype-4 infected patients. Retreatments for NS5A virologic failure are limited. The aim of this study is to provide real-life data regarding the effectiveness and safety of retreatment with different regimens after NS5A regimen virologic failure in GT4 patients. A total of 524 HCV patients (mean age 48 ± 11 years, 71% males), with virologic failure to sofosbuvir+daclatasvir, n = 450 and sofosbuvir/ledipasvir, n = 74 were included in this study. Patients were retreated with sofosbuvir + ombitasvir/paritaprevir/ritonavir + ribavirin, n = 278 and sofosbuvir + simeprevir + daclatasvir + ribavirin, n = 246. Response was evaluated 12 weeks after the end of treatment (SVR12). Overall, SVR12 was 95.2% [95% confidence interval (CI) 93.3%-97.1%]. In sofosbuvir + ombitasvir/paritaprevir/ritonavir + ribavirin and sofosbuvir + simeprevir + daclatasvir + ribavirin, SVR12s were 94.9% (95% CI 92.5%-97.4%) and 95.5% (95% CI 92.8%-98%), respectively. In liver cirrhosis patients, SVR12s were 96.4% (95% CI 90.7%-100%) and 98% (95% CI 94.9%-100%), respectively. Relapse in the sofosbuvir + ombitasvir/paritaprevir/ritonavir + ribavirin was n = 14 patients, and n = 11 patients in sofosbuvir + simeprevir + daclatasvir + ribavirin. Three patients developed hepatic encephalopathy, haematemesis, lower limb oedema, and one patient died in the SOF + OBV/PTV/RTV + RIB. In the sofosbuvir + simeprevir + daclatasvir + ribavirin, three patients developed hepatocellular carcinoma and one patient died. No treatment discontinuation due to anaemia. Salvage treatment for NS5A-treatment failure is effective and well tolerated in genotype-4 patients, in both noncirrhotic and compensated cirrhotic groups.


Task-sharing in menstrual regulation services: Implementation efforts and lessons learned in Bangladesh.
To explore the strategies undertaken to decentralize menstrual regulation services and implement task-sharing, including barriers and facilitators, with nonphysician providers in Bangladesh. We conducted a desk review of relevant policies and health service information from grey and published literature on task-sharing in menstrual regulation services, plus stakeholder interviews with 19 representatives of relevant health organizations to investigate facilitators for and barriers to the implementation of task-sharing of these services. Task-sharing in menstrual regulation began in 1979 as part of the national family planning program. The Ministry of Health and Family Welfare has guidelines for menstrual regulation services provided by a wide range of healthcare workers using manual vacuum aspiration and the medications misoprostol and mifepristone. Despite government approval, implementation of task-sharing is challenging owing to lack of skilled providers, lack of facility readiness, and unmet need for family planning. The government needs to implement effective planning for skills building of nonphysician providers and ensuring facility readiness for provision of menstrual regulation services to reduce unsafe abortion in Bangladesh.


Biomechanical evaluation of interference screw fixation techniques for distal radioulnar ligament reconstruction: a cadaveric experimental study.
In the reconstruction of distal radioulnar ligaments (DRULs), interference screws can be used for antegrade or retrograde fixation of grafts to the ulna. However, the biomechanics of interference screw fixation are currently unknown. This study aimed to determine the biomechanical effects of these two fixations on the distal radioulnar joint (DRUJ) in a cadaveric model and to investigate the appropriate initial tension. A total of 30 human cadaver upper extremities were used, and the DRULs were reconstructed according to Adams' procedure. First, eight specimens were randomly divided into two groups: antegrade and retrograde, followed by translational testing and load testing. Then, the other eight specimens were divided into the two groups above, and the contact mechanics, including forces, areas, and pressures, were measured. Finally, to investigate the appropriate initial tension, the remaining 14 specimens were fixed with interference screws under different tensions in an antegrade way, and the translational testing was repeated as before. In the neutral position, antegrade fixation exhibited less translation than retrograde fixation (7.21 ± 0.17 mm versus 10.77 ± 1.68 mm, respectively). The maximum failure load was 70.45 ± 6.20 N in antegrade fixation, while that in retrograde fixation was 35.17 ± 2.95 N (P < 0.0001). Antegrade fixation exhibited a larger increase in contact force than retrograde fixation (99.72% ± 23.88% versus 28.18% ± 10.43%) (P = 0.001). The relationship between tension and displacement was nonlinear (Y = - 1.877 ln(x) + 7.94, R2 = 0.868, P < 0.0001). Compared with retrograde fixation, the antegrade fixation of interference screws may be a more reliable surgical technique, as it shows a higher failure load and stability. In addition, to avoid the risk of potential arthritis caused by anterograde fixation, we propose an equation to determine the appropriate initial tension in DRUL reconstruction.


Increased dermal collagen density in amyotrophic lateral sclerosis.
We examined specimens of skin overlying the sacral region, among the most common sites of bedsores, from patients with amyotrophic lateral sclerosis (ALS) and controls, and found that in ALS patients, collagen fibrils had a greater density and became more tightly packed with the duration of illness. Our results suggest that the increased density of collagen fibrils may protect the skin of ALS patients from pressure ischemia, a major cause of bedsore formation.


