Neutrophil migration is defective during recombinant human granulocyte-macrophage colony-stimulating factor infusion after autologous bone marrow transplantation in humans.
We have previously reported that continuous intravenous (IV) administration of recombinant granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) to humans following high-dose alkylating agent chemotherapy and autologous bone marrow support (ABMS) results in myeloid bone marrow maturation, accelerated granulocyte recovery, and reduced treatment-related toxicity. However, we found that leukocyte counts declined rapidly after discontinuation of rHuGM-CSF therapy, which suggests possible growth factor effects on leukocyte margination and migration. For these reasons we studied granulocyte margination by using 111In-labeled autologous granulocytes and found similar granulocyte margination before (21.5% +/- 13.4%) and during continuous IV rHuGM-CSF infusion (23.3% +/- 9.6%). Phagocytosis of Cryptococcus neoformans and granulocyte hydrogen peroxide production was similar before and during rHuGM-CSF infusion and similar to patients treated with the same high-dose chemotherapy and ABMS but not receiving growth factor. However, migration of granulocytes to a sterile inflammatory site was markedly reduced during continuous rHuGM-CSF infusion (1.2 +/- 0.9 WBCs/cm2, 24 hr) as compared with baseline (39.6 +/- 17.7 WBCs/cm2/24 hr; P less than .0008). These findings may be of relevance when extravascular granulocytes are required for host defense.


Depressive symptoms, quality of life, and neuropsychological performance in HIV/AIDS: the impact of gender and injection drug use.
Limited attention has been paid to the potential impact of gender and injection drug use (IDU) on mood, quality of life, and neuropsychological performance in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Several studies that describe the natural history of HIV/AIDS in terms of mental health and neuropsychological ability have focused solely on men or have excluded injection drug users. Women and injection drug users are two groups for whom the incidence of HIV infection is increasing. Additionally, the National Academy of Sciences recently recommended that studies concerned with health-related research include males and females, and that researchers analyze their data for gender differences. The goals of the current study were to investigate possible relationships between HIV and IDU status and depressive symptoms, quality of life, and neuropsychological performance in women and men matched for age, race, and education. Overall, women reported more depressive symptoms than men, and this gender difference was most evident in women who were both infected with HIV and who were also injection drug users. Women and HIV-infected individuals reported the poorest quality of life scores. Women outperformed men on a measure of verbal memory and HIV(-) participants outperformed HIV(+) participants on a measure of perceptual speed. Finally, gender and HIV status interacted such that uninfected women performed the best, and infected men performed the worst, on a test of verbal memory. A better understanding of how men and women with different drug use profiles respond to HIV/AIDS may substantially improve survival, as well as aspects of daily functioning, of affected individuals. Thus, further study and development of treatment protocols targeted at including women and IDU are needed.


Dorsal slab fracture of the fourth carpal bone in a racing greyhound.
To report the diagnosis and surgical management of a dorsal slab fracture of the fourth carpal bone in a racing greyhound. Clinical report. Three-year-old, male racing Greyhound. The fracture was not visible on orthogonal radiographs and the diagnosis was made by computed tomography. Open reduction and internal fixation with 2 countersunk 2.0-mm screws inserted in lag fashion was performed via a dorsal approach. Outcome was analyzed objectively by comparing preinjury and postsurgery racing performances. Internal fixation resulted in fracture healing and the dog returned to racing recording times similar to those before injury. Fractures of the fourth carpal bone may not be visible on standard orthogonal radiographic views and cross-sectional imaging may be required for more accurate identification. Surgical management was successful with the dog returning to preinjury levels of competition.


Magnetosome Gene Duplication as an Important Driver in the Evolution of Magnetotaxis in the Alphaproteobacteria.
The evolution of microbial magnetoreception (or magnetotaxis) is of great interest in the fields of microbiology, evolutionary biology, biophysics, geomicrobiology, and geochemistry. Current genomic data from magnetotactic bacteria (MTB), the only prokaryotes known to be capable of sensing the Earth's geomagnetic field, suggests an ancient origin of magnetotaxis in the domain Bacteria Vertical inheritance, followed by multiple independent magnetosome gene cluster loss, is considered to be one of the major forces that drove the evolution of magnetotaxis at or above the class or phylum level, although the evolutionary trajectories at lower taxonomic ranks (e.g., within the class level) remain largely unstudied. Here we report the isolation, cultivation, and sequencing of a novel magnetotactic spirillum belonging to the genus Terasakiella (Terasakiella sp. strain SH-1) within the class Alphaproteobacteria The complete genome sequence of Terasakiella sp. strain SH-1 revealed an unexpected duplication event of magnetosome genes within the mamAB operon, a group of genes essential for magnetosome biomineralization and magnetotaxis. Intriguingly, further comparative genomic analysis suggests that the duplication of mamAB genes is a common feature in the genomes of alphaproteobacterial MTB. Taken together, with the additional finding that gene duplication appears to have also occurred in some magnetotactic members of the Deltaproteobacteria, our results indicate that gene duplication plays an important role in the evolution of magnetotaxis in the Alphaproteobacteria and perhaps the domain Bacteria IMPORTANCE A diversity of organisms can sense the geomagnetic field for the purpose of navigation. Magnetotactic bacteria are the most primitive magnetism-sensing organisms known thus far and represent an excellent model system for the study of the origin, evolution, and mechanism of microbial magnetoreception (or magnetotaxis). The present study is the first report focused on magnetosome gene cluster duplication in the Alphaproteobacteria, which suggests the important role of gene duplication in the evolution of magnetotaxis in the Alphaproteobacteria and perhaps the domain Bacteria A novel scenario for the evolution of magnetotaxis in the Alphaproteobacteria is proposed and may provide new insights into evolution of magnetoreception of higher species.


Pitfalls in the measurement and interpretation of thyroid function tests.
Thyroid function tests (TFTs) are amongst the most commonly requested laboratory investigations in both primary and secondary care. Fortunately, most TFTs are straightforward to interpret and confirm the clinical impression of euthyroidism, hypothyroidism or hyperthyroidism. However, in an important subgroup of patients the results of TFTs can seem confusing, either by virtue of being discordant with the clinical picture or because they appear incongruent with each other [e.g. raised thyroid hormones (TH), but with non-suppressed thyrotropin (TSH); raised TSH, but with normal TH]. In such cases, it is important first to revisit the clinical context, and to consider potential confounding factors, including alterations in normal physiology (e.g. pregnancy), intercurrent (non-thyroidal) illness, and medication usage (e.g. thyroxine, amiodarone, heparin). Once these have been excluded, laboratory artefacts in commonly used TSH or TH immunoassays should be screened for, thus avoiding unnecessary further investigation and/or treatment in cases where there is assay interference. In the remainder, consideration should be given to screening for rare genetic and acquired disorders of the hypothalamic-pituitary-thyroid (HPT) axis [e.g. resistance to thyroid hormone (RTH), thyrotropinoma (TSHoma)]. Here, we discuss the main pitfalls in the measurement and interpretation of TFTs, and propose a structured algorithm for the investigation and management of patients with anomalous/discordant TFTs.


Metabolic variables of cholesterol during squalene feeding in humans: comparison with cholestyramine treatment.
Squalene, a key intermediate of cholesterol synthesis, is present especially in olive oil. Regulation of cholesterol metabolism by dietary squalene in man is unknown, even though olive oil users in Mediterranean areas have low serum cholesterol levels. We have investigated absorption and serum levels of squalene and cholesterol and cholesterol synthesis with the sterol balance technique and serum levels of cholesterol precursors in humans during squalene feeding (900 mg/d for 7-30 days). The results were compared with those during cholestyramine treatment. Fecal analysis suggested that about 60% of dietary squalene was absorbed. Serum squalene levels were increased 17 times, but serum triglyceride and cholesterol contents were unchanged. The squalene feeding significantly (P less than 0.05) increased serum levels of free (1.7-2.3 times) and esterified (1.9-2.4 times) methyl sterol contents, while elevations of free and esterified delta 8-cholesterol and lathosterol levels were inconsistent. Cholestyramine treatment modestly augmented free methyl sterol levels (1.3-1.7 times), less consistently than those of esterified ones, while, in contrast to the squalene feeding, serum contents of free and esterified delta 8-cholesterol and lathosterol were dramatically increased (3.3-8 times). Neither of the treatments significantly affected serum plant sterol and cholestanol levels. The squalene feeding had no consistent effect on absorption efficiency of cholesterol, but significantly increased (paired t-test, P less than 0.05) the fecal excretions of cholesterol and its nonpolar derivatives coprostanol, epicoprostanol, and coprostanone (655 +/- 83 SE to 856 +/- 146 mg/d) and bile acids (212 +/- 24 to 255 +/- 24 mg/d), indicating an increase of cholesterol synthesis by about 50%. We suggest that a substantial amount of dietary squalene is absorbed and converted to cholesterol in humans, but this squalene-induced increase in synthesis is not associated with consistent increases of serum cholesterol levels. The clearly increased serum contents of esterified methyl sterols may reflect stimulated tissue acyl CoA: cholesterol acyltransferase (ACAT, EC 126.96.36.199) activity during squalene feeding as these sterols are not esterified in serum.


