[Toxicity of targeted therapies and immunotherapy with checkpointinhibitors in Hodgkin lymphoma].
TOXICITY OF TARGETED THERAPIES AND IMMUNOTHERAPY WITH CHECKPOINT INHIBITORS IN HODGKIN LYMPHOMA. In patients at increased risk of recurrence or progression after autotransplantation, or in cases of relapse after autotransplantation or after at least two lines of treatment when intensive multidrug therapy is no longer a treatment option, targeted anti-CD30 therapy with brentuximab vedotin may be proposed. Brentuximab vedotin is a monoclonal antibody directed against CD30 and coupled with an anti-microtubule cytotoxic agent, monomethyl auristatin E (MMAE). The main adverse side effect of brentuximab vedotin is peripheral neuropathy. In patients who have relapsed after intensive chemotherapy, including autograft for patients eligible for this treatment, and after failure of brentuximab vedotin, anti-PD1 immunotherapy (nivolumab or pembrolizumab) may be offered. Anti-PD1 (Programmed cell death protein 1) side effects are immune-related, varied and unpredictable (endocrinopathies, rash, colitis, interstitial lung disease). The tolerability profiles of brentuximab vedotin and anti-PD1 and the management of the main undesirable side effects of these treatments are detailed for clinical practice.


Ecological Meanings: A Consensus Paper on Individual Differences and Contextual Influences in Embodied Language.
Embodied theories of cognition consider many aspects of language and other cognitive domains as the result of sensory and motor processes. In this view, the appraisal and the use of concepts are based on mechanisms of simulation grounded on prior sensorimotor experiences. Even though these theories continue receiving attention and support, increasing evidence indicates the need to consider the flexible nature of the simulation process, and to accordingly refine embodied accounts. In this consensus paper, we discuss two potential sources of variability in experimental studies on embodiment of language: individual differences and context. Specifically, we show how factors contributing to individual differences may explain inconsistent findings in embodied language phenomena. These factors include sensorimotor or cultural experiences, imagery, context-related factors, and cognitive strategies. We also analyze the different contextual modulations, from single words to sentences and narratives, as well as the top-down and bottom-up influences. Similarly, we review recent efforts to include cultural and language diversity, aging, neurodegenerative diseases, and brain disorders, as well as bilingual evidence into the embodiment framework. We address the importance of considering individual differences and context in clinical studies to drive translational research more efficiently, and we indicate recommendations on how to correctly address these issues in future research. Systematically investigating individual differences and context may contribute to understanding the dynamic nature of simulation in language processes, refining embodied theories of cognition, and ultimately filling the gap between cognition in artificial experimental settings and cognition in the wild (i.e., in everyday life).


[Brazilian nursing leaders -- their view about leadership issues and their perception of the nursing-leadership relationship].
Fourteen Brazilian nurses singled out for their leadership skills were asked about their view on leadership issues and about their perceptions of the relationship between nursing and leadership. The analysis of the data provided by the professionals showed that the interviewed leaders had a clear-cut view of these issues and of their important role in the nursing profession. They understood leadership as a group process through which people or behaviors are influenced. Such a process is carried out aiming to reach a goal. They also realized a close relationship between leadership and nursing.


A Paper-Based Sandwich Format Hybridization Assay for Unlabeled Nucleic Acid Detection Using Upconversion Nanoparticles as Energy Donors in Luminescence Resonance Energy Transfer.
Bioassays based on cellulose paper substrates are gaining increasing popularity for the development of field portable and low-cost diagnostic applications. Herein, we report a paper-based nucleic acid hybridization assay using immobilized upconversion nanoparticles (UCNPs) as donors in luminescence resonance energy transfer (LRET). UCNPs with intense green emission served as donors with Cy3 dye as the acceptor. The avidin functionalized UCNPs were immobilized on cellulose paper and subsequently bioconjugated to biotinylated oligonucleotide probes. Introduction of unlabeled oligonucleotide targets resulted in a formation of probe-target duplexes. A subsequent hybridization of Cy3 labeled reporter with the remaining single stranded portion of target brought the Cy3 dye in close proximity to the UCNPs to trigger a LRET-sensitized emission from the acceptor dye. The hybridization assays provided a limit of detection (LOD) of 146.0 fmol and exhibited selectivity for one base pair mismatch discrimination. The assay was functional even in undiluted serum samples. This work embodies important progress in developing DNA hybridization assays on paper. Detection of unlabeled targets is achieved using UCNPs as LRET donors, with minimization of background signal from paper substrates owing to the implementation of low energy near-infrared (NIR) excitation.


Intramucosal gastric cancer with fifteen metastatic lymph nodes: report of a case.
This report describes very rare intramucosal gastric cancer with metastasis to 15 lymph nodes. A 65-year-old Japanese man was admitted to our hospital with epigastralgia. Endoscopic examination revealed a 3.5 cm type IIc ulcerated lesion on the posterior wall near the lesser curvature of the angle of the stomach with mucosal tumor invasion. Neither enlarged lymph nodes nor distant metastasis was revealed by abdominal computer tomography. He was treated by pylorus-preserving gastrectomy with lymph node dissection. A histological examination of biopsy specimens revealed signet-ring cell carcinoma with ulcer scar that was limited to the mucosal layer. Although lymphatic vessel invasion was not evident, 15 of 23 retrieved nodes were actually involved. The final diagnosis was stage II gastric cancer, designated T1N2M0 according to the Japanese classification of gastric carcinoma. Twelve months after surgery, the patient remains alive without recurrence.


Structural and electronic analysis of lanthanide complexes: reactivity may not necessarily be independent of the identity of the lanthanide atom--a DFT study.
Density functional theory calculations were used to study a given complex for the whole series of lanthanide cations: [Ln(C3H5)Cp(OMe)] (1) [Ln = La (Z = 57)-Lu (Z = 71)], the radioactive lanthanide promethium (Z = 61) excepted. Contrary to the common assumptions, the calculations suggested a significant, albeit indirect, contribution of f electrons to bonding. Relativistic effects were considered in the calculations of the bonding energies, as well as in geometry optimizations in both spin-restricted and unrestricted formalisms. The unrestricted orbitals were finally used for the analysis of the charges and the composition of the frontier orbitals. It was confirmed that the ionic character was more pronounced for complexes of the late lanthanides.


Post-transcriptional control by RNA-binding proteins in diabetes and its related complications.
Diabetes mellitus (DM) is a fast-growing chronic metabolic disorder that leads to significant health, social, and economic problems worldwide. Chronic hyperglycemia caused by DM leads to multiple devastating complications, including macrovascular complications and microvascular complications, such as diabetic cardiovascular disease, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. Numerous studies provide growing evidence that aberrant expression of and mutations in RNA-binding proteins (RBPs) genes are linked to the pathogenesis of diabetes and associated complications. RBPs are involved in RNA processing and metabolism by directing a variety of post-transcriptional events, such as alternative splicing, stability, localization, and translation, all of which have a significant impact on RNA fate, altering their function. Here, we purposed to summarize the current progression and underlying regulatory mechanisms of RBPs in the progression of diabetes and its complications. We expected that this review will open the door for RBPs and their RNA networks as novel therapeutic targets for diabetes and its related complications.


IL-2 enhanced MHC class I expression in papillary thyroid cancer with Hashimoto's thyroiditis overcomes immune escape in vitro.
The impact of Hashimoto's thyroiditis (HT) on the progression of papillary thyroid cancer (PTC) is still unclear. Interleukin-2 (IL-2) is a growth factor and crucial for HT development. This study aimed at investigating the effect of IL-2 on MHC class I expression in PTC cells and immune activation with experimental treatment for PTC using PTC cell lines. We assessed the expression of IL-2, HLA class I, PD-L1, CD3, CD8 and CD16 molecules in paired PTC tissues and HLA-ABC and PD-L1 expression in IL-2 pre-treated K1, TPC-1 and BCPAP cells by immunohistochemistry, qPCR, flow cytometry and Western blotting. The effect of IL-2 on immunogenicity of PTC cells to stimulate activated human T cells was determined for the percentages of activated CD8+ T cells and their cytokine production as well as PD-1 and PD-L1 expression. Compared with non-tumor tissues, we found that IL-2 expression was up-regulated in PTC tissues, particularly in PTC+HT tissues and correlated positively with HLA-class I, CD3 and CD8 expression in PTC+HT tissues. Conversely, PD-L1 expression decreased in PTC+HT tissues. Treatment with IL-2 significantly up-regulated HLA-class I expression, but down-regulated PD-L1 expression in PTC cells. Co-culture with IL-2-pre-treated PTC cells significantly promoted the proliferation of activated CD8+ T cells and their IL-2 secretion, but decreased their PD-1 expression, accompanied by decreased PD-L1 expression in IL-2-treated PTC cells in vitro. In conclusion, IL-2 up-regulated HLA-class I expression and enhanced anti-tumor T cell immunity during the development of PTC and HT. IL-2 may be a promising immunotherapy for PTC.


Porokeratosis with large skin lesions. Histologic, cytologic and cytogenetic study of three cases.
Three porokeratosis patients with large skin lesion(s) are reported. The histopathology of the large lesions revealed that the epidermis 1) frequently presented slight or marked acanthosis and/or elongation of the rete ridge, and 2) contained abnormal cells, e.g. hyperchromatic, large, multinucleated, and/or irregular shaped nuclei. The DAPI-DNA microfluorometric study revealed DNA polyploidy and/or an increased population of epidermal cells with hyperdiploid and/or tetraploid DNA content. These results indicate the proliferating potential of the epidermis and the existence of a neoplastic clone or clones therein. This finding may explain the enlargement of skin lesions and possibly the development of malignancy, as sometimes occurs in large skin lesions. Furthermore, cultured skin fibroblasts from a patient's skin lesion or its surrounding skin revealed various kinds of chromosomal structural abnormalities, which may serve as a basis for the development of abnormal neoplastic clones in the porokeratotic epidermis.