α-terpineol reduces mechanical hypernociception and inflammatory response.
α-Terpineol (TPN), a volatile monoterpene alcohol, is relatively non-toxic and one of the major components of the essential oils of various plant species. In this study, we tested for the antihypernociceptive activity of TPN (25, 50 or 100 mg/kg, i.p.) in mice using mechanical models of hypernociception induced by carrageenan (CG, 300 μg/paw) and the involvement of important mediators of its cascade signalling, such as tumour necrosis factor-α (TNF-α, 100 pg/paw), prostaglandin E₂ (PGE₂, 100 ng/paw) or dopamine (DA, 30 μg/paw). We also investigated the anti-inflammatory effect of TPN on the model of carrageenan-induced pleurisy and the LPS-induced nitrite production in murine macrophages. Pre-systemic treatment with TPN (25, 50 or 100 mg/kg, i.p.) inhibited the development of mechanical hypernociception induced by CG or TNF-α. A similar effect was also observed upon PGE₂ and DA administration. In addition, TPN significantly inhibited the neutrophil influx in the pleurisy model. TPN (1, 10 and 100 μg/mL) also significantly reduced (p < 0.01) nitrite production in vitro. Our results provide information about the antinociceptive and anti-inflammatory properties of TPN on mechanical hypernociception and suggest that this compound might be potentially interesting in the development of new clinically relevant drugs for the management of painful and/or inflammatory disease.


The theoretical bases of indirect calorimetry: a review.
Indirect calorimetry is the method by which the type and rate of substrate utilization, and energy metabolism are estimated in vivo starting from gas exchange measurements. This technique provides unique information, is noninvasive, and can be advantageously combined with other experimental methods to investigate numerous aspects of nutrient assimilation, thermogenesis, the energetics of physical exercise, and the pathogenesis of metabolic diseases. Since its use as a research tool in metabolism is growing, the theoretical bases of indirect calorimetry are here reviewed in a detailed and orderly fashion. Special cases, such as the occurrence of net lipid synthesis or gluconeogenesis, are formally considered with derivation of explicit stoichiometric equations. The limitations of indirect calorimetry, both theoretical and technical, are discussed in the context of circumstances of clinical interest in metabolism.


Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance, cross-tolerance, and blockade by naloxone.
Morphine and buprenorphine have analgesic and anxiolytic-like properties. While their analgesic effects have been well characterized, their anxiolytic-like properties have not. Effects of acute morphine and buprenorphine on the expression of acoustic fear-potentiated startle (FPS) and naloxone pretreatment were assessed. Effects of chronic morphine and buprenorphine on tolerance, cross-tolerance, and withdrawal were also examined. Fear-conditioned rats were given subcutaneous drug treatment immediately before testing for FPS. Experiment 1, rats were administered morphine (0.03, 0.25, 0.63, 2.5, or 10 mg/kg) or buprenorphine (0.004, 0.0075, 0.015, 0.03, or 0.25 mg/kg). Experiment 2, rats were given saline or naloxone (0.5 mg/kg) and 5 min later given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg). Experiment 3, rats received once-daily injections of saline, morphine (10 mg/kg), or buprenorphine (0.25 mg/kg) for 7 days. Immediately before testing, saline-treated rats were given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg), morphine-treated rats were given morphine (2.5 mg/kg) or buprenorphine (0.03 mg/kg), and buprenorphine-treated rats were given buprenorphine (0.03 mg/kg) or morphine (2.5 mg/kg). Tolerance and cross-tolerance in analgesia were assessed via the tail-flick test, as were naloxone-precipitated withdrawal. Morphine and buprenorphine had parallel dose-response curves in blocking FPS, with buprenorphine 40 times more potent than morphine. Naloxone reversed these effects. Morphine and buprenorphine showed tolerance and cross-tolerance in their anxiolytic-like and analgesic effects. Chronic buprenorphine produced less withdrawal than chronic morphine. Cross-tolerance between morphine and buprenorphine suggests a common receptor mediating their anxiolytic-like and analgesic effects.


A review of pathobiology and therapies for classic Hodgkin lymphoma.
Hodgkin lymphoma can be classified as classical Hodgkin lymphoma (cHL) based on the presence of hallmark Hodgkin and Reed-Sternberg cells. Through radiotherapy and modern chemotherapy, cHL has an impressive cure rate. We discuss normal B-cell maturation and the pathobiology of cHL, correlate significant cHL maturation steps with the sites of action of novel drugs, and highlight these drugs' efficacy in prior trials. In relapsed cHL, the approved agents brentuximab vedotin and immune checkpoint inhibitors have shown efficacy both alone and in combination with chemotherapy for salvage therapy, as maintenance after an autologous stem cell transplant, and after failure of this transplant. Chimeric antigen receptor T-cell therapy is being explored as a potential treatment option in relapsed/refractory cHL, and ongoing clinical trials show promising data without significant toxicity. We illustrate available novel therapeutic options and their efficacy in frontline and relapsed settings and discuss therapeutic benefit in relation to regimen toxicity.