Joint water-fat separation and deblurring for spiral imaging.
Most previous approaches to spiral Dixon water-fat imaging perform the water-fat separation and deblurring sequentially based on the assumption that the phase accumulation and blurring as a result of off-resonance are separable. This condition can easily be violated in regions where the B0 inhomogeneity varies rapidly. The goal of this work is to present a novel joint water-fat separation and deblurring method for spiral imaging. The proposed approach is based on a more accurate signal model that takes into account the phase accumulation and blurring simultaneously. A conjugate gradient method is used in the image domain to reconstruct the deblurred water and fat iteratively. Spatially varying convolutions with a local convergence criterion are used to reduce the computational demand. Both simulation and high-resolution brain imaging have demonstrated that the proposed joint method consistently improves the quality of reconstructed water and fat images compared with the sequential approach, especially in regions where the field inhomogeneity changes rapidly in space. The loss of signal-to-noise-ratio as a result of deblurring is minor at optimal echo times. High-quality water-fat spiral imaging can be achieved with the proposed joint approach, provided that an accurate field map of B0 inhomogeneity is available. Magn Reson Med 79:3218-3228, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Retinopathy of prematurity.
With improved survival of very low birth infants in India, Retinopathy of Prematurity (ROP) is emerging as a significant problem. The most important risk factor in the pathogenesis of ROP is prematurity. Other factors like, problems with oxygenation frequent blood transfusions, sepsis and apnea have also been implicated in the causation of ROP. Essentially asymptomatic in the initial stages, a good screening program is essential for the early detection and treatment of this condition. Description of the various stages of ROP has been included in the protocol. Guidelines regarding the procedure of dilatation, ophthalmic examination and treatment (if required) have been provided. Close co-operation between the ophthalmologist and neonatologist is essential for a successful outcome.


Natural history of opportunistic disease in an HIV-infected urban clinical cohort.
To determine the effect of contemporary clinical care on the natural history of opportunistic disease in an urban population infected with human immunodeficiency virus (HIV). Urban university HIV clinic. Retrospective and prospective observational study. 1246 HIV-infected patients with CD4+ counts of 300 cells/mm3 or less. Incidence rates and Kaplan-Meier estimates of the probability of developing opportunistic disease with time, distribution of the CD4+ counts at which opportunistic disease develops, survival after the development of opportunistic disease, and the association between preventive drug therapies and the occurrence of opportunistic infection. The most common opportunistic disease was Candida esophagitis, which had an incidence of 13.3 events per 100 person-years and a 3-year Kaplan-Meier probability of 0.30. Pneumocystis carinii pneumonia, Mycobacterium avium complex bacteremia, cytomegalovirus, and the acquired immunodeficiency syndrome dementia complex occurred at rates of 5 to 9 events per 100 person-years and 3-year Kaplan-Meier probabilities of 0.15 to 0.22. Toxoplasmosis, cryptococcal meningitis, herpes zoster, the wasting syndrome, and Kaposi sarcoma occurred at rates of about 2 to 4 events per 100 person-years and with 3-year Kaplan-Meier probabilities of 0.05 to 0.10. Non-Hodgkin lymphoma, M. tuberculosis infection, progressive multifocal leukoencephalopathy, and cryptosporidiosis were the least common disorders, with an incidence of about 1 to 2 events per 100 person-years and a 3-year Kaplan-Meier probability less than 0.05. Only the incidences of cryptococcal meningitis, secondary P. carinii pneumonia, and herpes zoster decreased (P < 0.05) between 1989-1992 and 1993-1995. Fluconazole use was associated with a decreased relative rate of 0.49 (P = 0.06) for cryptococcal meningitis and a decreased relative rate of 0.61 (P = 0.005) for esophageal candidiasis. Rifabutin use was associated with a decreased relative rate of 0.37 (P = 0.002) for M. avium complex bacteremia, and trimethoprim-sulfamethoxazole use was associated with decreased relative rates of 0.33 (P = 0.02) for secondary P. carinii pneumonia and 0.55 (P = 0.08) for primary P. carinii pneumonia. Candidiasis, herpes zoster, and M. tuberculosis infection first occurred at a median CD4+ count greater than 100 cells/mm3, but all other opportunistic diseases first occurred at a median CD4+ count less than 50 cells/mm3. Median survival after diagnosis varied from 35 days for non-Hodgkin's lymphoma to 680 days for herpes zoster. In the patients studied, the incidences of secondary P. carinii pneumonia, cryptococcal meningitis, and herpes zoster have declined in the past 5 years. The incidences of primary P. carinii pneumonia and Kaposi sarcoma appear to be declining compared with historical estimates. However, although these and other opportunistic diseases continue to be relatively frequent complications of HIV infection, they are first occurring at more advanced immunosuppression than in the past. Continued efforts are needed to develop effective strategies for preventing opportunistic disease in very advanced HIV infection.


Molecular symmetry breaking in the Frizzled-dependent planar polarity pathway.
The core planar polarity pathway consists of six proteins that form asymmetric intercellular complexes that segregate to opposite cell ends in developing tissues and specify polarized cell structures or behaviors. Within these complexes, the atypical cadherin Flamingo localizes on both sides of intercellular junctions, where it interacts homophilically in trans via its cadherin repeats, whereas the transmembrane proteins Frizzled and Strabismus localize to the opposite sides of apposing junctions. However, the molecular mechanisms underlying the formation of such asymmetric complexes are poorly understood. Using a novel tissue culture system, we determine the minimum requirements for asymmetric complex assembly in the absence of confounding feedback mechanisms. We show that complexes are intrinsically asymmetric and that an interaction of Frizzled and Flamingo in one cell with Flamingo in the neighboring cell is the key symmetry-breaking step. In contrast, Strabismus is unable to promote homophilic Flamingo trans binding and is only recruited into complexes once Frizzled has entered on the opposite side. This interaction with Strabismus requires intact intracellular loops of the seven-pass transmembrane domain of Flamingo. Once recruited, Strabismus stabilizes the intercellular complexes together with the three cytoplasmic core proteins. We propose a model whereby Flamingo exists in a closed conformation and binding of Frizzled in one cell results in a conformational change that allows its cadherin repeats to interact with a Flamingo molecule in the neighboring cell. Flamingo in the adjacent cell then undergoes a further change in the seven-pass transmembrane region that promotes the recruitment of Strabismus.


Diagnosis, management and outcomes of necrotising soft tissue infection within a Plastic and Reconstructive Surgery unit.
Necrotising soft tissue infection (NSTI) is an extremely serious condition that relies on a high index of suspicion, prompt diagnosis and emergent radical surgical treatment. We explored the presentation, management and outcomes of NSTI within our department. We also assessed the potential benefit of using risk predictor scoring system. Retrospective review using departmental electronic database and hospital records. Twenty-four patients were treated for NSTI within our department between 2004 and 2010. Seventeen presented in our hospital to various surgical and medical teams. All patients presented with pain, swelling, erythema and tenderness at palpation. Only 40% of necrotising fasciitis and 28.6% of Fournier's gangrene were diagnosed as NSTI at initial assessment. Average mean interval time from admission to primary surgery was 17.7 h and 4 h from diagnosis to primary surgery. There were four mortalities. The average risk predictor Laboratory Risk Indicator for Necrotising Fasciitis score was 7.9. Significant morbidities post-operatively included bowel stoma, long-term urinary catheter and new diagnoses of carcinomas. Physicians and surgeons need to be suspicious of NSTI in severe cases of soft tissue infection to prevent delay in diagnosis and life-saving treatment. Scoring system can be used judiciously as adjunct to aid diagnosis.


[In vitro study of morphology of the bladder wall using MR tomography at 1.0 Tesla: correlation with histology].
Evaluation of the potential of various MR techniques to differentiate bladder wall layers verified by histological findings. 6 bladder specimens of pigs were examined in vitro using T1-weighted spin-echo-sequences, T2-weighted Turbo-SE, fat suppressed T2-weighted SE, and inversion recovery sequences. The MR images were obtained before and after fixating the specimens in formalin. Measurements of the thickness of bladder wall layers were performed on both sets of MR images as well as on histological sections, T2-weighted SE images showed three layers of different signal intensities: one innermost band of very high signal, one inner band of low and one outer band of intermediate signal corresponding histologically tunica propria and two different muscle layers. Inversion recovery technique provided similar findings but were able to avoid chemical-shift artifacts. After 24 hours in formalin, the signal intensity relation of the two muscle layers was inverted. The thickness of total bladder wall was not reduced significantly. Concerning the thickness of urinary bladder wall, histological measurements and evaluation of MR images correlated well. MR imaging enables the differentiation of three bladder wall layers. Inversion recovery technique achieved the best image quality by avoiding chemical shift artifact.


Factor VIII-induced superaggregation of human platelets.
High concentrations of bovine factor VIII cause clumping of platelets into a few very large aggregates. This response is termed superaggregation. It is distinct from factor-VIII-induced agglutination but is also independent of both extracellular calcium ions and platelet energy metabolism. Neither agglutinating lectins nor aggregating agents, including thrombin, ADP, the ionophore A23187, and U46619, a prostaglandin analog, can induce superaggregation, even at very high concentrations. Washed platelets undergo superaggregation, and superaggregation does not increase the amounts of fibrinogen or albumin trapped by agglutinated platelets. It is not inhibited by membrane-stabilizing drugs or by colchicine or cytochalasin-B. Formaldehyde and glutaraldehyde prevent superaggregation without affecting the binding of radiolabeled factor VIII to the platelets. Superaggregated platelets are separated by approximately 50 nm and are not shape-changed or degranulated. In adenosine diphosphate (ADP) induced aggregation, the platelets are distorted and only 30 nm apart. Superaggregation is reversed by dextran sulfate, and the dispersed platelets are still able to respond to ADP. Our observations are consistent with the binding of high molecular weight multimers of bovine factor VIII to more than one receptor on each platelet, with superaggregation occurring through recruitment of additional receptors. This process may be interrupted by protein crosslinking reagents, such as formaldehyde and glutaraldehyde.


Two new edge detectors.
This paper introduces two new edge detection algorithms. One uses multiple difference-based edge detectors. This scheme selects peak center by absolute maximum or center of mass techniques. The other algorithm is motivated by the observation that second-order enhancement improves human contour extraction, but generally confuses difference-based edge detectors. This algorithm translates intensity images into three state images (plus one, zero, and minus one), then uses multiple three-state edge masks to find edge positions. The second scheme has a multiple hardware implementation and interesting biological analogs. Finally, the two operators introduced are compared to some popular edge detection techniques from the literature.