The Relationship between Plant-Based Diet Index and Semen Parameters of Men with Infertility: A Cross-Sectional Study.
Infertility is a major clinical problem that affects people psychologically and medically. For the past 40 years, studies have linked nearly 50% of childlessness to male infertility. It is worth noting that unlike other factors contributing to infertility, diet is a tunable factor and can be applied in counseling infertile men. The goal of this study was to determine the relationship between plant diet index (PDI) and semen parameters in Iranian infertile men. In this cross-sectional study, dietary intake was determined by a valid 168-item questionnaire (FFQ). In this study, four dependent semen parameters, including total sperm motility (TSM), sperm concentration (SC), normal sperm morphology (NSM), and semen volume (SV) were measured. Results of this study stated that greater adherence to the healthful plant-based diet index (hPDI), can significantly increase sperm density and motility in men, as well as greater adherence to the PDI dietary pattern is related to a lower risk of sperm volume deficiency, and ultimately more adherence to the unhealthful plant-based diet index (uPDI), can reduce the risk of sperm motility. In this study, for the first time, the relationship between PDI, hPDI, uPDI and male infertility was evaluated. Altogether, this study demonstrated that nutrition has an impact on semen quality and fertility of men.


[Feverfew lactone induces autophagic death of hepatocellular carcinoma SMMC 7721 cells].
To explore the effect and mechanism of feverfew lactone on inducing autophagic death of hepatocellular carcinoma. The proliferation of hepatocellular carcinoma SMMC 7721 cells treated with feverfew lactone was measured by MTT assay. The autophagy of SMMC 7721 induced with feverfew lactone was assessed by acridine orange staining, autophagic marker LC3 and p62 detecting and autophagic flows analyzing. In addition, a role of ROS in this process was stated by treatment with antioxidant agent N-acetyl-L-cysteine (NAC). The proliferation of SMMC 7721 cells were inhibited by feverfew lactone in a concentration dependence manner. The expression of LC3 and autophagic flows of SMMC 7721 cells were increased by feverfew lactone, while p62 was decreased, which implied that feverfew lactone could induce the autophagy of SMMC 7721 cells. Further more, the autophagy effect induced by feverfew lactone was declined obviously when treated with NAC suggested that ROS played an important role in this effect. Feverfew lactone induces autophagic death of SMMC 7721 cells by stimulating cells to produce ROS. The study will be helpful for the treatment of hepatocellular carcinoma and to provide theoretical basis for the clinical application of feverfew lactone.


Discharge against medical advice from the emergency department in a university hospital.
Patients discharged against medical advice (DAMA) act as a high-risk population for the Emergency Department (ED), regardless of their presentations, and can pose a serious burden for the hospital. This study examines the prevalence, demographic and clinical characteristics, reasons, and clinical outcomes of a small sample of DAMA patients in a teaching university hospital, including readmission, morbidity, and mortality. A prospective, descriptive cross-sectional study was conducted in the ED of King Hamad University Hospital (KHUH) with 98,992 patient visits during a 1-year period from June 2018 to June 2019. Consenting DAMA patients were asked to complete a data collection form. Patients (n = 413) had a mean age of 44.1 years with a female majority (57.1%). The majority were categorized as triage level-3 (87.7%). The main reasons for DAMA included refusal of the procedure/operation (23.2%), long ED waiting time (22.2%), subjective improvement with treatment (17.7%), and children at home (14.8%), whereas the least selected reason was dissatisfaction with medical care (1.2%). Follow-up of DAMA patients revealed that 86 cases (20.8%) were readmitted to the ED within 72 h of which 41 (47.7%) cases were morbidity and 2 (2.3%) were mortality. Marital status was a predictor of DAMA patients who revisit the ED within 72 h. The results act as a pilot study to examine a small sample of DAMA patients' characteristics, diagnosis, and ED revisits. Hospitals should investigate further the DAMA population on a larger scale, reasons for refusing procedures, and utilize this knowledge to improve the healthcare process.


Renal aspects of thalassaemia a changing paradigm.
Beta-thalassaemia is characterised by progressive anaemia necessitating regular blood transfusions to sustain life. With the advent of effective chelating agents that can reduce the iron burden and extend patients' survival, renal disease, as in other ageing populations, has become more prevalent. In recent years, chronic kidney disease (CKD) has become overwhelming; indeed, approximately 8% or 6 million people of the UK population has evidence of CKD. Several factors, which occur in patients with thalassaemia, account for the relative explosion of renal disease in the general population including increasing age, diabetes, hypertension and the advent of novel measures of renal function facilitating early detection of kidney disease. In addition, some patients with thalassaemia develop renal tubular dysfunction related to the disease itself, the effects of iron overload and the effects of chelator therapy, while other patients have an increased creatinine clearance leading to hyperfiltration. More recently, there is a noticeable increasing prevalence of impaired renal function and proteinuria because of several putative factors including chelators. We review current data on the potential mechanisms leading to renal abnormalities seen in patients with thalassaemia, the potential effects of iron loading within the kidney and the potential renal effects of chelator therapy. This article gives a speculative account of possible mechanisms and theories to consider providing pause for thought and direct future research in this area.


Cyclic AMP phosphodiesterase in Thermomonospora curvata.
Cyclic AMP phosphodiesterase (PDE; EC 18.104.22.168) in Thermomonospora curvata was purified and characterized. Fractionation of cell extracts by ion-exchange and size-exclusion chromatography revealed four PDE isozymes, which differed markedly in molecular weight, theophylline sensitivity, pH optima, and substrate affinity. Although the enzyme was labile after purification, total recovery of PDE activity was fivefold that of the crude extract. PDE biosynthesis appeared sensitive to the growth phase, growth rate, and carbon source. PDE levels in batch cultures peaked and declined rapidly during mid-exponential-phase growth. In continuous culture, maximal PDE and cellulase production occurred at dilution rates yielding mean cell generation times of about 5 and 17 h, respectively. The addition of glucose to cellulose-grown cells caused declines in both cyclic AMP and PDE levels, suggesting that the enzyme was subject to, rather than the agent of, catabolite repression.


Effect of processing parameters on the microstructure and mechanical behavior of silica-calcium phosphate nanocomposite.
Silica-calcium phosphate nanocomposite (SCPC) is a bioactive ceramic characterized by superior bone regenerative capacity and resorbability when compared to traditional bioactive ceramics. The aim of the present study is to evaluate the effect of processing parameters on the microstructure and mechanical properties of SCPC. Cylinders were prepared by pressing the ceramic powder at 200, 300 or 400 MPa and sintering at 900, 1000 or 1100 degrees C for 3 h, respectively. XRD results indicate that the crystalline structure of the material is made of beta-NaCaPO(4) and alpha-cristobalite solid solutions. The increase in sintering temperature results in an increase in the grain size and the formation of a melting phase that coats the grains. TEM analyses reveal that the melting phase is amorphous and rich in silicon. The mechanical properties of SCPC cylinders are dependent on the content of the melting phase and the microstructure of the material. The ranges of compressive strength and modulus of elasticity of the SCPC are 62-204 MPa and 6-14 GPa, respectively, which are comparable to those of cortical bone. The results suggest that the interaction between crystalline and amorphous phases modulated the mechanical behavior of SCPC. It is possible to engineer the mechanical properties of SCPC by controlling the processing parameters to synthesize various fixation devices for orthopedic and cranio-maxillofacial applications.


[Transthalamic conduction of visual impulses into the cortex and subcortical portions of the turtle forebrain].
Thalamic structures relaying impulses originating from optic stimulation of the retina and electric stimulation of the tectum on the way to the general cortex, hyperstriatum dorsal ventricular ridge and striatum were studied in turtles Emys orbicularis. Anodal polarization of the n. rotundus temporarily, and the lesion of this nucleus irreversibly, suppressed the main negative component of responses evoked by tectal stimulation and light flashes in the dorsal ventricular ridge without affecting them in the general cortex. Polarization and lesions of the lateral thalamic region, including nucleus geniculatum lateralis produced an opposite effect. A conditioning single stimulation of the tectum or n. rotundus suppressed flash-evoked potentials in the hyperstriatum. However evoked potentials and single unit responses appeared following stimulation of the lateral thalamic region. They exhibited blocking interactions with the tectum-evoked responses. A conclusion is made that in the turtle the main pathways conducting visual information to the cortex and hyperstriatum are different: in the former case it is relayed in the lateral geniculatum region in the latter--in n. rotundus, although an overlap of the projections in dorsal ventricular ridge and striatum can be suggested.


New approaches to prevention of staphylococcal infection in surgery.
The present review describes the literature about the prevention of Staphylococcus aureus infections in surgery, published from August 2006 to January 2008, and puts it into perspective. To prevent Staphylococcus aureus infections after surgical procedures, three methods were described, that is, isolation precautions after methicillin-resistant Staphylococcus aureus screening, vancomycin as an antibiotic prophylaxis in patients at risk for methicillin-resistant Staphylococcus aureus, and topical decolonization of carriage. Identified methicillin-resistant Staphylococcus aureus carriers can be treated with the appropriate antibiotic prophylaxis to prevent infection with methicillin-resistant Staphylococcus aureus. Topical decolonization with chlorhexidine gluconate resulted in a reduced overall nosocomial infection rate, but no effect was found on the Staphylococcus aureus infection rate. Topical decolonization with mupirocin reduced the overall Staphylococcus aureus infection rate after surgery in Staphylococcus aureus nasal carriers. The treatment of proven carriers of Staphylococcus aureus with mupirocin is an effective method to prevent Staphylococcus aureus nosocomial infections after surgery. Cost-analysis studies show that this screen-and-treat approach is cost saving as long as the prevalence of mupirocin resistance in Staphylococcus aureus is low. The effect of chlorhexidine gluconate on the Staphylococcus aureus infection rate in carriers should be determined in future studies.


Clarithromycin resistance and 23S rRNA gene point mutations of Helicobacter pylori infection in children.
This study aims to evaluate Helicobacter pylori with clarithromycin resistant genotypes in Manisa region, Turkey. Two hundred patients, who received diagnosis of Helicobacter pylori infection histopathologically, were included. The sex, age and endoscopy indications of the patients were recorded. Polymerase chain reaction method was applied to determine the clarithromycin resistance rate and resistance genotypes at the histologic sections prepared from gastric biopsies that had been embedded in paraffin after fixation by formalin. Helicobacter pylori resistance to clarithromycin was found in 19/200 (9.5%) patients. 10/19 (52.6%) of these clarithromycin-resistant patients had A2143G mutation and 9/19 (47.4%) had A2142G mutation. A2142C mutation on 23S rRNA gene was not detected for any of the patients. Clarithromycin can be used as a first step treatment in the eradication of Helicobacter pylori for the children in our region; if the treatment fails for some patients, clarithromycin resistance, especially A2143G and A2142G mutations should be considered.


