Respiratory, laryngeal, and tracheal responses to nasal insufflation of volatile anesthetics in anesthetized humans.
In order to determine whether or not irritation of the nasal passage with commonly used volatile anesthetics can elicit airway reflexes, we investigated respiratory, laryngeal, and tracheal responses to nasal insufflation of three volatile anesthetics (enflurane, isoflurane, and halothane) in 13 patients anesthetized with flunitrazepam, pentazocine, and nitrous oxide. The trachea of each patient was intubated with a saline-filled double-cuffed endotracheal tube. Changes in breathing pattern were measured with a pneumotachograph while changes in laryngeal wall tension and tracheal wall tension were assessed by measuring changes in the proximal cuff pressure and the distal cuff pressure, respectively. In 8 of 13 patients, the dose-response relationship for each anesthetic was determined by administering different concentrations (1, 3, and 5%) of gas mixtures. In these patients, nasal insufflation of 1 and 3% of each anesthetic did not produce any reflex response, whereas reflex responses were evident during nasal insufflation of 5% enflurane, isoflurane, and halothane. In all 13 patients, nasal insufflation of all three anesthetics at a concentration of 5% invariably produced changes in breathing pattern characterized by prolongation of expiratory time (TE). However, prolongation of TE was the most pronounced for enflurane (from a control value of 2.1 +/- 0.5 to a maximum value of 4.8 +/- 2.2 s [mean +/- standard deviation]), less for isoflurane (from 2.2 +/- 0.5 to 3.9 +/- 1.7 s), and the least for halothane (from 2.2 +/- 0.6 to 2.9 +/- 0.9 s).(ABSTRACT TRUNCATED AT 250 WORDS)


Effectiveness of active nasal surveillance culture for Methicillin-resistant Staphylococcus aureus in patients undergoing colorectal surgery.
The aim of this study was to clarify the role of Methicillin-resistant Staphylococcus aureus (MRSA) carriers in the development of surgical site infection (SSI) after colorectal surgery. MRSA is commonly implicated in hospital-acquired infections. Active surveillance culture (ASC) using the nasal swab test is useful to detect MRSA in surgical patients. We hypothesized that MRSA carriers would be more susceptible to SSI after colorectal surgery METHODS: Patients who underwent ASC between 2010 and 2013 were included in this study. The incidence of SSI was compared between MRSA carriers and non-carriers using the chi-square test. The odds ratio for SSI was computed using logistic regression analyses. Among 355 patients, 12 (3.4%) were identified as MRSA carriers and 343 as non-carriers. Of all the patients, 65 patients (18.3%) developed an SSI. Of these, 6 cases were in MRSA carriers and 59 cases were in non-carriers (p < 0.01). This meant that half of the 12 MRSA carriers developed an SSI, compared with only 17.2% of non-carriers (59 cases out of 343 patients). Therefore, MRSA carriers had a significantly higher risk of SSI (adjusted odds ratio = 4.77 [1.37 to 16.6], p = 0.01). Detection of MRSA via ASC is significantly associated with the development of SSI after colorectal surgery. These findings indicate that ASC for MRSA is useful to predict an SSI.


Tcf- and Vent-binding sites regulate neural-specific geminin expression in the gastrula embryo.
Vertebrate neural development has been extensively investigated. However, it is unknown for any vertebrate gene how the onset of neural-specific expression in early gastrula embryos is transcriptionally regulated. geminin expression is among the earliest markers of dorsal, prospective neurectoderm at early gastrulation in Xenopus laevis. Here, we identified two 5' sequence domains that are necessary and sufficient to drive neural-specific expression during gastrulation in transgenic Xenopus embryos. Each domain contained putative binding sites for the transcription factor Tcf, which can mediate Wnt signaling and for Vent homeodomain proteins, transcriptional repressors that mediate BMP signaling. Results from embryos transgenic for constructs with mutated Tcf or Vent sites demonstrated that signaling through the Tcf sites was required for dorsal-specific expression at early gastrulation, while signaling through the Vent sites restricted geminin expression to the prospective neurectoderm at mid-gastrulation. Consistent with these results, geminin 5' regulatory sequences and endogenous Xgem responded positively to Wnt signaling and negatively to BMP signaling. The two 5' sequence domains were also conserved among geminin orthologs. Together, these results demonstrate that signaling through Tcf and Vent binding sites regulates transcription of geminin in prospective neurectoderm during gastrulation.