[Ultrastructural changes in the cerebral cortex of an 100 1/2-year-old man].
Age changes in fields 39 and 40 (after Broadman) have been studied in a 100 years and 6 months old man died from peritonitis resulted from the surgical intervention, performed in connection with strangulation of the hernia. In the medical history there were no ++neuro-physical signs. The material was taken in 1 h 15 min after clinical death had been stated. The results obtained have been compared with those studied in the brain of persons, who had not yet reached the age of 100 years and had not any signs of ++neuro-physical disturbances and died after urgent surgical interventions in the abdominal cavity. In this group of persons the material for investigation was taken in 15-30 min after clinical death had been stated. The technique for treatment the material, its preparation for electron-microscopical examination is identical. Immersion fixation has been applied. The material obtained from an old animal fixed by means of vital perfusion of 2.5% glutaraldehyde solution is also used. In the person of 100 years and 6 months old the changes do not practically differ from those obtained from persons of younger age, however, the time from the statement of clinical death up to obtaining the material essentially influences preservation of the synaptic apparatus components.


Nanohybrid carriers: the yin-yang equilibrium between natural and synthetic in biomedicine.
Nanotechnology has seen an outburst in biomedicine applications through the use of nanoparticles of different sources in therapy and diagnostics. The needs of theranostics evolved through the years for the development of tailored treatments. In this regard, nanocarriers have shown a great impact on the field via the use of natural lipidic vesicles for drug delivery. This breakthrough allowed the medical field to protect the drug from undesired interactions in the bloodstream and lowered the drug load usually given to reach therapeutical doses. Nanocarriers further continued by using block polymers to create more stable structures with higher protection levels of their content. In this review, we introduce both lipidic and polymeric vesicles with their specific characteristics and discuss the advantages and disadvantages of each type which was taken as a base to introduce the newly known lipid-polymer hybrids that take the advantages from both sides to present an interesting approach to regulate the physicochemical features, pharmacokinetics and other parameters used in tailoring treatments for cancer therapy. In addition, from the many hybrids proposed we have focused our efforts in discussing two major groups that are lipid-polymer hybrid nanoparticles LPHNs (polymersomes inside liposomes), and capsosomes (liposomes inside polymersomes) showing the many potential benefits of combining lipids and polymers for biomedicine.


Unplanned readmissions to acute care from a pediatric postacute care hospital: incidence, clinical reasons, and predictive factors.
To identify the incidence, clinical reasons, and predictive factors for unplanned readmissions to acute care from a pediatric postacute care hospital. A retrospective cohort analysis of all discharges between October 1, 2011, and September 30, 2013 (n=298), in 1 pediatric postacute care hospital was conducted. Descriptive statistics were used to summarize the incidence and assess the clinical reasons for all readmissions to an acute care hospital. Logistic regression was used to identify predictive factors of any unplanned readmission to an acute care hospital. Thirty percent of all postacute care hospital discharges were unplanned readmissions to an acute care hospital. The primary clinical reasons for unplanned readmissions to acute care were respiratory decompensation (54%) and infection (20%). Requiring invasive mechanical ventilation, being <1 year of age, and having a postacute care length of stay<30 days were the 3 predictive factors. This is the first study to examine readmission to acute care from a postacute care hospital and to identify age, length of stay, and dependence on mechanical ventilation as predictive factors. Understanding which children are likely to require an unplanned readmission may allow providers to develop strategies to minimize this occurrence.


[Use of cephalosporins in pediatric practice with the study of the immunoleukolysis (leukocytolysis) reaction].
The aim of the study was to determine the value of preliminary assay of hypersensitivity to cephalosporin antibiotics such as cephazolin, cefuroxime and cefotaxime with the immunoleukolysis test (ILT). 130 children at the age of 2 months to 7 years treated with one of the antibiotics for various inflammatory diseases of the bronchopulmonary system were examined. Hypersensitivity (the ILT indices over 30 per cent) was observed in 9.2 per cent of the children with respect to cephazolin (kefzol), in 3.9 per cent of the children with respect to cefuroxime (ketocef) and in 0.8 per cent of the children with respect to cefotaxime (klaforan). The results of the ILT combined with those of the conjunctival test allowed to increase the number of indications to differential use of the cephalosporins in children with various pathological processes in the bronchopulmonary system.


A defect in the oxidative metabolism of human polymorphonuclear leukocytes that remain in circulation early in hemodialysis.
Human granulocytes harvested from uremic volunteers 15 min after the initiation of dialysis (at the nadir of neutropenia) were compared to predialysis controls. These intradialysis cells had a significant defect in peak luminol-enhanced chemiluminescence in response to opsonized zymosan, f-Met-Leu-Phe, and phorbol myristate acetate relative to predialysis control cells from the same patients. This defect could not be explained by a decrease in PMN myeloperoxidase concentration. H2O2 secretion by intradialysis cells (2 patients) was also depressed relative to predialysis controls. The ability to perform an independent function, orientation (polarization), was normal in both pre- and intradialysis cells relative to control. Whereas 125I-labeled formyl peptide binding studies demonstrated identical values for affinity and receptor number for predialysis and normal control cells, intradialysis cells displayed a 27% decrease in receptor number. This decrease in available receptor number. This decrease in available receptors may be related to the decreased chemiluminescence observed in response to f-Met-Leu-Phe. Furthermore, the results are consistent with the hypothesis that a defective PMN population remains in the circulation during the neutropenia of hemodialysis.


CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.
Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.


The interconnection between biofilm formation and horizontal gene transfer.
Recent research has revealed that horizontal gene transfer and biofilm formation are connected processes. Although published research investigating this interconnectedness is still limited, we will review this subject in order to highlight the potential of these observations because of their believed importance in the understanding of the adaptation and subsequent evolution of social traits in bacteria. Here, we discuss current evidence for such interconnectedness centred on plasmids. Horizontal transfer rates are typically higher in biofilm communities compared with those in planktonic states. Biofilms, furthermore, promote plasmid stability and may enhance the host range of mobile genetic elements that are transferred horizontally. Plasmids, on the other hand, are very well suited to promote the evolution of social traits such as biofilm formation. This, essentially, transpires because plasmids are independent replicons that enhance their own success by promoting inter-bacterial interactions. They typically also carry genes that heighten their hosts' direct fitness. Furthermore, current research shows that the so-called mafia traits encoded on mobile genetic elements can enforce bacteria to maintain stable social interactions. It also indicates that horizontal gene transfer ultimately enhances the relatedness of bacteria carrying the mobile genetic elements of the same origin. The perspective of this review extends to an overall interconnectedness between horizontal gene transfer, mobile genetic elements and social evolution of bacteria.


Effects of tissue dielectric properties on the electric field induced in tDCS: a sensitivity analysis.
Numerical modeling studies remain the only viable way to accurately predict the electric field (E-field) distribution in transcranial direct current stimulation (tDCS). Despite the existence of multiple studies of this kind, a wide range of different values and properties for the electrical conductivities of the tissues represented is employed. This makes it difficult to predict whether the changes observed between models are due to differences in the geometries of the volume conductors or to the different electrical properties of the tissues. In this study we used the finite element method to calculate the E-field distribution in several spherical head models whose tissues were represented with different isotropic and anisotropic conductivity profiles. Results show that the distribution of the E-field is especially sensitive to the conductivity of the skull, skin and GM. These results might help comparing numerical modeling studies that employ different conductivity values.


"Put Myself Into Your Place": Embodied Simulation and Perspective Taking in Autism Spectrum Disorders.
Embodied cognition theories hold that cognitive processes are grounded in bodily states. Embodied processes in autism spectrum disorders (ASD) have classically been investigated in studies on imitation. Several observations suggested that unlike typical individuals who are able of copying the model's actions from the model's position, individuals with ASD tend to reenact the model's actions from their own egocentric perspective. Here, we performed two behavioral experiments to directly test the ability of ASD individuals to adopt another person's point of view. In Experiment 1, participants had to explicitly judge the left/right location of a target object in a scene from their own or the actor's point of view (visual perspective taking task). In Experiment 2, participants had to perform left/right judgments on front-facing or back-facing human body images (own body transformation task). Both tasks can be solved by mentally simulating one's own body motion to imagine oneself transforming into the position of another person (embodied simulation strategy), or by resorting to visual/spatial processes, such as mental object rotation (nonembodied strategy). Results of both experiments showed that individual with ASD solved the tasks mainly relying on a nonembodied strategy, whereas typical controls adopted an embodied strategy. Moreover, in the visual perspective taking task ASD participants had more difficulties than controls in inhibiting other-perspective when directed to keep one's own point of view. These findings suggested that, in social cognitive tasks, individuals with ASD do not resort to embodied simulation and have difficulties in cognitive control over self- and other-perspective.


A BEME (Best Evidence in Medical Education) review of the use of workplace-based assessment in identifying and remediating underperformance among postgraduate medical trainees: BEME Guide No. 43.
The extent to which workplace-based assessment (WBA) can be used as a facilitator of change among trainee doctors has not been established; this is particularly important in the case of underperforming trainees. The aim of this review is to examine the use of WBA in identifying and remediating performance among this cohort. Following publication of a review protocol a comprehensive search of eight databases took place to identify relevant articles published prior to November 2015. All screening, data extraction and analysis procedures were performed in duplicate or with quality checks and necessary consensus methods throughout. Given the study-level heterogeneity, a descriptive synthesis approach informed the study analysis. Twenty studies met the inclusion criteria. The use of WBA within the context of remediation is not supported within the existing literature. The identification of underperformance is not supported by the use of stand-alone, single-assessor WBA events although specific areas of underperformance may be identified. Multisource feedback (MSF) tools may facilitate identification of underperformance. The extent to which WBA can be used to detect and manage underperformance in postgraduate trainees is unclear although evidence to date suggests that multirater assessments (i.e. MSF) may be of more use than single-rater judgments (e.g. mini-clinical evaluation exercise).