The road best traveled: Neural crest migration upon the extracellular matrix.
Neural crest cells have the extraordinary task of building much of the vertebrate body plan, including the craniofacial cartilage and skeleton, melanocytes, portions of the heart, and the peripheral nervous system. To execute these developmental programs, stationary premigratory neural crest cells first acquire the capacity to migrate through an extensive process known as the epithelial-to-mesenchymal transition. Once motile, neural crest cells must traverse a complex environment consisting of other cells and the protein-rich extracellular matrix in order to get to their final destinations. Herein, we will highlight some of the main molecular machinery that allow neural crest cells to first exit the neuroepithelium and then later successfully navigate this intricate in vivo milieu. Collectively, these extracellular and intracellular factors mediate the appropriate migration of neural crest cells and allow for the proper development of the vertebrate embryo.


Novel [18F]-labeled thiol for the labeling of Dha- or maleimide-containing biomolecules.
Prosthetic approach for the radiolabeling of biologics with fluorine-18 is a robust strategy and has been employed for many years. It requires fast, biocompatible and selective reactions suited to these fragile molecules. Michael addition of a nucleophilic thiol moiety on α,β-unsaturated carbonyl entities is an interesting compromise between simplicity of preparation of the prosthetic reagent and control of the selectivity of the addition. The α,β-unsaturated carbonyl entity of the biologic can easily be generated by addition of a maleimide function using adequate heterobifunctional linkers or generated by selective modification of a cysteine residue leading to a dehydroalanine moiety. We report here the design, synthesis and radiosynthesis of a new fluoropyridine-based thiol [18F]FPySH and its conjugation via Michael addition on model dehydroalanine- or maleimide-containing biologics. The preparation of cold reference and labeling precursor of [18F]FPySH was achieved and its radiosynthesis was fully automated, enabling production of the thiol prosthetic group with a 7 ± 2.1% radiochemical yield after two steps. The conjugation of [18F]FPySH to two model Dha-containing molecules was then carried out in reducing conditions, yielding the corresponding adducts in 30-45 min reaction time. Furthermore, [18F]FPySH was employed to radiolabel the maleimide-modified c(RGDfK) peptide, affording the radiofluorinated analogue in 15 min. We have developed an original [18F]-labeled thiol for site-selective conjugation and radiolabeling of Dha or maleimide-containing biomolecules of interest. Labeling of three model compounds was successfully carried out and gave the expected radiofluorinated adducts in less than 45 min, thus compatible with fluorine-18 half-life.


Precise excision of intervening sequences from precursor tRNAs by a membrane-associated yeast endonuclease.
Splicing of transfer RNA precursors containing intervening sequences proceeds in two distinct stages: endonucleolytic cleavage, followed by ligation. We have physically separated endonuclease and ligase activities from extracts of yeast cells, and we report properties of the partially purified endonuclease preparation. The endonuclease behaves as an integral membrane protein: it is purified from a membrane fraction from which it can be solubilized with nonionic detergents, and the activity of the endonuclease in the membrane fraction is stimulated by nonionic detergents. The endonuclease cleaves precursor tRNAs at two sites to excise the intervening sequence precisely. Both the extent and the accuracy of cleavage are enhanced by the presence of spermidine; the degree of stimulation varies with the pre-tRNA substrate. The cleavage products possess 5'-hydroxyl and 2',3'-cyclic phosphodiester termini. The cyclic phosphodiester termini can be opened to 2'-phosphates by a cyclic phosphodiesterase activity in the preparation.


The Role of Probiotics in the Treatment of Dysentery: a Randomized Double-Blind Clinical Trial.
Diarrhea is considered as an important cause of morbidity and mortality, even though one of the main reasons of death following diarrhea is initiated by dysentery. In recent years, the consumption of probiotics has been proposed for the treatment of infectious diarrhea. Despite most of the studies on probiotics have focused on acute watery diarrhea, few studies in the field of dysentery have found beneficial effects of probiotics. This study is a randomized double-blind clinical trial. The patients were randomly placed into control and case groups. In the intervention group, the patients received probiotics in the form of Kidilact® sachet, which contained high amounts of 7-strain friendly bacteria strains of Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Bifidobacterium infantis, Bifidobacterium breve, and Streptococcus thermophiles. On the other hand, the patients in the control group received placebo sachets on a daily basis for 5 days. It is notable that the treatment protocol of acute dysentery was done on both groups. The results of this study showed significant differences in the duration of blood in diarrhea between probiotic consumers (2.62 days) and the control group (3.16 days) (P value = 0.05). Additionally, significant differences in the average length of hospitalization in probiotic consumers (3.16 days) and control (3.66 days), (P value = 0.02) could be claimed that the consumption of probiotics is effective in reducing the duration of dysentery and diarrhea. The results of this study suggest that the use of probiotics can be effective in reducing the duration of blood in diarrhea. This study was also recorded in the Iran center of clinical trials registration database (IRCT2014060617985N1).