Effects of 5-fluorouracil and a combination of tegafur and uracil (UFT) on nucleotide metabolism in L1210 ascites tumor.
Changes in the deoxyribonucleotide pools following a single oral administration of 13 mg/kg of 5-fluorouracil (5-FU) or of 64.8 mg/kg of UFT (a mixed compound of tegafur and uracil) were investigated. We compared their pharmacodynamics and effects on nucleotide metabolism in L1210 ascites tumor on day 3 after intraperitoneal tumor inoculation. The intracellular dTTP pool decreased to half the control level 1-6 hr after the administration of 5-FU. The dTTP pools rapidly recovered after 6 hr. In contrast, UFT kept the intracellular dTTP level to 1/3 to 1/2 of the control level for 24 hr. Either drug elevated the intracellular dATP pools, but decreased dCTP pools. UFT influenced the intracellular dATP and dCTP levels longer than 5-FU. Orally administered UFT seemed to exert a longer and more potent inhibitory effect on thymidylate synthetase than equimolar 5-FU. In view of these results, we suggest that UFT could be a more potent chemotherapeutic drug than 5-FU in oral administration.


A Nomogram to Predict Regrowth After Ultrasound-Guided Radiofrequency Ablation for Benign Thyroid Nodules.
To develop and validate a nomogram to predict regrowth for patients with benign thyroid nodules undergoing radiofrequency ablation (RFA). A total of 200 patients with 220 benign thyroid nodules who underwent RFA were included in this respective study. After RFA, patients were followed up at 1, 3, 6, and 12 months, and every 12 months thereafter. Regrowth was defined as an increase in nodule volume 50% over the previously recorded smallest volume. A nomogram was developed based on the variables identified by multivariate logistic regression and the model performance was evaluated by discrimination(concordance index) and calibration curves. The incidence of regrowth was 13.64% (30/220) after a mean follow-up period of 27.43 ± 17.99 months. Multivariate logistic regression revealed initial volume (OR = 1.047, 95%CI 1.020-1.075), vascularity (OR = 2.037, 95%CI 1.218-3.404), and location close to critical structure (OR = 4.713, 95%CI 1.817-12.223) were independent factors associated with regrowth. The prognostic nomogram incorporating these three factors achieved good calibration and discriminatory abilities with a concordance index of 0.779 (95%CI 0.686-0.872). A prognostic nomogram was successfully developed to predict nodule regrowth after RFA, which might guide physician in stratifying patients and provide precise guidance for individualized treatment protocols.


The 'epidemic' of melanoma between under- and overdiagnosis.
In the past decades, the incidence of melanoma has been reported to rise in epidemic proportions. The chief reason for that pseudo-epidemic is improved criteria for diagnosis that allow melanomas to be recognized far more accurately and at earlier stages. The rising number of melanomas diagnosed has resulted in increased diagnostic scrutiny, more pigmented lesions being biopsied and more melanomas recognized, thus enhancing the 'epidemic' in self-perpetuating fashion. Regression of melanomas may, in part, explain why lesions undetected before did not result in a far higher mortality. Another potential reason for the disparity between increasing incidence of melanoma and relatively steady mortality may be overdiagnosis of melanoma. The latter may be curtailed by establishment of well-defined diagnostic categories, efforts to establish reliable criteria for recognition of those categories, better clinicopathologic correlation, postponement of biopsy of pigmented lesions in the case of irritation and excisional rather than incisional biopsies.


Oral ulcerations in a patient with autosomal dominant hyper-IgE syndrome (AD-HIES).
A 23-year-old woman with autosomal dominant hyper-IgE syndrome complicated by recurrent pneumonia and sinusitis presented with 1 week of multiple painful oral ulcers unresponsive to empiric antiviral and antifungal treatment. Her ulcers progressively worsened and she required hospitalisation for intravenous hydration and pain control. PCR swab of an ulcer was positive for varicella-zoster virus. Her symptoms never fully resolved despite antiviral therapy, and within 2 weeks, she relapsed with new and worsening ulcers. Biopsy revealed chronic active inflammation with no evidence of viral inclusion bodies or fungal hyphae. She was diagnosed with recurrent aphthous stomatitis and referred to a local dentist for CO2 laser treatments with rapid resolution of her symptoms. This case highlights the broad differential for recurrent oral ulcers in people with a primary immunodeficiency. It also raises awareness of the benefits of laser therapy for aphthous stomatitis treatment and the importance of partnering with our colleagues in dentistry.