Methodological issues in international comparison of interval breast cancers.
International comparisons of interval cancers (IC) are important to better understand the relationship between programmes' performance and screening practices. In this respect, differences in (i) definition, (ii) identification and (iii) quantification of IC have received little attention. To examine these 3 comparability issues and activities involving IC, an assessment was conducted among member countries of the International Breast Cancer Screening Network, and the impact of accuracy of identification and quantification practices was estimated using 1996-98 data from the Dutch breast cancer screening programme. Information was obtained from 19 screening programmes in 18 countries, 16 of which acknowledged the coexistence of opportunistic screening. IC data were collected to evaluate performance of the screening programme (100% of programmes) and the radiologists (89%); 53% of programmes had a designated review process for IC. Most programmes (84%) agreed with the European Guidelines definition of IC, but a case situation exercise evidenced substantial discrepancy in classification of cancers that occurred after a positive screen. Completeness of identification of IC appears to contribute most to international variation, and cannot be easily controlled for in methodologically rigorous comparisons. Statistically significant differences of about 4% were measured between quantification methods for IC. An operational definition of IC is proposed to enhance international comparability. Valid comparisons of IC are possible with careful attention to the definition but true differences in IC frequency across screening programmes should exceed 10% to be possibly indicative of real differences between programmes.


TCDD receptor ligands present in extracts of urban air particulate matter induce aryl hydrocarbon hydroxylase activity and cytochrome P-450c gene expression in rat hepatoma cells.
In previous studies we have shown that substances associated with particulates collected from urban air and automobile exhaust bind with high affinity to the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor present in rat liver cytosol. In this study we used a rat hepatoma cell line, H4IIE, to investigate the effect of such substances on an enzyme system, aryl hydrocarbon hydroxylase (AHH), which is regulated via the TCDD receptor. The results demonstrate that AHH activity in the H4IIE cell line can be induced by extracts of particulates collected from urban air and automobile exhausts in a dose-dependent manner, and that the AHH activity is inducible by five polycyclic aromatic hydrocarbons (PAHs) including 1-/3-nitrobenzo[a]pyrene and 6-chlorochrysene, all present in extracts of particulates from urban air and automobile exhausts. The induction of AHH activity is correlated to apparent TCDD receptor affinity for investigated PAHs (r = 0.85) and particulate extracts. Biochemically, treatment of the cells with 5,6-benzoflavone significantly increased the level of cytochrome P-450c but not P-450d as shown by immunoblotting and analysis of mRNA levels. The data indicate that substances present in extracts of urban air particulates can interact with the TCDD receptor in intact cells and cause an accumulation of cytochrome P-450c mRNA leading to an increased synthesis of the gene product and thus an increase in enzyme activity.


Mechanical damping by intercrystalline diffusion of hydrogen in metallic polycrystals.
Anelastic relaxation by intercrystalline atomic diffusion-analogous to thermal diffusion (i.e., thermoelastic) effects but never observed hitherto-was recently suggested as a new mechanism to explain part of the hydrogen damping spectra in intermetallic compounds. A critical experimental test of this model is now presented using a Zr65Cu17.5Ni10Al7.5 alloy, which allows for a quantitative kinetic analysis in comparison to a closely related reorientation process. The results are in full agreement with the predictions of the model and clearly corroborate the proposed "intercrystalline Gorsky effect" as a new type of mechanical damping in sufficiently fine-grained polycrystals.


Bacterial Whack-a-Mole: Reconsidering the Public Health Relevance of Using Carbadox in Food Animals.
Carbadox is an antibiotic used to control dysentery and promote growth in swine in the United States; however, the drug also causes tumors and birth defects in laboratory animals. Despite this and because the drug has no analogs in human medicine, it is not considered "medically important" and can be used in livestock without veterinarian oversight. In their recent study, T. A. Johnson et al. (mBio 8:e00709-17, 2017, https://doi.org/10.1128/mBio.00709-17) demonstrated that carbadox has profound effects on the swine gut microbiome, including the induction of transducing phage carrying tetracycline, aminoglycoside, and beta-lactam resistance genes. In swine production, carbadox can be used in conjunction with other antibiotics (e.g., oxytetracycline) that could fuel the emergence of strains carrying phage-encoded resistance determinants. Johnson et al.'s findings underscore the potential unforeseen consequences of using antibiotics in livestock production and call into question our current methods for classifying whether or not a veterinary drug has relevance to human health.


[Dementia and diabetes mellitus].
Dementia and Diabetes mellitus (DM) are major health problems nowadays. DM leads to a significant cognitive decline and increases the risk of dementia, mostly Alzheimer's Disease (AD) and vascular dementia (VaD) by 50-100% and 100-150%, respectively. Amyloid beta (Abeta), the main pathogenic factor in AD development, is eliminated by advanced glycation end products (AGEs) and degraded by insulin degrading enzyme (IDE) for which it competes with insulin. Insulin stimulates secretion of Abeta and promotes brain inflammation. DM I and II cause slowing down of mental speed, lowering of mental flexibility and DM II learning and memory disturbances. DM acts both directly by hyperglycaemia and hyperinsulinaemia and by the blood vessel changes. Hyperglycaemia changes synapse plasticity and leads to cognitive decline. AGEs disrupt the neuron function and bonding to Abeta increases its aggregability. Glycation of tau protein promotes production of neurofibrillary tangles (NFT), the main intracellular pathogenic factor in AD. AGE 2 in DM causes pathological angiogenesis and apoptosis of neurons. AGE receptor (RAGE) is also the specific Abeta receptor with which it produces reactive oxygen species that has, as a result, disruption of mitochondrial function and reduction of neuronal energy resources. Insulinoresistance is linked with the dysexecutive syndrome, and hyperinsulinaemia increases the risk of AD especially by enhancing phosphorylation oftau protein and formation of NFT. Application of insulin showed improvement of memory, behaviour and affect in AD patients. Good glycoregulation emerged as an important factor in dementia prevention, and a better insight in relations of DM and brain function will lead to new potential dementia therapies.


Rapid Asia-Europe-North America geographic dispersal of earliest Eocene primate Teilhardina during the Paleocene-Eocene Thermal Maximum.
True primates appeared suddenly on all three northern continents during the 100,000-yr-duration Paleocene-Eocene Thermal Maximum at the beginning of the Eocene, approximately 55.5 mya. The simultaneous or nearly simultaneous appearance of euprimates on northern continents has been difficult to understand because the source area, immediate ancestors, and dispersal routes were all unknown. Now, omomyid haplorhine Teilhardina is known on all three continents in association with the carbon isotope excursion marking the Paleocene-Eocene Thermal Maximum. Relative position within the carbon isotope excursion indicates that Asian Teilhardina asiatica is oldest, European Teilhardina belgica is younger, and North American Teilhardina brandti and Teilhardina americana are, successively, youngest. Analysis of morphological characteristics of all four species supports an Asian origin and a westward Asia-to-Europe-to-North America dispersal for Teilhardina. High-resolution isotope stratigraphy indicates that this dispersal happened in an interval of approximately 25,000 yr. Rapid geographic dispersal and morphological character evolution in Teilhardina reported here are consistent with rates observed in other contexts.


Combined Anterior Cruciate Ligament Repair and Anterolateral Ligament Internal Brace Augmentation: Minimum 2-Year Patient-Reported Outcome Measures.
The anterolateral ligament (ALL) contributes to anterolateral rotational stability of the knee. Internal bracing of the anterior cruciate ligament (ACL) and ALL reinforces the ligaments and encourages natural healing by protecting both during the healing phase and supporting early mobilization. To assess the 2-year patient-reported outcomes of combined ACL repair and ALL internal brace augmentation. We hypothesized that significant improvements in outcomes would be seen. Case series; Level of evidence, 4. A total of 43 consecutive patients with acute proximal ACL ruptures were prospectively evaluated for a minimum of 2 years. The mean age at the time of surgery was 25.7 years (range, 13-56 years). Indications for the combined ACL/ALL procedure were associated Segond fractures, grade 3 pivot shift, or high levels of sporting activity. Patients with chronic ruptures or with multiligament injuries were excluded. The Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain, Veterans RAND 12-Item Health Survey (VR-12), and Marx activity scale were collected preoperatively and at 12 and 24 months postoperatively. Patients with any postoperative complications were identified at the time of this analysis. The mean follow-up period was 44.8 months. Five patients were lost to follow-up, leaving 38 patients (88.4%) in the final analysis. The mean KOOS for Pain, Symptoms, Activities of Daily Living, Sport/Recreation, and Quality of Life improved from a respective 64.9, 58.6, 75.0, 33.7, and 28.9 preoperatively to 91.1, 81.8, 96.1, 82.8, and 74.3 at the 2-year follow-up (P < .0001). The mean WOMAC scores for pain, stiffness, and function improved from 77.5, 65.3, and 75.0 preoperatively to 94.6, 88.6, and 96.0 at the 2-year follow-up (P < .0001). The VAS pain score improved from 3.4 preoperatively to 0.7 at the 2-year follow-up, and the VR-12 physical score improved from 34.4 preoperatively to 52.7 at the 2-year follow-up (P < .0001 for both ). However, the Marx activity score decreased from 13.3 preinjury to 10.6 at the 2-year follow-up (P = .01). Two patients (5.3%) sustained a rerupture. Combined ACL repair and ALL internal brace augmentation demonstrated excellent outcomes in 94.7% of the study patients. Based on our experience with this cohort as well as our isolated ACL repair data, we suggest that high-risk patients with ACL ruptures have an additional ALL procedure to provide rotational stability.