The Evolution of Clinicopathological Diagnostic Features of Upper Tract Urothelial Carcinoma in China: A Summary of 2561 Cases in the Last 20 Years.
To summarize the clinicopathological diagnostic features and evolutionary trends of upper tract urothelial carcinoma (UTUC) in China over the past 20 years. All patients diagnosed with upper tract urothelial carcinoma in the Peking University First Hospital from 2001 to 2020 were retrospectively collected. Data were divided into two groups (2001-2010 and 2011-2020) according to the date of diagnosis. Statistical analysis was done with the SPSS V22.0. Chi-square analysis and t-test were adopted to analyze depending on the data type. Subgroup analysis based on 5 years was used for visualization to present trends. Both Kaplan-Meier curve and Cox regression were used for univariate and multivariate survival analysis. The study included 2561 cases diagnosed with upper tract urothelial carcinoma in total. Compared with the first decade (2001-2010), patients of the second decades (2011-2020) had elder mean age (66.65 versus 67.59, years, p=0.025), higher male proportion (43.5% versus 49.0%, p=0.034), lower incidence of renal pelvic tumors (53.4% versus 45.8%, p<0.001) and multifocality (18.6% versus 12.0%, p<0.001), higher incidence of ureteral tumors (52.2% versus 60.9%, p<0.001).In recent ten years, the incidence of muscle-invasive urothelial carcinoma (pT2+) decreased significantly (64.4% versus 54.9%, p<0.001),and the mean size of renal pelvic tumors increased(3.46 versus 3.73, cm, p=0.043). The size of the ureteral tumor, the histopathologic grade showed no significant change. The prognostic analysis based on 709 patients regularly followed at our center revealed that the male gender and G3 histopathological grade were independent risk factors for poorer prognosis in patients with UTUC. In the past 20 years, the clinicopathological diagnostic features of upper tract urothelial carcinoma in the Chinese population has changed significantly, suggesting an increased risk of a poorer prognosis for UTUC. This trend may be related to updating diagnostic techniques and self-monitoring awareness. However, we need more high-grade, multicenter trials to verify it in the future.


Native forests transformed into cash crops reduced soil multi-functionality by modifying the microbial community composition and keystone species' abundance in the Jianghuai Hilly Region.
Conversion of native forest to cash crops is the predominant form of land use change in the Jianghuai Hilly Region. However, how plantations with different cash crops affect the soil multi-functionality is not well documented. In this study, we collected three kinds of cash crops soils (vegetable, orchard, and tea) and forest soil, to systematically review the relationship between soil microbial communities and soil multi-functionality. Soil multi-functionality had decreased in vegetable and orchard as compared to native forest, whereas tea plantation had no significant effects on soil multi-functionality. The results also showed that cash crop plantations decreased soil multi-functionality by shifting keystone species' abundance, for forest, vegetable, and orchard, the keystone species that were classified as module hubs in the bacterial co-occurrence network significantly negatively contributed to soil multi-functionality, but the keystone species categorized as module hubs in fungal co-occurrence network positively affected soil multi-functionality. Multiple soil properties were the drivers of the soil microbial community; thus, indicating that the altered soil properties under cash crop plantations were vital in determining microbial composition and biological processes. These results identified that sustainable management strategy in cash crop plantation needed to be developed for improving soil multi-functionality.


Quo Vadis Psychiatry? Why It Is Time to Endorse Evolutionary Theory.
In recent decades, psychiatry and the neurosciences have made little progress in terms of preventing, diagnosing, classifying, or treating mental disorders. Here we argue that the dilemma of psychiatry and the neurosciences is, in part, based on fundamental misconceptions about the human mind, including misdirected nature-nurture debates, the lack of definitional concepts of "normalcy," distinguishing defense from defect, disregarding life history theory, evolutionarily uninformed genetic and epigenetic research, the "disconnection" of the brain from the rest of the body, and lack of attention to actual behavior in real-world interactions. All these conceptual difficulties could potentially benefit from an approach that uses evolutionary theory to improve the understanding of causal mechanisms, gene-environment interaction, individual differences in behavioral ecology, interaction between the gut (and other organs) and the brain, as well as cross-cultural and across-species comparison. To foster this development would require reform of the curricula of medical schools.


New method of electrode placement for determination of cardiac output using impedance cardiography.
In thirty eight young healthy adult subjects, cardiac output was determined non-invasively by using two methods of electrode placement viz. vertical (uses silver braided wires in a band shape) and horizontal (conventional stick-on type surface ECG electrodes), using the technique of Impedance Cardiography. The recordings were taken in supine position on the same day in two separate sets with 30.0 min interval between two sets. In each set of recording, five successive recordings, each at an interval of five minutes were taken. The mean values of cardiac out put by two methods were compared. For the set I, the respective values (Mean +/- SD) of cardiac output by horizontal and vertical methods for the each of the five recordings were 4.87 +/- 0.77 and 5.03 +/- 0.64 for the first, 4.87 +/- 0.71 and 4.91 +/- 0.66 for the second, 4.99 +/- 0.67 and 5.00 +/- 0.70 for the third, 4.78 +/- 0.69 and 4.98 +/- 0.61 for the fourth, 4.84 +/- 0.69 and 4.98 +/- 0.62 for the fifth recording in supine position. The respective P values for these pairs for between the group comparisons were 0.33, 0.50, 0.96, 0.17, and 0.36. In addition, to see the repeatability for each method, within the group comparison was done, the P values were 0.71 and 0.91 for the horizontal and vertical methods, respectively. The mean value of cardiac output did not differ significantly between two methods for recordings of set II in supine position. The cardiac output measurement by placing four spot electrodes horizontally, gave consistent result on repeated measurements and their values showed concordance with the cardiac output values obtained by conventional four band electrodes tied around the chest.


Therapeutic application of chick early amniotic fluid: effective rescue of acute myocardial ischemic injury by intravenous administration.
Myocardial regeneration has been considered a promising option for the treatment of adult myocardial injuries. Previously, a chick early amniotic fluid (ceAF) preparation was shown to contain growth-related factors that promoted embryonic growth and cellular proliferation, though the nature of the components within ceAF were not fully defined. Here we tested whether this ceAF preparation is similarly effective in the promotion of myocardial regeneration, which could provide an alternative therapeutic for intervening myocardial injury. In this study, a myocardial ischemic injury model was established in adult mice and pigs by multiple research entities, and we were able to show that ceAF can efficiently rescue damaged cardiac tissues and markedly improve cardiac function in both experimental models through intravenous administration. ceAF administration increased cell proliferation and improved angiogenesis, likely via down-regulation of Hippo-YAP signaling. Our data suggest that ceAF administration can effectively rescue ischemic heart injury, providing the key functional information for the further development of ceAF for use in attenuating myocardial injury.


Early cellular responses in the Malpighian tubules of the mosquito Aedes taeniorhynchus to infection with Dirofilaria immitis (Nematoda).
Early ultrastructural changes in the Malpighian tubules of the mosquito, Aedes taeniorhynchus, were examined following infection with the nematode, Dirofilaria immitis. After ingestion by the mosquito, the microfilariae enter the cells of the Malpighian tubules, becoming intracellular. During early development, the filarial prelarvae reside in the cell cytoplasm surrounded by a clear zone without a delimiting membrane. Cells infected with prelarvae differed from uninfected cells and from cells in uninfected mosquitoes in that the volume of the apical microvilli was reduced and mitochondria were retracted from these microvilli. Morphometric analysis was used to quantify the ultrastructural consequences of infection. In infected cells, microvillar volume, the percent of microvillar volume occupied by mitochondria, and volume of mitochondria within the microvilli were significantly reduced.


Preventing accidental transmission of human transmissible spongifom encephalopathies.
The mechanism by which humans became infected with the BSE agent is discussed, and the matter of potential person-to person transmission of TSEs through contagion or medical procedures is considered. There is some discussion regarding the current evidence relating to whether or not the blood of humans infected with TSEs is infectious. Considerable emphasis is placed on the fact that TSE agents are known to be relatively resistant to decontamination by procedures that are effective with conventional micro-organisms, including (under worst-case conditions) the autoclaving procedures used to sterilise surgical instruments. Methods for providing additional re-assurance with regard to the safety of instruments are described. Safety in the pathology laboratory is discussed extensively because TSE agents are not inactivated by the usual processes used to fix tissues, and such laboratories will receive fixed tissues that are still highly infectious as far as TSE agents are concerned.


BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity.
Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.


Valosin Containing Protein as a Specific Biomarker for Predicting the Development of Acute Coronary Syndrome and Its Complication.
Acute coronary syndrome (ACS) consists of a range of acute myocardial ischemia-related manifestations. The adverse events of ACS are usually associated with ventricular dysfunction (VD), which could finally develop to heart failure. Currently, there is no satisfactory indicator that could specifically predict the development of ACS and its prognosis. Valosin-containing protein (VCP) has recently been proposed to protect against cardiac diseases. Hence, we aimed to assess whether VCP in serum can serve as a valuable biomarker for predicting ACS and its complication. Human serum samples from 291 participants were collected and classified into four groups based on their clinical diagnosis, namely healthy control (n = 64), ACS (n = 40), chronic coronary syndrome (CCS, n = 99), and nonischemic heart disease (non-IHD, n = 88). Clinical characteristics of these participants were recorded and their serum VCP levels were detected by enzyme-linked immunosorbent assay (ELISA). Association of serum VCP with the development of ACS and its complication VD was statistically studied. Subsequently, GWAS and eQTL analyses were performed to explore the association between VCP polymorphism and monocyte count. A stability test was also performed to investigate whether VCP is a stable biomarker. Serum VCP levels were significantly higher in the ACS group compared with the rest groups. Besides, the VCP levels of patients with ACS with VD were significantly lower compared to those without VD. Multivariate logistic regression analysis revealed that VCP was associated with both the risk of ACS (P = 0.042, OR = 1.222) and the risk of developing VD in patients with ACS (P = 0.035, OR = 0.513) independently. The GWAS analysis also identified an association between VCP polymorphism (rs684562) and monocyte count, whereas the influence of rs684562 on VCP mRNA expression level was further verified by eQTL analysis. Moreover, a high stability of serum VCP content was observed under different preservation circumstances. Valosin-containing protein could act as a stable biomarker in predicting the development of ACS and its complication VD.