Inhibition of UV-induced immune suppression and interleukin-10 production by plant oligosaccharides and polysaccharides.
Application of Aloe barbadensis poly/oligosaccharides to UV-irradiated skin prevents photosuppression of delayed-type hypersensitivity (DTH) responses in mice. We tested the hypothesis that these carbohydrates belong to a family of biologically active, plant-derived polysaccharides that can regulate responses to injury in animal tissues. C3H mice were exposed to 5 kJ/m2 UVB from unfiltered FS40 sunlamps and treated with between 1 pg and 10 micrograms tamarind xyloglucans or control polysaccharides methylcellulose or dextran in saline. The mice were sensitized 3 days later with Candida albicans. Tamarind xyloglucans and purified Aloe poly/oligosaccharides prevented suppression of DTH responses in vivo and reduced the amount of interleukin (IL)-10 observed in UV-irradiated murine epidermis. Tamarind xyloglucans were immunoprotective at low picogram doses. In contrast, the control polysaccharides methylcellulose and dextran had no effect on immune suppression or cutaneous IL-10 at any dose. Tamarind xyloglucans and Aloe poly/oligosaccharides also prevented suppression of immune responses to alloantigen in mice exposed to 30 kJ/m2 UVB radiation. To assess the effect of the carbohydrates on keratinocytes, murine Pam212 cells were exposed to 300 J/m2 UVB radiation and treated for 1 h with tamarind xyloglucans or Aloe poly/oligosaccharides. Treatment of keratinocytes with immunoprotective carbohydrates reduced IL-10 production by approximately 50% compared with the cells treated with UV radiation alone and completely blocked suppressive activity of the culture supernatants in vivo. The tamarind xyloglucans also blocked UV-activated phosphorylation of SAPK/JNK protein but had no effect on p38 phosphorylation. These results indicate that animals, like plants, may use carbohydrates to regulate responses to environmental stimuli.


Kinetic mechanism of chain folding in polymer crystallization.
I develop a kinetic mechanism to explain chain folding in polymer crystallization which is based on the competition between the formation of stems, which is due to frequent occupations of trans states along the chains in the supercooled polymer melt, and the random coil structure of the polymer chains. Setting equal the average formation time of stems of length d(l) with the Rouse time of a piece of polymer of the same arc length d(l) yields a lower bound for the thickness of stems and bundles. The estimated lamellar thickness is inversely proportional to the supercooling. The present approach emphasizes the importance of repulsive interactions in polymer crystallization, which are expected to be responsible for the logarithmic lamellar thickening and the increase of lamellar thickness with pressure. An expression for the growth rate for formation and deposition of stems is derived by considering the growth as a dynamic multistage process.


Solid Lipid Nanoparticles of Mycophenolate Mofetil: An Attempt to Control the Release of an Immunosuppressant.
Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. Currently, the nanoprecipitation method was employed to fabricate β-cyclodextrin (βCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.


[Brachial diplegia of traumatic origin as a result of injuries of the cervical cord].
Described by Dide and Lhermitte (1917) the brachial diplegia or bilateral paralysis of the upper limbs, is called since Schneider's data acute central spinal cord injury (1956). It is characterized by disproportionately more motor impairment of the upper than of the lower limbs, bladder dysfunction and variable sensory loss (pain and temperature) below the level of the cervical injury. For Richard C. Schneider the mechanism is a severe hyperextension injury and the anatomical finding indicate a central cord destruction with bleeding and hematomyelia. The pattern of the recovery is first return of the motor power in lower extremities; then bladder function and finally strength in the upper extremities reappears (finer finger movements coming back last). In our experience (28 cases) the incidence of the brachial diplegia is 20% of the cervical spinal cord injury and 31% of the incomplete cord lesions. The average age is 54 years. In the half of our cases hyperextension is the responsible mechanism and hyperflexion is present in one third of patients. Radiological findings indicate some vertebral displacement in 40% of cases and no patent loss of the bodies alignment in 28% of patients. Clinical investigations authorize the description of 4 clinical patterns: 1--Incomplete tetraplegia with more motor impairment of the upper extremities (57%), 2--Brachial diplegia (without loss of function of the lower limbs) 25%, 3--Brachial diparesis with total recovery (11%), 4--Incomplete cord lesions with Brown Sequard syndrome and brachial diplegia (7%). The review of the literature (Bohlman, Barraquer) and our anatomical findings show that central hematomyelia is not constant.(ABSTRACT TRUNCATED AT 250 WORDS)