Regulation of prostaglandin F2 alpha and E receptor mRNA by prostaglandin F 2 alpha in ovine corpora lutea.
Prostaglandins regulate many physiological functions, including reproduction, by binding to specific plasma membrane receptors. In this study we evaluated the regulation of PGF2 alpha (FP) and PGE (EP3 subtype) receptors in ovine corpora lutea. In the first study, tissue distribution of FP and EP3 receptors was evaluated in 13 ovine tissues. FP receptor mRNA was present in 100-fold higher concentration in corpora lutea than in other tissues. Similarly, [3H]PGF2 alpha binding was much greater in luteal plasma membranes than in membranes from other tissues. In contrast, EP3 receptor mRNA was more uniformly distributed, with high concentrations in adrenal medulla, inner myometrium, kidney medulla and heart. The distribution of [3H]PGE1 binding was generally similar to EP3 mRNA, with the exception that ovarian stroma, endometrium and outer myometrium had high [3H]PGE1 binding but low concentrations of EP3 receptor mRNA. The second study evaluated the action of PGF2 alpha on luteal mRNA encoding FP and EP3 receptors. Ewes had PGF2 alpha or saline infused into the ovarian artery and corpora lutea were removed at 0, 1, 4, 12 and 24 h. FP receptor mRNA decreased by 50% at 12 and 24 h after infusion with PGF2 alpha, whereas EP3 mRNA was unchanged. Treatment of large luteal cells with PGF2 alpha, phorbol didecanoate (protein kinase C activator), or ionomycin (calcium ionophore) decreased FP receptor mRNA after 24 h (P < 0.05). Glyceraldehyde 3-phosphate dehydrogenase mRNA was not changed by any treatment. These results show that EP3 receptors are expressed in many tissues and expression is not regulated by PGF2 alpha. In contrast, FP receptors are primarily expressed in corpora lutea and expression is inhibited by PGF2 alpha.


Detection of right ventricular infarction by gadolinium DTPA-enhanced magnetic resonance imaging.
We investigated the usefulness of gadolinium-enhanced magnetic resonance (Gd-MR) imaging for diagnosis of right ventricular (RV) infarction in 14 patients with acute inferior infarction. Myocardial perfusion images with thallium 201 and technetium 99m pyrophosphate (dual single-photon emission computed tomography: dual SPECT) and haemodynamic data were obtained on admission. Patients were classified into three groups based on dual SPECT and Gd-MR findings: no accumulation in the right ventricle (negative, Type 1), posterior RV infarction (Type 2) and anterior and posterior RV infarction (Type 3). No patients exhibited the haemodynamic criteria for RV infarction (a mean right atrial pressure above 10 mmHg and a ratio of mean right atrial pressure to pulmonary artery wedge pressure above 0.8). Dual SPECT identified RV infarction in eight patients (three Type 2 and five Type 3, 57% of the total). Gd-MR imaging also identified eight patients (57%) as positive (five Type 2 and three Type 3). Our results showed that Gd-MR imaging was not only useful for diagnosis of RV infarction, but also equal to dual SPECT in sensitivity and specificity, and superior to it as regards acquisition time and assessing the spatial anatomy of heart. In conclusion, Gd-MR imaging is superior to dual SPECT for detection of RV infarction.


Risk Factors of Breast Cancer in Hadramout Valley and Desert, Yemen.
The incidence of breast cancer is on rise in low- and middle-income countries as populations increasingly adopt western lifestyles. Studies on risk factors of cancers including breast cancer are lacking in Yemen. Therefore, this study aimed to determine the risk factors of breast cancer among women registered at Hadramout Valley and Desert Oncology Center (HVDOC). A case-control study was conducted at HVDOC, Yemen. All women who were registered in HVDOC and diagnosed with breast cancer and confirmed by histopathology during 2011-2015 were selected as cases. Age-matched controls were selected from women who underwent mammography in HVDOC during 2011-2015 and were confirmed to be free of breast cancer. Data were collected using semi-structured questionnaire and clinical data were abstracted from the medical records. A total of 105 patients and 210 controls were included in this study. About 70.5% of cases and 72.4% of control were 50 years old or younger. Compared with married women, divorced women had higher odds of breast cancer [odds ratio (OR) = 2.2]. The odds of breast cancer was higher for women who had never breastfed a child (OR = 1.7). Having hypertension (OR = 2.5), family history of malignancy (OR = 2.4), and postmenopausal status (OR = 2.0) were significantly associated with higher odds of breast cancer in multivariate analysis. The main risk factors for breast cancer among women in Yemen are divorced marital status, never breastfed a child, having hypertension, family history of malignancy, and postmenopause. Regular screening especially among women with high risk is needed.


Degradation of pharmaceuticals and metabolite in synthetic human urine by UV, UV/H2O2, and UV/PDS.
To minimize environmental pharmaceutical micropollutants, treatment of human urine could be an efficient approach due to the high pharmaceutical concentration and toxic potential excreted in urine. This study investigated the degradation kinetics and mechanisms of sulfamethoxazole (SMX), trimethoprim (TMP) and N4-acetyl-sulfamethoxazole (acetyl-SMX) in synthetic fresh and hydrolyzed human urines by low-pressure UV, and UV combined with H2O2 and peroxydisulfate (PDS). The objective was to compare the two advanced oxidation processes (AOPs) and assess the impact of urine matrices. All three compounds reacted quickly in the AOPs, exhibiting rate constants of (6.09-8.53) × 10(9) M(-1)·s(-1) with hydroxyl radical, and (2.35-16.1) × 10(9) M(-1)·s(-1) with sulfate radical. In fresh urine matrix, the pharmaceuticals' indirect photolysis was significantly suppressed by the scavenging effect of urine citrate and urea. In hydrolyzed urine matrix, the indirect photolysis was strongly affected by inorganic urine constituents. Chloride had no apparent impact on UV/H2O2, but significantly raised the hydroxyl radical concentration in UV/PDS. Carbonate species reacted with hydroxyl or sulfate radical to generate carbonate radical, which degraded SMX and TMP, primarily due to the presence of aromatic amino group(s) (k = 2.68 × 10(8) and 3.45 × 10(7) M(-1)·s(-1)) but reacted slowly with acetyl-SMX. Ammonia reacted with hydroxyl or sulfate radical to generate reactive nitrogen species that could react appreciably only with SMX. Kinetic simulation of radical concentrations, along with products analysis, helped elucidate the major reactive species in the pharmaceuticals' degradation. Overall, the AOPs' performance was higher in the hydrolyzed urine than fresh urine matrix with UV/PDS better than UV/H2O2, and varied significantly depending on pharmaceutical's structure.


The association between preoperative anemia and postoperative morbidity in pediatric surgical patients: A secondary analysis of a prospective observational cohort study.
The prevalence of anemia in the South African pediatric surgical population is unknown. Anemia may be associated with increased postoperative complications. We are unaware of studies documenting these findings in patients in low- and middle-income countries (LMICs). The primary aim of this study was to describe the association between preoperative anemia and 26 defined postoperative complications, in noncardiac pediatric surgical patients. Secondary aims included describing the prevalence of anemia and risk factors for intraoperative blood transfusion. This was a secondary analysis of the South African Paediatric Surgical Outcomes Study, a prospective, observational surgical outcomes study. Inclusion criteria were all consecutive patients aged between 6 months and <16 years, presenting to participating centers during the study period who underwent elective and nonelective noncardiac surgery and had a preoperative hemoglobin recorded. Exclusion criteria were patients aged <6 months, undergoing cardiac surgery, or without a preoperative Hb recorded. To determine whether an independent association existed between preoperative anemia and postoperative complications, a hierarchical stepwise logistic regression was conducted. There were 1094 eligible patients. In children in whom a preoperative Hb was recorded 46.2% had preoperative anemia. Preoperative anemia was independently associated with an increased risk of any postoperative complication (odds ratio 2.0, 95% confidence interval: 1.3-3.1, P = .002). Preoperative anemia (odds ratio 3.6, 95% confidence interval: 1.8-7.1, P < .001) was an independent predictor of intraoperative blood transfusion. Preoperative anemia had a high prevalence in a LMIC and was associated with increased postoperative complications. The main limitation of our study is the ability to generalize the results to the wider pediatric surgical population, as these findings only relate to children in whom a preoperative Hb was recorded. Prospective studies are required to determine whether correction of preoperative anemia reduces morbidity and mortality in children undergoing noncardiac surgery.


Susceptibility difference between methicillin-susceptible and methicillin-resistant Staphylococcus aureus to a bovine myeloid antimicrobial peptide (BMAP-28).
A bovine myeloid antimicrobial peptide antimicrobial peptide (BMAP-28) is a member of the cathelicidin family and acts as a component of innate immunity. There are few reports of susceptibility difference of methicillin-resistant Staphylococcus aureus (MRSA) and susceptible strains (MSSA) against BMAP-28. This study aims to clarify how a few amino acid substitutions of BMAP-28 are related to its antimicrobial activity using four analog peptides of BMAP-28. We also compared cellular fatty acid components of MSSA and MRSA using gas chromatography. We found that a few amino acid substitutions of BMAP-28 do not change antimicrobial activity. It was also revealed that the percentage of cis-11-eicosenoic acid in total detected fatty acids of MRSA was significantly higher than that of MSSA. In addition, the percentage of palmitic acid in total detected fatty acids of MRSA tended to be lower than that of MSSA. Our results will provide new information to deal with the question of differences in bacterial susceptibility against BMAP-28.