Dancers' Perceived and Actual Knowledge of Anatomy.
Dancers are highly susceptible to musculoskeletal injuries and frequently require interaction with medical professionals. While many dancers have a finely tuned awareness of their bodies, their knowledge of the fundamentals of human anatomy is not uniform. There is a paucity of literature on the benefits of human anatomy education in dancers, though it seems intuitive that there should be a relationship. The purpose of this study was to assess dancers' perceived and actual knowledge of basic musculoskeletal anatomy and its relationship to function. Adult dancers at the undergraduate, pre-professional, and professional levels were surveyed through an anonymous online questionnaire. Questions included demographic information, dance techniques studied, anatomy training, and injury history. Subjects rated their perceived knowledge of anatomy and were tested with 15 multiple-choice questions on basic musculoskeletal anatomy. Four hundred seventy-five surveys were completed. Ordinal regression showed a correlation of perceived to actual knowledge of anatomy (p < 0.001). Factors that correlated with increases in both perceived and actual knowledge of anatomy included having taken an anatomy course of any type (p < 0.001) and increased age (p ≤ 0.001). Years of dance training and professional dancer status both significantly correlated with increased knowledge of anatomy (p < 0.001) but not perceived knowledge. Chi-square analysis showed that dancers with training in either modern or jazz dance had a significantly higher perceived, but not actual, knowledge when compared to those without training in those styles of dance (p < 0.001 and p = 0.011, respectively). In conclusion, dancers generally scored well on questions pertaining to basic musculoskeletal anatomy, and their perception correlated with their actual knowledge of anatomy. Factors that contribute to dancers' knowledge of anatomy include age, years of experience, professional dancer status, and anatomy training.


Gingival mucinous adenocarcinoma of a minor salivary gland.
A 47-year-old male non-smoker with a history of psoriasis sought a consultation because of a painless, hard-on-palpation, 1-cm exophytic lesion with a smooth and speckled surface located on the hard palate adjacent to tooth #12. The radiologic examination revealed no bone destruction. The lesion was clinically diagnosed as a fibrous hyperplasia or chronic pyogenic granuloma. The lesion was surgically removed, fixed in 10% neutral buffered formalin for 24 hours, and, following common practice, embedded in paraffin. Sections, 4 mum thick, were stained with hematoxylin and eosin, periodic acid-Schiff, and alcian blue, pH 2.5. An immunohistochemical study was also performed. A definitive diagnosis of a mucinous adenocarcinoma (MAC), a very rare, high-grade malignancy tumor that more frequently appears in the elderly, was made. With the definitive diagnosis of an MAC of the palate, the upper-left premolars were extracted using a box osteotomy, and the surgical wound was reconstructed with a Bichat fat-pad flap. After a 6-month follow-up, no recurrence or cervical metastases were identified. An MAC of a minor salivary gland may arise as a gingival exophytic lesion with a clinical appearance similar to a pyogenic granuloma. The existence of a light speckled pattern on the surface of the lesion indicates that an incisional biopsy is needed before surgical treatment to make possible a definitive diagnosis. To avoid delays in diagnosis and erroneous clinical approaches to exophytic gingival lesions, periodontists and practitioners should routinely perform a pathologic analysis to confirm the diagnosis when dealing with these kinds of lesions.


[The manifestation of synergy during simultaneous thermochemical action on yeast cells].
In order to obtain new fundamental knowledge, patterns of manifestation of synergy have been studied after simultaneous combined action of hyperthermia (47.5-60 degrees C) with anti-tumor agents (cyclophosphamide, cisplatin) on the survival of yeast cells. To calculate the efficiency of the synergistic interaction, the dependence of cell survival on the duration of exposure at separate and simultaneous action of chemical agents and hyperthermia was used. We have found that there is a certain temperature range within which there is a synergistic enhancement of anticancer drugs and high temperature effects. Any deviation from the optimum values of the temperature results in a decrease in synergy. The possible mechanism of the revealed patterns is discussed.


High-Throughput Analysis Identifying Drugs That Regulate Apolipoprotein A-I Synthesis.
Apolipoprotein A-I (apo A-I) is the primary antiatherogenic protein in high-density lipoprotein (HDL). Despite the controversy as to the clinical effectiveness of raising HDL, the search is ongoing for safe and effective drugs that increase HDL and apo A-I levels. To identify novel compounds that can increase hepatic apo A-I production, two drug libraries were screened. The NIH clinical collection (NCC) and the NIH clinical collection 2 (NCC2) were purchased from Evotec (San Francisco, CA). The NCC library contains 446 compounds and the NCC2 library contains 281 compounds, all dissolved in dimethylsulfoxide at a concentration of 10 mM. Hepatoma-derived cells (HepG2) and primary hepatocytes in culture were treated with various compounds for 24 h and apo A-I in media samples was measured by enzyme immunoassay. Samples with significant changes in apo A-I concentrations were retested in independent experiments by Western blot analysis to confirm the immunoassay findings. Of a total of 727 compounds screened at a concentration of 50 μM, 15 compounds increased hepatic apo A-I production by 35%-54%, and 9 compounds lowered hepatic apo A-I concentrations in the culture media by 25%-52%. Future trials should explore the clinical effectiveness of these agents when standard doses of these drugs are used in humans.


Sonographic appearance of benign intratesticular lesions.
58 patients with a purely intratesticular lesion were investigated with scrotal ultrasound. A pathognomonic echo pattern could be found for simple parenchymal cysts and hemangiomas only. The nature of all other lesions (chronic orchitis, hematoma, epidemoid cyst, testicular necrosis, abscess and tuberculosis) could not be defined solely on sonographic grounds.


[Comparative analysis of clinical diagnosis application of two intrauterine adhesion scoring criteria].
Objective: To explore the similarities and differences of China Society of Gynecology Endoscopy (CSGE) and American Fertility Society (AFS) intrauterine adhesion (IUA) scoring criteria on IUA grading and their predictive value of reproductive prognosis. Methods: From January 2016 to January 2019, a total of 1 249 patients were diagnosed with IUA by hysteroscopy at Beijing Obstetrics and Gynecology Hospital. Totally, 378 patients with complete clinical data were enrolled, and the results diagnosed by CSGT and AFS scoring criteria were compared and analyzed.And follow-up for 2 years, the pregnancy rate and live birth rate were statistical analysis. Results: (1) The grade of IUA according to AFS and CSGE scoring criteria was less consistent (κ=0.295, P<0.001). Compared with AFS, the proportion of severe IUA cases diagnosed by CSGE was significantly lower [45.8% (173/378) vs 15.1% (57/378); RR=0.22, 95%CI: 0.15-0.30, P<0.01); the proportions of both mild and moderate IUA cases were significantly higher (RR=4.16, 95%CI: 2.38-7.14; RR=2.38, 95%CI: 1.75-3.23; both P<0.01). (2) The pregnancy rates of mild, moderate and severe IUA diagnosed according to CSGE were 11/13, 64.5% (147/228), 31.8% (7/22), live birth rates were 11/13, 54.8% (125/228) and 22.7% (5/22), respectively; there were statistically significant differences between the groups (all P<0.01). The pregnancy rates of mild, moderate and severe IUA diagnosed based on AFS were 3/3, 66.9% (97/145) and 56.5% (65/115), respectively, with no statistically significant difference between the groups (P>0.05). (3) IUA grades based on both CSGE and AFS criteria were significantly negatively correlated with pregnancy rates and live birth rates (CSGE: r=-0.210, r=-0.226; AFS: r=-0.130, r=-0.147; all P<0.05). Univariate logistic regression analysis showed that CSGE had higher OR for both pregnancy rates and live birth rates compared to AFS (3.889 vs 1.657, 3.983 vs 1.554, respectrvely). Conclusions: Compared with AFS, the IUA grade based on CSGE is better related with reproductive prognosis, suggesting that the CSGE standard might be more objective and comprehensive and has better predictive value for reproductive prognosis, thus avoiding overdiagnosis and overtreatment.


[PRIMARY STUDY ON IMPLANT COVERAGE WITH LOCAL SOFT TISSUE IN IMMEDIATE IMPLANT-BASED BREAST RECONSTRUCTION].
To explore the method of implant coverage with local soft tissue in immediate implant-based breast reconstruction and to evaluate the early effectiveness. Between April 2014 and August 2015, 11 patients with breast cancer underwent immediate breast reconstruction with implants after mastectomy, and the clinical data were reviewed retrospectively. The age ranged 29-48 years (mean, 36 years). The disease duration was from 7 days to 12 months (median, 3 months). According to tumor staging, 3 cases were rated as T(is)N0M0, 4 cases as T1N0M0, and 4 cases as T2N0M0. The implants were covered with local soft tissue according to the volume of mastectomy and contralateral breast size, including pectoralis major myocutaneous flaps with inframammary adipofasical flaps (3 cases), with serratus anterior fascial flap (5 cases), with rectus sheath fascial flap (1 case), and with serratus anterior fascial flap and rectus sheath fascial flap (2 cases). The size of pectoralis major myocutaneous flaps ranged from 15 cm x 9 cm to 20 cm x 15 cm, and the serratus anterior fascial flaps from 10 cm x 8 cm to 15 cm x 10 cm, and the rectus sheath fascial flap from 8 cm x 6 cm to 10 cm x 8 cm. One patient had partial nipple necrosis postoperatively and was cured, and no other postoperative complications of hematoma, infection, or implant exposure was found. The patients were followed up 4-13 months (median, 8 months). The reconstructive outcomes were excellent in 10 cases and good in 1 case, with an excellent and good rate of 100%. During follow-up, no rupture or exposure of the implant was observed; capsular contracture (Baker grade II) occurred in 1 case. Adequate coverage of implants with different local soft tissue flaps can achieve satisfactory early effectiveness in immediate implant-based breast reconstruction after mastectomy.


Rehabilitation after coronary bypass surgery: coping strategies predict metabolic improvement and return to work.
Thirty-six consecutive male patients who underwent coronary bypass surgery were investigated before and repeatedly up to 5 years after surgery. We followed the patients' physical capacity, dietary and exercise habits, mood, perception of health and return to work. Discriminant analysis identified four variables from the preoperative interview and the psychological tests which correctly classified 22 out of 24 patients into either metabolic responders--who were characterized by favourable changes in their lipoprotein profile, related to a successful clinical outcome--or non-responders. Responders were found to acknowledge subjective, emotional aspects of their situation whereas non-responders minimised their disease. Six preoperative variables successfully predicted the classification of all but one patient into full-time workers or not, one year after surgery. Full-time workers were more frequent among minimizers. The results suggest that whereas minimising of disease is adaptive in a short-term perspective, acknowledgement may be successful in the long run.


Management of Nasopharyngeal Carcinoma: Is Adjuvant Therapy Needed?
Nasopharyngeal carcinoma of the undifferentiated histologic subtype is endemic and prevalent in southeast Asia. The dramatic improvement of treatment outcomes and overall prognosis during the past few decades has been attributed to advances in disease screening and diagnosis, diagnostic imaging, radiotherapy techniques, use of combination systemic therapy, and dedicated clinical and biomarker surveillance. The current practice of treating patients with advanced locoregional disease using cisplatin concurrent with conventional fractionated radiotherapy, followed by adjuvant cisplatin and fluorouracil, was established in 1998 when the landmark Intergroup-0099 Study demonstrated a survival benefit with the addition of systemic therapy. There is little doubt regarding the need for concurrent chemotherapy, but there has been uncertainty about the magnitude of the benefit attributed to the adjuvant phase. Furthermore, instead of one-size-fits-all recommendations, it will be ideal if we can tailor adjuvant therapy to high-risk patients only to avoid unnecessary toxicities. In addition, recent evidence suggests that induction chemotherapy before concurrent chemoradiation can achieve better outcomes, especially in distant control, even in the modern era of intensity-modulated radiation therapy. This article provides a comprehensive review of key literature on the current management of locoregionally advanced nasopharyngeal carcinoma and highlights future research directions to unravel these controversies.


Exposure to noise on board locomotives.
Personal and area noise dosimetry measurements were taken in the cabs of leading and trailing locomotives on 48 trips, under winter and summer conditions, on 9 different routes. The mean equivalent sound level (L(EQ), 3 dB exchange rate, 50 dBA threshold) of the engineers and conductors was 84 dBA during winter and 88 dBA during summer. The corresponding time-weighted average levels (L(TWA), 5 dB exchange rate, 80 dBA threshold) were 80 and 84 dBA respectively. The L(EQ) of 56% of the engineers sampled was > or =85 dBA and of 13% was > or =90 dBA. Plots of L(EQ) time history show that under normal operating conditions L(EQ) reaches its steady-state value in about 3 hours. The mean noise levels in the trailing cabs were lower than the personal exposure levels of the engineers and conductors. The mean L(EQ) on the engineer and conductor sides was 80 dBA during winter, and 85 dBA during summer. Locomotive configuration has a significant effect on the noise levels in the trailing cab. The forward-backward configuration resulted in higher noise levels than the forward-forward configuration. Octave and one-third octave band spectra taken during a variety of locomotive operating conditions are presented. The octave band centered at 31.5 Hz contains nearly 46% of the acoustical energy, and those centered at and below 250 Hz contain nearly 99% of the acoustical energy. Wheel-rail interaction appears to be the predominant source of the low frequency noise. Recommendations for controlling exposure are made.


Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase.
Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) constitute an important, yet relatively poorly understood, family of heme-containing enzymes. Here, we report extensive structural and biochemical studies of the Xanthomonas campestris TDO and a related protein SO4414 from Shewanella oneidensis, including the structure at 1.6-A resolution of the catalytically active, ferrous form of TDO in a binary complex with the substrate L-Trp. The carboxylate and ammonium moieties of tryptophan are recognized by electrostatic and hydrogen-bonding interactions with the enzyme and a propionate group of the heme, thus defining the L-stereospecificity. A second, possibly allosteric, L-Trp-binding site is present at the tetramer interface. The sixth coordination site of the heme-iron is vacant, providing a dioxygen-binding site that would also involve interactions with the ammonium moiety of L-Trp and the amide nitrogen of a glycine residue. The indole ring is positioned correctly for oxygenation at the C2 and C3 atoms. The active site is fully formed only in the binary complex, and biochemical experiments confirm this induced-fit behavior of the enzyme. The active site is completely devoid of water during catalysis, which is supported by our electrochemical studies showing significant stabilization of the enzyme upon substrate binding.


Management of life-threatening autonomic hyper-reflexia using magnesium sulphate in a patient with a high spinal cord injury in the intensive care unit.
We report the successful use of i.v. magnesium sulphate to control life-threatening autonomic hyper-reflexia associated with chronic spinal cord injury in the intensive care environment. A 37-yr-old, male was admitted to the intensive care unit with a diagnosis of septic shock and acute renal failure secondary to pyelonephritis. He had been found unresponsive at home following a 2-day history of pyrexia and purulent discharge from his suprapubic catheter. He had sustained a T5 spinal cord transection 20 yr previously. Initial management included assisted ventilation, fluid resuscitation, vasopressor support, and continuous veno-venous haemofiltration. The sepsis was treated with antibiotic therapy and percutaneous nephrostomy drainage of the pyonephrosis. On the fifth day, the patient developed profuse diarrhoea. This was associated with paroxysms of systemic hypertension and diaphoresis, his arterial pressure rising on occasion to 240/140 mm Hg. A diagnosis of autonomic hyper-reflexia was made and a bolus dose of magnesium sulphate 5 g was administered over 15 min followed by an infusion of 1-2 g h(-1). There was an almost immediate decrease in the severity and frequency of the hypertensive episodes. There were no adverse cardiac effects associated with the administration of magnesium, only a slight decrease in minute ventilation as the plasma level approached the upper end of the therapeutic range (2-4 mmol litre(-1)). In view of the beneficial effects observed in this case we advocate further research into the use of magnesium sulphate in the treatment or prevention of autonomic hyper-reflexia secondary to chronic spinal cord injury in the intensive care unit.


Serological and biochemical characterization of class II antigens in B10.W lines.
Class II molecules of 17 B10.W lines (i.e., congenic lines carrying H-2 haplotypes of wild mice on C57BL/10Sn or B10 strain background) were analyzed by immunochemical methods of precipitation and co-precipitation. The analysis included typing for previously defined antigenic determinants, as well as determinants defined by new reagents, and mapping of the genes controlling these determinants. Using this approach, an Ia chart of the typed B10.W lines could be constructed. Genes controlling determinants Ia.38, 102, 103, 104, 105, and 106 were mapped into A (A beta or A alpha) locus; genes controlling determinants Ia.41. 107. 108, and 109 were mapped in the E (E beta or E alpha) locus. The study suggests that the polymorphism of at least some of the class II loci could be as high as that of the class I loci.


Skin permeability enhancement by Bacillus subtilis alkaline protease: Application to transdermal drug delivery.
Enzymes may offer great potentials in topical pharmaceutical applications provided that treatment conditions are controlled for efficacy and safety. In this study, the effect of alkaline protease produced by recombinant Bacillus subtilis cells on the ex-vivo permeability of rabbit ear skin was investigated under different conditions of enzyme activity (5-60 units) and exposure time (15-60min). Data for transepidermal water loss (TEWL) and permeation of a hydrophilic dye, rhodamine B (Rb), indicated biphasic activity-dependent and exposure time-dependent skin permeability. Maximum effects were obtained at 20 proteolytic units and 30min exposure. Findings proved consistent with histopathological changes indicating progressive stratum corneum (SC) loss and disruption of the dermo-epidermal junction at 20 units and up to 30min exposure time followed by dermal hyalinization at longer exposure. This was associated with progressive loss of skin hair. Applying the identified pretreatment conditions to transdermal delivery of vardenafil in a gel base across dorsal rat skin indicated a significant increase in plasma levels at 30 and 60min with minimal histopathological changes 5days post enzyme treatment. Accordingly, the recombinant B. subtilis alkaline protease offers promise as a pharmaceutical enzyme for transdermal drug delivery bioenhancement and dermatological applications.


Genome-wide significant locus of beta-trace protein, a novel kidney function biomarker, identified in European and African Americans.
Beta-trace protein (BTP), measured in serum or plasma, has potential as a novel biomarker for kidney function. Little is known about the genes influencing BTP levels. We conducted a genome-wide association study of log-transformed plasma BTP levels in 6720 European Americans (EAs) and replicated the significant associations in 1734 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant locus in EA upstream of Prostaglandin D2 synthase (PTGDS), the gene encoding BTP. Each copy of the A allele at rs57024841 was associated with 5% higher BTP levels (P = 1.2 × 10(-23)). The association at PTGDS was confirmed in AAs (6% higher BTP for each A allele at rs57024841, P = 1.9 × 10(-7)). The index single nucleotide polymorphisms (SNPs) in EAs and AAs explained ∼1.1% of the log(BTP) variance within each population and explained over 30% of the difference in log(BTP) levels between EAs and AAs. The index SNPs at the PTGDS locus in the two populations were not associated with the estimated glomerular filtration rate (eGFR) or the urine albumin creatinine ratio (P > 0.05). We further tested for the associations of BTP with 16 known loci of the eGFR in EA, and BTP was associated with 3 of 16 tested. The identification of a novel BTP-specific (non-renal related) locus and the confirmation of several genetic loci of the eGFR with BTP extend our understanding of the metabolism of BTP and inform its use as a kidney filtration biomarker.