[Abuse of "pheticol" and its interference to the analysis of methamphetamine].
The study was to eliminate interference from ephedrine in the analysis of methamphetamine. The extraction procedure for methamphetamine was modified to include an oxidation step (2 ml urine specimen was treated with 0.5 ml of 1 mol/L phosphate buffer (pH 6.8) and 0.5 ml 0.3 mol/L sodium periodate). Results showed that ephedrine could be oxidized in the presence of periodate ions into smaller fragments while leaving methamphetamine intact. It is recommended that specimens be treated with sodium periodate prior to extraction in order to eliminate any interference caused by ephedrine.


The Discontinuation Rate With Collagenase Clostridium histolyticum for Peyronie's Disease in a High-volume Practice Is Unexpectedly High: Identifying Opportunities for Patient Care Improvement.
To elucidate reasons for premature discontinuation of Collagenase Clostridium histolyticum (CCH) injections for the treatment of penile curvature associated with Peyronie's disease. A database of men who underwent CCH injections at a single institution was queried to identify men who completed fewer than 8 injections. Chart review was conducted to identify reasons for treatment discontinuation. When this could not be identified, patients were contacted first via the online patient portal and next by phone. Of 406 patients who underwent CCH treatment, 133 did not complete 8 injections (32.8%). The most common reasons for discontinuation were satisfactory curve reduction (27%), unsatisfactory curve reduction (21%), bothersome side effect (15%), and pursuit of surgery (12%). Other less common reasons included other health concerns, pausing treatment due to the COVID-19 pandemic, high cost, transferring care elsewhere, and lack of awareness that more injections were indicated. We present the largest series of patients to date dedicated to evaluation of CCH discontinuation. We find that up to 1/3 of patients who begin CCH injections will not complete the full treatment course. Understanding the reasons for discontinuation can help providers better stratify patients for CCH treatment vs other modalities. In addition, as previous studies indicate curvature improvements are equally likely to be seen in the final four injections as the first four, our data points to the potential impact of improved patient education for individuals who discontinue due to unsatisfactory curve reduction.


Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women.
The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (> or =5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 x 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer.


Mechanisms of action of 17βH-neriifolin on its anticancer effect in SKOV-3 ovarian cancer cell line.
Abnormalities in apoptotic signalling pathways often occur in cancer cells and limit the successful chemotherapy outcomes in cancers. Therefore, there is an urgent need to discover new anticancer agents with novel mechanisms of action to overcome the resistance effect in chemotherapy. In the present study, the anticancer effects and the mechanisms of action of 17βH-neriifolin (cardiac glycoside) were evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and a proteomic approach in treated and non-treated SKOV-3 ovarian cancer cells. 17βH-neriifolin was found to be active with IC50 values of 0.01 ± 0.001 in SKOV-3 ovarian cancer cell line, as evaluated by the sulforhodamine B (SRB) assay. RESULTS from TUNEL assay indicated that 17βH-neriifolin caused apoptosis in SKOV-3 cells in a dose-dependent manner. Based on differential analysis of treated and non-treated SKOV-3 two-dimensional electrophoresis (2-DE) profiles, four proteins, namely vimentin (VIM), pyruvate kinase, muscle (PKM), heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and transgelin (TAGLN1) were identified to be involved in apoptosis. Other proteins including piggybac transposable element derived 5 (PGBD5), DENN/MADD domain containing 2D (DENND2D) and formin-like 1(FMNL) have also been identified to be associated in SKOV-3 cell death induced by 17βH-neriifolin. These findings may provide new insights on the potential of 17βH-neriifolin's mechanism of action in killing ovarian cancer cells.


Fibroblast selection in scleroderma. An alternative model of fibrosis.
Human preputial skin fibroblasts were cloned in vitro, and studies in 21 clones were shown to exhibit a 3-fold difference in collagen synthesis; this heterogeneity of phenotypic expression was conserved over multiple population doublings. When the clones were exposed to sera from 10 scleroderma patients, selective growth of high-collagen-producing fibroblasts was observed. Prostaglandin E2 abrogated the selective effect of scleroderma serum on high-collagen-producing fibroblast clones. Besides enhanced collagen synthesis, these clones of normal fibroblasts shared an insensitivity to feeding schedule with fibroblasts from scleroderma skin. These data raise the possibility that scleroderma represents a process of selection of fibroblasts programmed to produce increased amounts of collagen.


Clinical Impact of Exosomes in Colorectal Cancer Metastasis.
Cancer is a complex deadly disease that has caused a global health crisis in recent epochs. Colorectal cancer (CRC) is the third most common malignant gastrointestinal disease. It has led to high mortality due to early diagnostic failure. Extracellular vesicles (EVs) come with promising solutions for CRC. Exosomes (a subpopulation of EVs) play a vital role as signaling molecules in CRC tumor microenvironment. It is secreted from all active cells. Exosome-based molecular transport (DNA, RNA, proteins, lipids, etc.) transforms the recipient cell's nature. In CRC, tumor cell-derived exosomes (TEXs) regulate multiple events of CRC development and progression such as immunogenic suppression, angiogenesis, epithelial-mesenchymal transitions (EMT), physical changes in the extracellular matrix (ECM), and metastasis. Biofluid-circulated tumor-derived exosomes (TEXs) are a potential tool for CRC liquid biopsy. Exosome-based colorectal cancer detection creates a great impact in CRC biomarker research. The exosome-associated CRC theranostics approach is a state-of-the-art method. In this review, we address the CRC and exosomes complex associated with cancer development and progression, the impact of exosomes on CRC screening (diagnostic and prognostic biomarkers), and also highlight several exosomes with CRC clinical trials, as well as future directions of exosome-based CRC research. Hopefully, it will encourage several researchers to develop a potential exosome-based theranostic tool to fight CRC.


Assessment of the effect of laser irradiations at different wavelengths (660, 810, 980, and 1064 nm) on autophagy in a rat model of mucositis.
It is known that high-dose radiation has an effect on tissue healing, but tissue healing does not occur when low dose radiation is applied. To clarify this issue, we compare the treatment success of low dose radiation with programmed cell death mechanisms on wounded tissue. In this study, we aimed to investigate the interactions of low and high-dose radiation using an autophagic mechanism. We included 35 adult Wistar-Albino rats in this study. All animals were injected with 100 mg/kg of 5-fluorouracil (5-FU) on the first day and 65 mg/kg of 5-FU on the third day. The tips of 18-gauge needles were used to develop a superficial scratching on the left cheek pouch mucosa by dragging in a linear movement on third and fifth days. After mucositis formation was clinically detected, animals were divided into five groups (n = 7). Different wavelengths of laser irradiations (1064 nm, Fidelis Plus, Fotona, Slovenia; 980 nm, FOX laser, A.R.C., Germany; 810 nm, Fotona XD, Fotona, Slovenia; 660 nm, HELBO, Medizintechnik GmbH, Wels, Austria) were performed on four groups once daily for 4 days. The laser irradiation was not performed on the control group. To get the tissue from the left cheek at the end of fourth day from all animals, oval excisional biopsy was performed. Molecular analysis assessments of pathological and normal tissue taken were performed. For this purpose, the expression analysis of autophagy genes was performed. The results were evaluated by normalization and statistics analysis. We found that Ulk1, Beclin1, and Atg5 expression levels were increased in the rats when the Nd:YAG laser was applied. This increase showed that a 1064-nm laser is needed to activate the autophagic mechanism. However, in the diode applications, we found that Beclin1, Atg10, Atg5, and Atg7 expressions numerically decreased. Atg5 is responsible for the elongation of autophagosome. Becn1 is a control gene in the control mechanism of autophagy. The reduction of the expression of these genes leads us to think that it may depend on the effect of drug (5-FU) used to form model. Expressions of therapeutic genes increase to ensure hemostasis, but in our study, expressions were found to decrease. More detailed studies are needed.


Remifentanil in Combination With Propofol Is Suitable for Use in the Dental Outpatient Setting.
Although several adjuncts to the general anesthetic propofol have been proposed, there is insufficient research identifying the ideal agent, and in what dosage, to combine with propofol in dental outpatient anesthesia. Here we examined the combination of remifentanil or nitrous oxide and propofol in patients with severe dental avoidance undergoing dental treatment in the outpatient setting. Eighty patients were randomized to 4 groups and administered propofol/saline solution (PS; n = 20), propofol/remifentanil 0.25 μg/kg/min (PRe-0.25; n = 20), propofol/remifentanil 0.125 μg/kg/min (PRe-0.125; n = 20), or propofol/66% nitrous oxide (PN; n = 20). During anesthesia, the bispectral index value was kept between 40 and 60. Body movements and hemodynamic changes during anesthesia, emergence, and recovery as well as anesthetic cost were compared between the combinations. Body movements were observed in all patients administered PS but in no patients administered PRe-0.25, PRe-0.125, or PN. Postoperative nausea was observed in 5 patients (25%) administered PRe-0.25 and in 1 patient (5%) administered PN. Although both PRe-0.125 and PN were useful clinically, PRe-0.125 was the least expensive combination.


The morphological phenomenon of paravascular reorganization of nerve conductors.
The work is devoted to the study of a peculiar morphological phenomenon called paravascular reorganization of nerve conductors. In its most general form this phenomenon takes the form of a flattening and an enlargement of the nerve bundles which surround the vessel in the zones of their paravascular localization. The nerve fibres undergo a number of morphological changes, the most characteristic of which are: proliferation of Schwann elements, foci of "demyelinization", varicose swelling of axons, mesh-like formations in the axis-cylinders. These changes are seen mainly in the myelinated fibres of afferent origin. The unmyelinated vegetative fibres remain unchanged in the zones of paravascular localization. The phenomenon of paravascular reorganization of the nerve conductors is of wide-spread occurrence in mammals and humans. It is found most often in flat organs and tissues whose thinness results in contiguity of blood-supplying vessels and nerve conductors. The role of vascular mobility as factor in the morphological reorganization of nerve conductors at their points of intersection and contact within the vascular walls is discussed.


Applied aspects of neonicotinoid uses in crop protection.
Neonicotinoid insecticides comprise seven commercially marketed active ingredients: imidacloprid, acetamiprid, nitenpyram, thiamethoxam, thiacloprid, clothianidin and dinotefuran. The technical profiles and main differences between neonicotinoid insecticides, including their spectrum of efficacy, are described: use for vector control, systemic properties and versatile application forms, especially seed treatment. New formulations have been developed to optimize the bioavailability of neonicotinoids through improved rain fastness, better retention and spreading of the spray deposit on the leaf surface, combined with higher leaf penetration. Combined formulations with pyrethroids and other insecticides are also being developed with the aim of broadening the insecticidal spectrum of neonicotinoids and to replace WHO Class I products from older chemical classes. These innovative developments for life-cycle management, jointly with the introduction of generic products, will, within the next few years, turn neonicotinoids into the most important chemical class in crop protection.


Early onset anorexia nervosa.
This paper describes 48 children, aged 14 years or less, who met diagnostic criteria for anorexia nervosa modified from Morgan and Russell. The characteristics of the sample (13 boys and 35 girls) are described along with features of the illness, associated family characteristics, treatment in hospital, and a brief description of treatment. Difficulties in diagnosis are addressed, with reference in particular to the high incidence of depression in this group. Finally, the importance and difficulty of close paediatric/psychiatric liaison in diagnosis and treatment is emphasised.


Association between pregnancy affected by vaginal bleeding and women's mortality: A cohort study.
To investigate the association between vaginal bleeding (VB) in pregnancy and women's mortality, using VB-unaffected pregnancies, terminations and miscarriages as comparators. Observational cohort study. Nationwide registries of Denmark linked at an individual level. 1 354 181 women and their 3 162 317 pregnancies (1979-2017), including 70 835 VB-affected pregnancies and comparators: 2 236 359 VB-unaffected pregnancies ending in childbirth; 589 697 terminations; and 265 426 miscarriages. We followed pregnancies until the earliest date of woman's death, emigration or end of data. All-cause and cause-specific mortality rates per 10 000 person-years (PY) and hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted using Cox proportional hazards regression for age, calendar year, pre-existing chronic conditions and socio-economic factors. There were 2320 deaths from any cause among women following VB-affected pregnancy (mortality rate 15.2, 95% CI 14.6-15.9 per 10 000 PY); 55 030 deaths following VB-unaffected pregnancy (mortality rate 12.7, 95% CI 12.6-12.8); 27 500 deaths following a termination (mortality rate 21.9, 95% CI 21.6-22.1), and 10 865 deaths following a miscarriage (mortality rate 19.2, 95% CI 18.8-19.6). For comparison of VB-affected versus VB-unaffected pregnancies, associations with all-cause (HR 1.14, 95% CI 1.09-1.19), natural causes (HR 1.15, 95% CI 1.09-1.22) and non-natural causes (HR 1.27, 95% CI 1.08-1.48) mortality were attenuated in a sensitivity analysis of pregnancies recorded in 1994-2017 (HR 1.00, 95% CI 0.90-1.12, HR 0.98, 95% CI 0.85-1.14 and HR 1.04, 95% CI 0.72-1.51, respectively). Contrasts with remaining comparators did not suggest increased risks of all-cause, natural or non-natural mortality causes. We found no evidence of an increased risk of women's mortality following VB-affected versus VB-unaffected pregnancy, termination or miscarriage.


Eriobotrya japonica improves hyperlipidemia and reverses insulin resistance in high-fat-fed mice.
The effect of Eriobotrya japonica Lindl. (loquat) on insulin resistance was examined in mice fed a high-fat (HF) diet. First, the mice were divided randomly into two groups: the control (CON) group was fed a low-fat diet, whereas the experimental group was fed with a 45% HF diet for 10 weeks. After 6 weeks of induction, the HF group was subdivided into five groups and was given orally loquat or not for 4 weeks afterward. It was demonstrated that loquat was effective in ameliorating the HF diet-induced hyperglycemia, hyperleptinemia, hyperinsulinemia and hypertriglyceridemia, as well as in decreasing the levels of free fatty acid (FFA), but increasing the adipose PPARγ (peroxisomal proliferator-activated receptor γ) and hepatic PPARα mRNA levels. Loquat significantly decreased the body weight gain, weights of white adipose tissue and visceral fat accompanying the suppressed leptin mRNA levels. Loquat not only suppressed the hepatic mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1c (SREBP-1c) mRNA level, but also affected fatty acid oxidation enzyme levels. These regulations may contribute to triacylglycerol accumulation in white adipose tissue. The findings provide a nutritional basis for the use of loquat as a functional food factor that may have benefits for the prevention of hyperlipidemia and diabetes.


Endocytic membrane fusion and buckling-induced microtubule severing mediate cell abscission.
Cytokinesis and abscission are complicated events that involve changes in membrane transport and cytoskeleton organization. We have used the combination of time-lapse microscopy and correlative high-resolution 3D tomography to analyze the regulation and spatio-temporal remodeling of endosomes and microtubules during abscission. We show that abscission is driven by the formation of a secondary ingression within the intracellular bridge connecting two daughter cells. The initiation and expansion of this secondary ingression requires recycling endosome fusion with the furrow plasma membrane and nested central spindle microtubule severing. These changes in endosome fusion and microtubule reorganization result in increased intracellular bridge plasma membrane dynamics and abscission. Finally, we show that central spindle microtubule reorganization is driven by localized microtubule buckling and breaking, rather than by spastin-dependent severing. Our results provide a new mechanism for mediation and regulation of the abscission step of cytokinesis.


COVID-Classifier: an automated machine learning model to assist in the diagnosis of COVID-19 infection in chest X-ray images.
Chest-X ray (CXR) radiography can be used as a first-line triage process for non-COVID-19 patients with pneumonia. However, the similarity between features of CXR images of COVID-19 and pneumonia caused by other infections makes the differential diagnosis by radiologists challenging. We hypothesized that machine learning-based classifiers can reliably distinguish the CXR images of COVID-19 patients from other forms of pneumonia. We used a dimensionality reduction method to generate a set of optimal features of CXR images to build an efficient machine learning classifier that can distinguish COVID-19 cases from non-COVID-19 cases with high accuracy and sensitivity. By using global features of the whole CXR images, we successfully implemented our classifier using a relatively small dataset of CXR images. We propose that our COVID-Classifier can be used in conjunction with other tests for optimal allocation of hospital resources by rapid triage of non-COVID-19 cases.


Identification, properties and effect of hormones on rat preputial gland peroxidase.
A highly active soluble peroxidase has been identified in the preputial glands of the rat. The enzyme was detectable in the sebaceous secretion of the glands and showed catalytic properties characteristic of true peroxidase. It had a native molecular weight of around 73,000 as determined by gel-permeation studies. Immunologically the enzyme cross-reacted with an antiserum against bovine lactoperoxidase. Administration of progesterone resulted in a significant increase in the total activity of the enzyme, while testosterone and oestradiol had no such effect. The enzyme had a similar molecular weight and similar catalytic and immunological properties to rat uterine fluid peroxidase but differed markedly in respect to sensitivity to oestradiol.


Second-order phase transition in causal dynamical triangulations.
Causal dynamical triangulations are a concrete attempt to define a nonperturbative path integral for quantum gravity. We present strong evidence that the lattice theory has a second-order phase transition line, which can potentially be used to define a continuum limit in the conventional sense of nongravitational lattice theories.


Dietary protein and sugar differentially affect development and metabolic pools in ecologically diverse Drosophila.
We examined the effects of 3 diets differing in their relative levels of sugar and protein on development and metabolic pools (protein, TG, and glycogen) among sets of isofemale lines of 2 ecologically distinct Drosophila species, D. melanogaster and D. mojavensis. Our high protein:sugar ratio diet contained 7.1% protein and 17.9% carbohydrate, the EPS diet was 4.3% protein and 21.2% carbohydrate, and the LPS was only 2.5% protein and 24.6% carbohydrate. Larvae of D. melanogaster, a generalist fruit breeder, were able to survive on all 3 diets, although all 3 metabolic pools responded with significant diet and diet × line interactions. Development was delayed by the diet with the most sugar relative to protein. The other species, D. mojavensis, a cactus breeder ecologically unaccustomed to encountering simple sugars, completely failed to survive when fed the diet with the highest sugar and showed very poor survival even with the diet with equal parts of protein and sugar. Furthermore, the D. mojavensis adult metabolic pools of protein, TG, and glycogen significantly differed from those of D. melanogaster adults fed the identical diet. Thus, considerable within- and between-species differences exist in how diets are metabolized. Given that the genomes of both of these Drosophila species have been sequenced, these differences and their genetic underpinnings hold promise for understanding human responses to nutrition and for developing strategies for dealing with metabolic disease.


Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C.
Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg-1 day-1) and pair-fed]. Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.


A cell line that supports the growth of a defective early region 4 deletion mutant of human adenovirus type 2.
Cell lines that produce viral gene products and that can support the growth of viral mutants lacking those products have been valuable in the genetic analysis of the transforming regions of several animal viruses. To extend the advantages of such complementing cell systems to regions of the adenoviral genome not directly involved in transformation, we have constructed a cell line that will support the growth of a defective adenoviral deletion mutant, H2dl808, that lacks most of early region 4 (E4). The right-hand terminal adenovirus 5 EcoRI restriction fragment, which contains all of E4, was first inserted into the vector pSV2gpt, and the recombinant plasmid was introduced into Vero cells by calcium phosphate precipitation. Clones containing the hybrid plasmid were selected by their resistance to mycophenolic acid. Five mycophenolic acid-resistant clones were then tested for the ability to support the growth of H2dl808. One of the five lines, W162, permits plaque formation by H2dl808 at an efficiency that is greater than 10(6)-fold higher than that of the parental Vero cells and allows the production of high-titer, helper-free H2dl808 stocks. Thus, W162 cells are permissive for at least one defective E4 mutant. The line carries, as expected, an intact E4, detected by hybridization. Using an H2dl808 lysate produced on W162 cells, we have accurately mapped the 808 deletion. It extends from between BclI and SmaI sites at positions 91.4 and 92.0, respectively, to just beyond a HindIII site at position 97.2 and, therefore, falls entirely within E4. H2dl808 and W162 should be of value in determining the physiological role of E4 in adenoviral infection.