Why Do We Feel Sick When Infected--Can Altruism Play a Role?
When we contract an infection, we typically feel sick and behave accordingly. Symptoms of sickness behavior (SB) include anorexia, hypersomnia, depression, and reduced social interactions. SB affects species spanning from arthropods to vertebrates, is triggered nonspecifically by viruses, bacteria, and parasites, and is orchestrated by a complex network of cytokines and neuroendocrine pathways; clearly, it has been naturally selected. Nonetheless, SB seems evolutionarily costly: it promotes starvation and predation and reduces reproductive opportunities. How could SB persist? Former explanations focused on individual fitness, invoking improved resistance to pathogens. Could prevention of disease transmission, propagating in populations through kin selection, also contribute to SB?


Who can best influence the quality of teenagers' cars?
Because young drivers' vehicles have been found to offer poor occupant protection in many countries, this study sought to identify the most appropriate audience for information and publicity designed to change purchasing preferences to improve these vehicles and resultant injury outcomes. An analysis of New Zealand vehicles crashed by drivers aged 19 years or less linked to data on the owner of the vehicle was undertaken. Details on the crashed vehicles were merged with licensing information to identify the owner's age group. It was presumed that most vehicles driven by teens but owned by someone aged 30 to 59 would be owned by a parent of the teen. Only 14 percent of vehicles crashed by teens were owned by teens. Generally, older vehicles with poor crashworthiness were provided for the teenage driver, whatever the age group of the owner. However, cars crashed by teens but owned by their parents were on average almost 2 years younger and had relatively superior crashworthiness than the teenager-owned and crashed vehicles, although their crashworthiness was still poor compared to vehicles driven by older drivers. Evidently, parents are key people in making vehicle purchasing decisions regarding the cars that teenagers drive and should be the main audience for measures to improve the poor secondary safety performance of teenagers' vehicles.


Brief culturally adapted cognitive behaviour therapy for obsessive compulsive disorder: A pilot study.
To demonstrate the effectiveness of Brief Culturally adapted Cognitive Behavior Therapy (CaCBT) in the treatment of Obsessive Compulsive Disorder (OCD). This pre and post design study was conducted on out-patients with OCD at Centre for Cognitive Behaviour Therapy, Fountain House, Lahore, from April 2011 to April 2012. A semi structured questionnaire was developed to document demographic details of all the patients. All the participants were assessed at baseline (Pre Therapy session) with Yale Brown Obsessive Compulsive Disorder Scale (Y-BOCS), Hospital Anxiety & Depression Scale (Depression Subscale & Anxiety Subscale) and Brief Disability Questionnaire (BDQ). They were re-assessed on the same scales at the end of therapy in a follow up assessment session. Feedback from patients and their family member, who were trained as co-therapist, was obtained at the end of the therapy for assessing the satisfaction with the therapy. All the patients received six sessions of brief culturally adapted cognitive behavior therapy (CaCBT). Statistical analyses were carried out using SPSS v.22. The mean age of the sample (n=21) was 31.14±11.9 years. There were significant differences post CBT between the scores of Y-BOCS (p=0.000), HADS - Depression subscale (p=0.001), HADS - Anxiety subscale (p=0.000) and BDQ (p=0.000). This study provides preliminary evidence for effectiveness of culturally adapted CBT for OCD.


Breast cancer screening in Brazil. Barriers related to the health system.
Identify factors related to the health system that lead to a late diagnosis of breast cancer in Brazil. We performed a systematic review in the PubMed and LILACS databases using as keywords "Breast cancer," "system of health" and "Brazil or Brasil." We evaluated the content of the articles using the PRISMA methodology based on PICTOS. The final date was 12/16/2015. We were able to identify 94 publications in PubMed and 43 publications in LILACS. After assessing the title and summary, and excluding 21 repeated publications, we selected 51 publications for full evaluation. At this stage, we excluded 21 articles, with 30 publications remaining for study. The population coverage is low, and there are problems related to the quality of mammography. Patients with lower income, nonwhite and less educated are more vulnerable. We observed punctual and initial experiences in breast cancer screening. Diagnosis and treatment flows must be improved. The inequality in mortality reflects the differences related to screening structure and treatment. Better results are observed in well-structured services. There are several barriers in the health system leading to advanced stage at diagnosis and limiting the survival outcomes. The establishment of a rapid and effective order for diagnosis and treatment, based on hierarchical flow, are important steps to be improved in the public health context.


Presacral schwannoma: laparoscopic resection, a viable option.
Schwannomas are benign nerve sheath tumours arising from Schwann cells. Presacral schwannomas are rare with only case report and short case series being reported in literature. Complete surgical resection is the treatment of choice for these rare tumours. Approach to surgical resection depends on the type of the tumour. Type 3 tumours have conventionally been treated with open intra or extra peritoneal approach. With improvement in the laparoscopic surgical skills, more and more complex surgical procedures have been attempted via this approach. We are presenting a case of presacral schwannoma in an overweight lady treated by laparoscopic resection.


Species specificity of interleukin 2 binding to individual receptor components.
The affinity of recombinant human and murine interleukin 2 (IL 2), which differ significantly in structure in the amino terminal alpha helix, for the human or murine interleukin 2 receptors was compared. Murine IL 2 showed a 10-fold higher affinity than human IL 2 for the murine high-affinity receptor expressed on T lymphocytes, whereas human IL 2 bound 100-fold more strongly than murine IL 2 to the human high-affinity receptor. As the high-affinity IL 2 receptor on T lymphocytes has been demonstrated to be composed of two IL 2 binding components, p55 and p75, the role of the individual chains in the determination of species specificity was then investigated. Recombinant retroviral vectors were used to generate populations of 3T3 fibroblasts expressing either human or murine p55 in isolation, and their binding characteristics were determined. While the murine p55 showed an identical species preference to the murine p55/p75 high-affinity complex, the human p55 had an equal affinity for human and murine IL 2. This suggested that the human p75 chain was responsible for the preference for human IL 2 shown by the human high-affinity receptor, which was confirmed by performing a binding experiment using gibbon MLA 144 cells, expressing only p75. These data suggest that the amino terminal region of the IL 2 molecule interacts with the p75 chain of the IL 2 receptor.


Potential savings from increased use of generic drugs in the elderly: what the experience of Medicaid and other insurance programs means for a Medicare drug benefit.
Generic medications provide the same clinical effect at lower cost than brand name drugs but little is known about the extent to which such savings are achieved in drug benefit programs serving the elderly. Using patient-level claims data for participants aged 65 or more in one state Medicaid program and in a non-Medicaid drug insurance program for the elderly, we compared the expenditures in each program for brand name prescriptions with the amount that would have been paid for generic versions of the same agents. We then estimated potential savings from increased use of substitutable brand name drugs. There was an unrealized annual savings of 3.4 million dollars (3.6% of total drug expenditure) in the Medicaid program studied and 13.7 million dollars (9.5% of total drug expenditure) in the non-Medicaid drug insurance program for the elderly, with corresponding reductions in mean annual per-patient drug costs. More widespread use of generic medications represents an important source of unrealized savings in drug coverage programs for the elderly. The Medicaid program limits the excess spending on brand name drugs by imposing pricing restrictions, but many non-Medicaid programs could realize even larger savings from reducing the use of brand name drugs when identical generic products are available. These findings offer some insight into the potential expense of a Medicare prescription drug benefit.


Outer membrane vesicle-mediated serum protection in Aggregatibacter actinomycetemcomitans.
Aggregatibacter actinomycetemcomitans belongs to the HACEK group of fastidious Gram-negative organisms, a recognized cause of infective endocarditis. A. actinomycetemcomitans is also implicated in periodontitis, with rapid progress in adolescents. We recently demonstrated that the major outer membrane protein, OmpA1 was critical for serum survival of the A. actinomycetemcomitans serotype a model strain, D7SS, and that the paralogue, OmpA2 could operate as a functional homologue to OmpA1 in mediating serum resistance. In the present work, an essentially serum-sensitive ompA1 ompA2 double mutant A. actinomycetemcomitans strain derivative was exploited to elucidate if A. actinomycetemcomitans OMVs can contribute to bacterial serum resistance. Indeed, supplementation of OMVs resulted in a dose-dependent increase of the survival of the serum-sensitive strain in incubations in 50% normal human serum (NHS). Whereas neither OmpA1 nor OmpA2 was required for the OMV-mediated serum protection, OMVs and LPS from an A. actinomycetemcomitans strain lacking the LPS O-antigen polysaccharide part were significantly impaired in protecting D7SS ompA1 ompA2. Our results using a complement system screen assay support a model where A. actinomycetemcomitans OMVs can act as a decoy, which can trigger complement activation in an LPS-dependent manner, and consume complement components to protect serum-susceptible bacterial cells.


Systems thinking: what business modeling can do for public health.
Today's public health programs are complex business systems with multiple levels of collaborating federal, state, and local entities. The use of proven systems engineering modeling techniques to analyze, align, and streamline public health operations is in the beginning stages. The authors review the initial business modeling efforts in immunization and cancer registries and present a case to broadly apply business modeling approaches to analyze and improve public health processes.


[Clinical analysis of the results in 146 patients with benign tumors or malformations of the oral cavity treated by microwave].
To evaluate the clinical effect of microwave on commonly seen benign tumors or malformations of the oral cavity, 146 patients were randomly selected. There were 78 patients with mucous cyst, 22 patients with papilloma, 24 patients with hemangioma or malformation, 6 patients with lymphatic malformation and 16 patients with epulis. All the patients were treated by ECO-100 microwave. It is concluded that 126 patients were cured (86.3%), 20 patients had good response (13.7%) after treatment.


Missed diagnosis of stroke in the emergency department: a cross-sectional analysis of a large population-based sample.
Some cerebrovascular events are not diagnosed promptly, potentially resulting in death or disability from missed treatments. We sought to estimate the frequency of missed stroke and examine associations with patient, emergency department (ED), and hospital characteristics. Cross-sectional analysis using linked inpatient discharge and ED visit records from the 2009 Healthcare Cost and Utilization Project State Inpatient Databases and 2008-2009 State ED Databases across nine US states. We identified adult patients admitted for stroke with a treat-and-release ED visit in the prior 30 days, considering those given a non-cerebrovascular diagnosis as probable (benign headache or dizziness diagnosis) or potential (any other diagnosis) missed strokes. There were 23,809 potential and 2243 probable missed strokes representing 12.7% and 1.2% of stroke admissions, respectively. Missed hemorrhages (n = 406) were linked to headache while missed ischemic strokes (n = 1435) and transient ischemic attacks (n = 402) were linked to headache or dizziness. Odds of a probable misdiagnosis were lower among men (OR 0.75), older individuals (18-44 years [base]; 45-64:OR 0.43; 65-74:OR 0.28; ≥ 75:OR 0.19), and Medicare (OR 0.66) or Medicaid (OR 0.70) recipients compared to privately insured patients. Odds were higher among Blacks (OR 1.18), Asian/Pacific Islanders (OR 1.29), and Hispanics (OR 1.30). Odds were higher in non-teaching hospitals (OR 1.45) and low-volume hospitals (OR 1.57). We estimate 15,000-165,000 misdiagnosed cerebrovascular events annually in US EDs, disproportionately presenting with headache or dizziness. Physicians evaluating these symptoms should be particularly attuned to the possibility of stroke in younger, female, and non-White patients.


The modulation of brain network integration and arousal during exploration.
There is growing interest in how neuromodulators shape brain networks. Recent neuroimaging studies provide evidence that brainstem arousal systems, such as the locus coeruleus-norepinephrine system (LC-NE), influence functional connectivity and brain network topology, suggesting they have a role in flexibly reconfiguring brain networks in order to adapt behavior and cognition to environmental demands. To date, however, the relationship between brainstem arousal systems and functional connectivity has not been assessed within the context of a task with an established relationship between arousal and behavior, with most prior studies relying on incidental variations in arousal or pharmacological manipulation and static brain networks constructed over long periods of time. These factors have likely contributed to a heterogeneity of effects across studies. To address these issues, we took advantage of the association between LC-NE-linked arousal and exploration to probe the relationships between exploratory choice, arousal-as measured indirectly via pupil diameter-and brain network dynamics. Exploration in a bandit task was associated with a shift toward fewer, more weakly connected modules that were more segregated in terms of connectivity and topology but more integrated with respect to the diversity of cognitive systems represented in each module. Functional connectivity strength decreased, and changes in connectivity were correlated with changes in pupil diameter, in line with the hypothesis that brainstem arousal systems influence the dynamic reorganization of brain networks. More broadly, we argue that carefully aligning dynamic network analyses with task designs can increase the temporal resolution at which behaviorally- and cognitively-relevant modulations can be identified, and offer these results as a proof of concept of this approach.


Potent Inhibitory Effect of BJ-3105, a 6-Alkoxypyridin-3-ol Derivative, on Murine Colitis Is Mediated by Activating AMPK and Inhibiting NOX.
Inflammatory bowel disease (IBD) is a chronic relapsing inflammation in the gastrointestinal tract. Biological therapeutics and orally available small molecules like tofacitinib (a JAK inhibitor) have been developed to treat IBD, but half of the patients treated with these drugs fail to achieve sustained remission. In the present study, we compared the therapeutic effects of BJ-3105 (a 6-alkoxypyridin-3-ol derivative) and tofacitinib in IBD. BJ-3105 induced activation of AMP-activated protein kinase (AMPK) in the kinase activity measurement and recovery from cytokine-induced AMPK deactivation in HT-29 human colonic epithelial cells. Similar to tofacitinib and D942 (an AMPK activator), BJ-3105 inhibited IL-6-induced JAK2/STAT3 phosphorylation and TNF-α-stimulated activation of IKK/NF-κB, and consequently, stimulus-induced upregulations of inflammatory cytokines and inflammasome components. In addition, unlike tofacitinib or D942, BJ-3105 inhibited NADPH oxidase (NOX) activation and consequent superoxide production induced by activators (mevalonate and geranylgeranyl pyrophosphate) of the NOX cytosolic component Rac. In mice, oral administration with BJ-3105 ameliorated dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-induced colitis-associated tumor formation (CAT) much more potently than that with tofacitinib. Moreover, BJ-3105 suppressed the more severe form of colitis and CAT formation in mice with AMPK knocked-out in macrophages (AMPKαfl/fl-Lyz2-Cre mice) with much greater efficacy than tofacitinib. Taken together, our findings suggest BJ-3105, which exerted a much better anti-colitis effect than tofacitinib through AMPK activation and NOX inhibition, is a promising candidate for the treatment of IBD.


Dose-response relationship and time course of action of rocuronium bromide in perspective.
The available evidence indicates that rocuronium is one of the least potent non-depolarizing muscle relaxants, having a clinical duration, recovery index and reversal time similar to those of atracurium and vecuronium. The onset time, however, is significantly shorter than that of currently used non-depolarizing muscle relaxants. Rocuronium seems to be potentiated by the inhalational anaesthetics to the same degree as vecuronium. This effect is clinically most significant when using a continuous infusion of rocuronium. There is no difference in potency of rocuronium between adult and elderly patients, but it is not clear yet whether the potency differs between adults and neonates, infants or children. The onset time, duration of action, and recovery index are prolonged in elderly patients and the onset time, duration of action, and recovery index are longer in infants than in children.


Adaptive developmental plasticity: compartmentalized responses to environmental cues and to corresponding internal signals provide phenotypic flexibility.
The environmental regulation of development can result in the production of distinct phenotypes from the same genotype and provide the means for organisms to cope with environmental heterogeneity. The effect of the environment on developmental outcomes is typically mediated by hormonal signals which convey information about external cues to the developing tissues. While such plasticity is a wide-spread property of development, not all developing tissues are equally plastic. To understand how organisms integrate environmental input into coherent adult phenotypes, we must know how different body parts respond, independently or in concert, to external cues and to the corresponding internal signals. We quantified the effect of temperature and ecdysone hormone manipulations on post-growth tissue patterning in an experimental model of adaptive developmental plasticity, the butterfly Bicyclus anynana. Following a suite of traits evolving by natural or sexual selection, we found that different groups of cells within the same tissue have sensitivities and patterns of response that are surprisingly distinct for the external environmental cue and for the internal hormonal signal. All but those wing traits presumably involved in mate choice responded to developmental temperature and, of those, all but the wing traits not exposed to predators responded to hormone manipulations. On the other hand, while patterns of significant response to temperature contrasted traits on autonomously-developing wings, significant response to hormone manipulations contrasted neighboring groups of cells with distinct color fates. We also showed that the spatial compartmentalization of these responses cannot be explained by the spatial or temporal compartmentalization of the hormone receptor protein. Our results unravel the integration of different aspects of the adult phenotype into developmental and functional units which both reflect and impact evolutionary change. Importantly, our findings underscore the complexity of the interactions between environment and physiology in shaping the development of different body parts.


The incidence of reoperation for surgically treated pelvic organ prolapse: an 11-year experience.
The purpose of this study was to measure the rate of reoperation for surgically treated pelvic organ prolapse. An 11-year retrospective audit was conducted of women who had undergone surgery for pelvic organ prolapse between 1995 and 2005 in a large teaching hospital in the UK. Main outcome measure Variables examined included the type of primary procedure for pelvic organ prolapse overall and per year, the type of the repeat procedure and the interval between primary and repeat procedures. Analysis included calculation of the number and proportion of primary operations, the rate of reoperation, the type of repeat prolapse operation and the cumulative risk of reoperation each year for 11 years. During the study period, 2099 women underwent surgery for pelvic organ prolapse. Of these women, 142 underwent a second operation for prolapse and 13 a third. The overall cumulative rate of reoperation following surgery for pelvic organ prolapse was 10.8% at 11 years following the initial procedure. The majority (61.5%) of repeat procedures did not involve the same compartment as the initial operation and recurrences tended to occur in the first few years after the first operation. Women who undergo surgery for pelvic organ prolapse are at 10.8% risk of requiring a reoperation within the next 11 years, usually at a different site.


Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective.
Mutations of mitochondrial DNA (mtDNA) often underlie mitochondrial disease, one of the most common inherited metabolic disorders. Since the sequencing of the human mitochondrial genome and the discovery of pathogenic mutations in mtDNA more than 30 years ago, a movement towards generating methods for robust manipulation of mtDNA has ensued, although with relatively few advances and some controversy. While developments in the transformation of mammalian mtDNA have stood still for some time, recent demonstrations of programmable nuclease-based technology suggest that clinical manipulation of mtDNA heteroplasmy may be on the horizon for these largely untreatable disorders. Here we review historical and recent developments in mitochondrially targeted nuclease technology and the clinical outlook for treatment of hereditary mitochondrial disease.


ACL Roof Impingement Revisited: Does the Independent Femoral Drilling Technique Avoid Roof Impingement With Anteriorly Placed Tibial Tunnels?
Anatomic femoral tunnel placement for single-bundle anterior cruciate ligament (ACL) reconstruction is now well accepted. The ideal location for the tibial tunnel has not been studied extensively, although some biomechanical and clinical studies suggest that placement of the tibial tunnel in the anterior part of the ACL tibial attachment site may be desirable. However, the concern for intercondylar roof impingement has tempered enthusiasm for anterior tibial tunnel placement. To compare the potential for intercondylar roof impingement of ACL grafts with anteriorly positioned tibial tunnels after either transtibial (TT) or independent femoral (IF) tunnel drilling. Controlled laboratory study. Twelve fresh-frozen cadaver knees were randomized to either a TT or IF drilling technique. Tibial guide pins were drilled in the anterior third of the native ACL tibial attachment site after debridement. All efforts were made to drill the femoral tunnel anatomically in the center of the attachment site, and the surrogate ACL graft was visualized using 3-dimensional computed tomography. Reformatting was used to evaluate for roof impingement. Tunnel dimensions, knee flexion angles, and intra-articular sagittal graft angles were also measured. The Impingement Review Index (IRI) was used to evaluate for graft impingement. Two grafts (2/6, 33.3%) in the TT group impinged upon the intercondylar roof and demonstrated angular deformity (IRI type 1). No grafts in the IF group impinged, although 2 of 6 (66.7%) IF grafts touched the roof without deformation (IRI type 2). The presence or absence of impingement was not statistically significant. The mean sagittal tibial tunnel guide pin position prior to drilling was 27.6% of the sagittal diameter of the tibia (range, 22%-33.9%). However, computed tomography performed postdrilling detected substantial posterior enlargement in 2 TT specimens. A significant difference in the sagittal graft angle was noted between the 2 groups. TT grafts were more vertical, leading to angular convergence with the roof, whereas IF grafts were more horizontal and universally diverged from the roof. The IF technique had no specimens with roof impingement despite an anterior tibial tunnel position, likely due to a more horizontal graft trajectory and anatomic placement of the ACL femoral tunnel. Roof impingement remains a concern after TT ACL reconstruction in the setting of anterior tibial tunnel placement, although statistical significance was not found. Future clinical studies are planned to develop better recommendations for ACL tibial tunnel placement. Graft impingement due to excessively anterior tibial tunnel placement using a TT drilling technique has been previously demonstrated; however, this may not be a concern when using an IF tunnel drilling technique. There may also be biomechanical advantages to a more anterior tibial tunnel in IF tunnel ACL reconstruction.