ANF therapy® for pain management, feasibility, satisfaction, perceived symptom reduction and side effects: a real-world multisite observational study.
[Purpose] Non-invasive and drug-free interventions for pain are being developed. One of them is ANF (which stands for "Amino Neuro Frequency") Therapy®, which consists in the application of carbonized metal devices on a patient's skin. We aimed to: 1) test perceived changes in pain intensity after ANF application, 2) record frequency and severity of side effects, 3) assess clinician and patient satisfaction, 4) explore effects on swelling and range of motion (ROM). [Participants and Methods] In this real-world multisite observational study, N=113 physical therapists in 45 countries, applied ANF to N=1,054 patients (Mage=45.2, 56.2% female) with pain complaints. Demographic data, pain intensity (NRS-11), effects of ANF on swelling and ROM, clinician and patient satisfaction and side effects were collected. [Results] Main pain locations were: low back (14.9%), knee (12.4%), neck (10%), and shoulder (9.6%). Pre-treatment pain intensity was high (Mean=7.6, SD=1.9). It significantly decreased post-treatment (Mean=3.1, SD=2.0), t(1053)=7.25, with a large effect size (Cohen's d=2.2). Swelling decreased and ROM increased. Average satisfaction with ANF was 92/100. Patients often experienced mild side effects (42.3%): dry mouth, headache and fatigue. [Conclusion] Results show large effect sizes, high satisfaction, and mild and short-term side effects. This is very promising but should be interpreted with caution considering the study limitations.


Gender differences in human interpersonal conflicts: A reply to Ingram et al. (2012).
In the article, I comment on the study results of Ingram et al. (2012). Feelings of anger were hypothesized to be reported more often in the descriptions of past conflicts of boys than in the descriptions of past conflicts of girls. However, the authors found that boys were no more likely than girls to describe feelings of anger ensuing from a conflict. An explanation of this interesting finding is not provided in the discussion section. The present study provides possible theoretical explanations for this finding, also using the results of our studies published in the past.


Testing time-, ignorance-, and danger-based models of tolerance.
In this study, we present data showing that tolerance to Ags in the periphery is not determined by the time at which the Ag appears, or by special properties of tissues in newborn mice or newly developing immune systems. We placed male grafts onto immunoincompetent female mice, allowed the grafts to heal for up to 5 mo, and then repopulated the recipients with fetal liver stem cells. We found that the newly arising T cells were neither tolerant nor ignorant of the grafts, but promptly rejected them, though they did not reject female grafts, nor show any signs of autoimmunity. We also found that the H-Y Ag was continuously cross-presented on host APCs, that this presentation was immunogenic, not tolerogenic, and that it depended on the continuous presence of the graft. In searching for the stimulus that might activate the host APCs, we analyzed mRNA expression with a highly sensitive real-time quantitative PCR assay. By using two different "housekeeping" molecules for comparison, we analyzed the message levels for several stress and/or inflammatory molecules in the healed grafts. We found that the long-healed grafts were not equivalent to "normal" skin because the healed grafts expressed lower levels of GAPDH. Altogether, these data suggest that acceptance vs rejection of peripheral tissues is not attributable to ignorance, timing-based tolerance, or special circulation properties of naive T cells in neonatal tissues. It is more likely attributable to an aspect of the context of Ag presentation that remains to be identified.


Functionalized PDMS with Versatile and Scalable Surface Roughness Gradients for Cell Culture.
This manuscript describes a simple and versatile approach to engineering surface roughness gradients via combination of microfluidics and photopolymerization. Through UV-mediated polymerization, N-isopropylacrylamide with concentration gradients are successfully grafted onto PDMS surface, leading to diverse roughness degrees on the obtained PDMS substrate. Furthermore, the extent of surface roughness can be controllably regulated via tuning the flow rate ratio between the monomer solution and deionized water. Average roughness ranging from 2.6±0.7 nm to 163.6±11.7 nm has been well-achieved in this work. Such PDMS samples are also demonstrated to be capable of working as supporting substrates for controlling cell adhesion or detachment. Because of the different degrees of surface roughness on a single substrate, our method provides an effective approach for designing advanced surfaces for cell culture. Finally, the thermosensitive property of N-isopropylacrylamide makes our sample furnish as another means for controlling the cell detachment from the substrates with correspondence to the surrounding temperature.


Effect of recommendations from reviewers suggested or excluded by authors.
The Journal of the American Society of Nephrology (JASN) gives authors submitting original research the option of suggesting qualified reviewers or those they wish to exclude. This historical habit often leaves us wondering whether author preferences correlate with reviewer recommendations and whether differences related to reviewer selection affect decisions by editors. In a self-study presented here, we found that author-suggested reviewers, as a group, make more positive recommendations than editor-suggested reviewers (P = 0.01), although the difference disappears when recommendations are compared with those of editor-suggested reviewers of the same manuscript (P = 0.081). The distribution of recommendations by author-excluded reviewers, as a group, did not differ from those by editor-suggested reviewers; however, author-excluded reviewers impart significantly more negative recommendations than other reviewers of the same manuscript (P = 0.029). We further explored whether such differences result from individual reviewer tendencies to give generally more positive or more negative recommendations than editor-suggested reviewers and found no such tendency. Finally, editorial decisions on manuscripts reviewed by author-suggested or author-excluded reviewers do not differ from those decisions on manuscripts assigned but not reviewed by them. JASN's policy of editors making decisions independent from individual reviewer recommendations minimizes the effect of selection bias on publication decisions.


Conjoined Free Fibula Transplantation and First Carpometacarpal Joint Prosthesis for Functional Thumb Reconstruction-A Case Report.
Giant cell tumors grow locally invasive with osseous and soft tissue destruction, requiring wide resection to avoid recurrence. Stable reconstruction of the first carpometacarpal (CMC-1) joint remains a challenge due to its high range of mobility. The latter is of paramount for the functionality of the hand. Therefore, the aim of this study was to report our approach for a combined reconstruction of the first metacarpal and the CMC-1 joint. A 58-year-old woman underwent wide resection of a benign giant cell tumor at the base and shaft of the first metacarpal of the left thumb. Because of the loss of the CMC-1 joint and the instability of the thumb, an osseous reconstruction using a vascularized fibular graft combined with a TOUCH Dual Mobility CMC-1 prosthesis was performed to reconstruct the CMC-1 joint. Osseous healing was observed after 3 months. No tumor recurrence and good joint function were documented at the follow-up investigation after 1 year. The patient reported only minor restrictions during activities of daily living. Thumb opposition was possible with a Kapandji score of 8/10. A slight pain while walking remained as a donor-side morbidity at the right lower leg. Metacarpal reconstruction with vascularized fibula bone grafts allowed a combined joint reconstruction with a commercially available prosthesis, which is an approach to restore the complex range of motion of the thumb.


Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review.
Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.


The lncRNA expression profile signature of leukemia stem cells is altered upon PI3K/mTOR inhibition: an in vitro and in silico study.
Genetic and/or epigenetic alterations in hematopoietic stem cells (HSCs) contribute to leukemia stem cell (LSC) formation. We aimed to identify alterations in the lncRNA expression profile signature of LSCs upon inhibition of PI3K/Akt/mTOR signaling, which provides selective advantages to LSCs. We also aimed to elucidate the potential interaction networks and functions of differentially expressed lncRNAs (DELs). We suppressed PI3K/Akt/mTOR signaling in LSC and HSC cell-lines by specific PI3K/mTOR dual-inhibitor (VS-5584) and confirmed the inhibition by antibody-array. We defined DELs by qRT-PCR. Increased SRA, ZEB2-AS1, antiPeg11, DLX6-AS, SNHG4, and decreased H19, PCGEM1, CAR-Intergenic-10, L1PA16, IGF2AS, and SNHG5 levels (|log2fold-change|>5) were strictly associated with PI3K/Akt/mTOR pathway inhibition in LSC. We performed in silico analyses for DELs. ZEB2-AS1 was found to be specifically expressed in normal bone marrow and predominantly lower in leukemic cell-lines. Three sub-clusters were identified for DELs and they were associated with "abnormality of multiple cell lineages in the bone marrow." DELs were most highly enriched for "glucuronidation" Reactome pathway and "ascorbate and aldarate metabolism" and "inositol phosphate metabolism" KEGG pathways. Transcription factors, MBD4, NANOG, PAX6, RELA, CEBPB, and CEBPA were predicted to be associated with the DEL profile. SRA was predicted to interact with CREB1, RARA, and PPARA. The possible DELs' targets were predicted to form six ontological groups, be highly enriched for phosphoprotein, and be involved in "PPAR signaling pathway" and "ChREBP regulation by carbohydrates and cAMP." These results will help to elucidate the roles of lncRNAs in the mechanisms that provide selective advantages to leukemia stem cells.


[Use of quantitative immunofluorescence for determining the adsorption capacity of magnetic immunosorbents].
The adsorption capacity of microgranulated polyacrylamide magnetic immunosorbents has been studied by the method of quantitative immunofluorescence as applied to the causative agents of plague, cholera, and melioidosis. Similar regularity in the dynamics of antigen adsorption on the granules of magnetic immunoadsorbents has been established. This regularity consists in the direct relationship between this process and the concentration of infective agents interacting with magnetic sorbents.