Important role of the government in reducing pesticide use and risk sustainably in Thailand: Current situation and recommendations.
Agriculture is an important aspect of Thailand's GDP and development. It ranks as the 8th largest exporter in the world, however, pesticide use associated with the agriculture is ranked 18th in the world and 5th in Asia. Previous studies have clearly stated that pesticides are a threat to human health and the environment. The government is now making efforts to address pesticide use and the health impacts of pesticide use, however, these efforts are still in need of completion. This paper aims to summarize: (1) the current situation with regard to pesticide use in Thailand; (2) the current situation with regard to pesticide poisoning in Thailand; and (3) important role of government in reducing pesticide use and risk sustainably in Thailand: current situation and recommendations. This article suggests that government is a significant driver for reducing pesticide use and risk sustainably and the establishment of push and pull policies, legislation, and strategies. The government needs to strictly adhere to international conventions. Introducing a pesticide tax is essential to reduce redundant pesticide use. Updating of the current act, specific regulations with regard to pesticides and strict enforcement are urgently required. Licensing pesticide applicators should be implemented continuously. Promotion of alternative pest management is needed by supportive production inputs, technology, and markets as well as the development of a monitoring and certification system. Educating consumers on how to choose safe agricultural products and reduce risk from pesticide residues in the products is also necessary. All approaches should be implemented simultaneously and instantly. Importantly, the government needs to cooperate with agricultural sectors, health and environmental sectors, private sectors, as well as food industries to tackle complicate issues in a sustainable manner and lower pesticide use and risk sustainably in Thailand.


A ceramic radial insulation structure for a relativistic electron beam vacuum diode.
For one kind of a high current diode composed of a small disk-type alumina ceramic insulator water/vacuum interface, the insulation structure was designed and experimentally investigated. According to the theories of vacuum flashover and the rules for radial insulators, a "cone-column" anode outline and the cathode shielding rings were adopted. The electrostatic field along the insulator surface was obtained by finite element analysis simulating. By adjusting the outline of the anode and reshaping the shielding rings, the electric fields were well distributed and the field around the cathode triple junction was effectively controlled. Area weighted statistical method was applied to estimate the surface breakdown field. In addition, the operating process of an accelerator based on a spiral pulse forming line (PFL) was simulated through the PSPICE software to get the waveform of charging and diode voltage. The high voltage test was carried out on a water dielectric spiral PFL accelerator with long pulse duration, and results show that the diode can work stably in 420 kV, 200 ns conditions. The experimental results agree with the theoretical and simulated results.


Comment on "An optimized potential for carbon dioxide" [J. Chem. Phys. 122, 214507 (2005)].
A molecular model for carbon dioxide is assessed regarding vapor-liquid equilibrium properties. Large deviations, being above 15%, are found for vapor pressure and saturated vapor density in the entire temperature range.


Design, stray light analysis, and fabrication of a compact head-mounted display using freeform prisms.
It has been a challenge to design an optical see-through head-mounted display that is compact, lightweight, and stray-light-suppressed by using freeform optics. A new type of design based on freeform prisms is presented. The system consists of three optical elements and a micro-display. Two prisms serve as near-eye viewing optics that magnify the image displayed by the micro-display, and the other freeform lens is an auxiliary element attached to the main wedge-shaped prism to provide an undistorted see-through view of a real-world scene. The overall thickness of the optical system does not exceed 9.5 mm, and the weight is less than 9.8 g per eye. The final system is based on a 0.49-inch micro-display and features a diagonal field of view of 38°, an F/number of 1.8, with a 10 mm × 7 mm exit pupil diameter, and a 19 mm eye relief. The causes of stray light in the optical-mechanical system are investigated, and effective solutions or theoretical suppression of stray light are given. The freeform optical elements are successfully fabricated, and the system performance is carefully investigated. The results show that the performance of the optical see-through head-mounted display is adequate for practical applications.


Computational Methods to Model Persistence.
Bacterial persister cells are dormant cells, tolerant to multiple antibiotics, that are involved in several chronic infections. Toxin-antitoxin modules play a significant role in the generation of such persister cells. Toxin-antitoxin modules are small genetic elements, omnipresent in the genomes of bacteria, which code for an intracellular toxin and its neutralizing antitoxin. In the past decade, mathematical modeling has become an important tool to study the regulation of toxin-antitoxin modules and their relation to the emergence of persister cells. Here, we provide an overview of several numerical methods to simulate toxin-antitoxin modules. We cover both deterministic modeling using ordinary differential equations and stochastic modeling using stochastic differential equations and the Gillespie method. Several characteristics of toxin-antitoxin modules such as protein production and degradation, negative autoregulation through DNA binding, toxin-antitoxin complex formation and conditional cooperativity are gradually integrated in these models. Finally, by including growth rate modulation, we link toxin-antitoxin module expression to the generation of persister cells.


The M6 cell: A small-field bistratified photosensitive retinal ganglion cell.
We have identified a novel, sixth type of intrinsically photosensitive retinal ganglion cell (ipRGC) in the mouse-the M6 cell. Its spiny, highly branched dendritic arbor is bistratified, with dendrites restricted to the inner and outer margins of the inner plexiform layer, co-stratifying with the processes of other ipRGC types. We show that M6 cells are by far the most abundant ganglion cell type labeled in adult pigmented Cdh3-GFP BAC transgenic mice. A few M5 ipRGCs are also labeled, but no other RGC types were encountered. Several distinct subnuclei in the geniculate complex and the pretectum contain labeled retinofugal axons in the Cdh3-GFP mouse. These are presumably the principle central targets of M6 cells (as well as M5 cells). Projections from M6 cells to the dorsal lateral geniculate nucleus were confirmed by retrograde tracing, suggesting they contribute to pattern vision. M6 cells have low levels of melanopsin expression and relatively weak melanopsin-dependent light responses. They also exhibit strong synaptically driven light responses. Their dendritic fields are the smallest and most abundantly branched of all ipRGCs. They have small receptive fields and strong antagonistic surrounds. Despite deploying dendrites partly in the OFF sublamina, M6 cells appear to be driven exclusively by the ON pathway, suggesting that their OFF arbor, like those of certain other ipRGCs, may receive ectopic input from passing ON bipolar cells axons in the OFF sublayer.


A 28-kDa protein from Mycobacterium leprae is a target of the human antibody response in lepromatous leprosy.
The gene for a 28-kDa Mycobacterium leprae protein Ag, a major target of antibodies from patients with lepromatous leprosy, was cloned from a lambda-gt11-M. leprae DNA expression library and sequenced. Antibodies to this protein were detected in the serum of the majority of 15 individual lepromatous patients that were tested. The predicted amino acid sequence of the 28-kDa protein suggests that it is localized to the bacterial plasma membrane or cell wall.


Detecting osteoporosis. Beyond the history and physical examination.
A number of developments are contributing to clinicians' understanding of osteoporosis as a clinical continuum characterized by low bone mass and increased risk of fractures rather than as a disease characterized by fragility fractures. With improved capability for accurate measurement of bone mass, the prevalence of this disease has increased to include at least 25 million Americans. The responsibility of primary care physicians to detect and treat osteoporosis has increased accordingly. Parents should be counseled regarding their children's diet and lifestyle to optimize peak adult bone mass and ensure adequate dietary calcium intake. Adults should be counseled to minimize behaviors that result in accelerated bone loss (e.g., smoking, alcohol use, anorexia, bulimia). Physicians need to be aware of the serious potential complications of osteoporosis and offer counseling to menopausal women about the disease and the benefits and risks of hormone replacement and estrogen replacement therapy. Physicians should be familiar with technologies available in their community for measuring bone mass and recognize the need to consider prescribing pharmacologic and nonpharmacologic therapies for patients with low bone mass or osteoporosis. Physicians also can educate caregivers about prevention of falls and fractures in elderly patients who are unsteady on their feet. Improved technologies for bone mass measurement and fracture risk assessment, as well as expanded options for treatment and prevention of osteoporosis, are likely to become available within the next 5 to 10 years, thereby increasing the wisdom of early detection and treatment of osteoporosis.


Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children.
To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD. A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category. Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P < .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62). Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.


Immunohistopathological properties of pleomorphic adenoma in salivary gland.
Fifty-eight salivary gland pleomorphic adenomas and 5 normal salivary glands were studied immunohistochemically with respect to intermediate filaments (keratin, desmin, and vimentin), actin and S-100 protein to observe the cellular differentiation of these tumor cells. Normal myoepithelial cells showed positive immunostaining for actin, vimentin and S-100 protein. Pleomorphic adenomas expressed keratin, vimentin and S-100 protein to various degrees, but only a few tumor cells of pleomorphic adenoma revealed actin. The results indicate that the tumor cells of pleomorphic adenoma show a bipolar differentiation capability of both epithelial and mesenchymal origins, although normal myoepithelial cells show only mesenchymal characteristics. The findings also support previous reports using light and electron microscopy, and also contribute to more precise diagnosis and a better understanding of the histogenesis of this tumor.