The wound epithelium of regenerating limbs of Pleurodeles waltl and Notophthalmus viridescens: studies with mAbs WE3 and WE4, phalloidin, and DNase 1.
The wound epithelium of regenerating limbs of the American newt, Notophthalmus viridescens (Nv), up-regulates a number of antigens, including those recognized by mAbs WE3 and WE4. In the present study, we show that the WE3 antigen is up-regulated in a similar fashion in the wound epithelium of the European newt, Pleurodeles waltl (Pw). mAb WE3 and WE4 reactivities to secretory/transport body cell types, including integumentary glands, perineurium, endothelium, and conjunctiva, are also similar in these two species of newt. However, mAb WE4 reacts to both the epidermis and wound epithelium in Pw, whereas in Nv, mAb WE4 reacts only to the wound epithelium. Because the WE3 antigen is cytoskeleton-associated and Western blots reveal a 43 kDa species, we compared mAb WE3 reactivity with that of rhodamine-labeled phalloidin, a known actin-binding compound. Phalloidin did not react preferentially to the wound epithelium, conjunctiva, or other cell types strongly reactive to mAb WE3. Pretreatment of sections and tissue extracts with DNAse 1, a protein known to bind to actin, nearly abolished mAb WE3 reactivity in tissue sections and both WE3 and WE4 reactivity in ELISA assays, respectively. The results lead to the hypothesis that the WE3 and WE4 antigens are actin-binding proteins unique to the wound epithelium and other secretory/transport cell types.


Aspirin relieves the calcification of aortic smooth muscle cells by enhancing the heat shock response.
Vascular calcification is a major complication of chronic renal failure, which has been identified as an active process partly driven by osteogenic transition of vascular smooth muscle cells (VSMCs). Aspirin could prevent cardiomyocyte damage by inducing heat shock response. This study investigates the effect of aspirin on alleviating VSMC calcification. An in vitro VSMC calcification model was established by 10-day calcification induction in osteogenic medium. VSMCs were grouped as following: control group (normal medium), calcified group (osteogenic medium) and treated group (osteogenic medium with 1 or 4 mmol/L aspirin). VSMC calcification was evaluated by calcified nodules formation, intracellular calcium concentration and osteoblastic marker (OPN and Runx2) expression. After 10-day culture, the intracellular calcium concentration in calcified group was significantly higher than that in control group (1.16 ± 0.04 vs. 0.14 ± 0.01 μg/mg, p < 0.01), but significantly reduced in 1 mmol/L aspirin treated group (0.74 ± 0.05 μg/mg, p < 0.01), and 4 mmol/L aspirin treated group (0.93 ± 0.03 μg/mg, p < 0.01). The elevated expression of OPN and Runx2 induced by osteogenic medium was significantly relieved after 1 or 4 mmol/L aspirin treatment. The expression of HSF1, HSP70 and HSP90 was decreased in calcification-induced VSMCs, but significantly increased after treatment of aspirin. Furthermore, inhibition of HSP70 (or HSP90) by small-molecule inhibitor or small interfering RNA could partially abolish the anti-calcification effect of aspirin, proved by the changes of intracellular calcium concentration and osteoblastic marker expression. Aspirin could relieve the calcification of VSMCs partially through HSP70- or HSP90-mediated heat shock response. These findings expanded the understanding of aspirin pharmacology, and imply that local induction expression of HSPs might be a potential therapeutic strategy for the prevention and therapy of vascular calcification.


[A case of anaphlaxis caused by mite-contaminated Okonomi-yaki].
A 21-year-old man, who had suddenly developed dyspnea with sneeze, cough and nasal congestion following supper, was admitted to our hospital because of hypoxemia and hypercapnia. Physical examination revealed wheezing in all lung fields and skin flushing. He took home-made Okonomi-yaki made from flour, which had been opened few months ago, and then had been remained uncooked at room temperature. Skin prick tests showed positive for problem flour and mite, but negative for just opened control flour. Collectively, we gave his diagnosis of anaphylaxis caused by mite-contaminated Okonomi-yaki.


Completion pancreatectomy for treatment of a Clostridium perfringens pancreatic infection.
Pancreatic infection is associated with high morbidity and mortality. Drainage of the infection is the usual therapeutic approach. Clostridium perfringens infection can cause fulminant sepsis, but it rarely occurs within the pancreas. The case of a 76-year-old man with cystic pancreatic lesions in which sepsis developed after endoscopic ultrasound with fine-needle aspiration biopsy is described. The sepsis was managed with pancreatic resection and antibiotics. Clostridium perfringens was isolated from blood cultures and microbiologic smears from the pancreas. Invasive intraductal papillary mucinous neoplasm with lymph node involvement was identified on histologic examination. The patient made a complete recovery from surgery without complications.


Local Application of Gentamicin in the Prophylaxis of Perineal Wound Infection After Abdominoperineal Resection: A Systematic Review.
Use of topical antibiotics to improve perineal wound healing after abdominoperineal resection (APR) is controversial. The aim of this systematic review was to determine the impact of local application of gentamicin on perineal wound healing after APR. The electronic databases Pubmed, EMBASE, and Cochrane library were searched in January 2015. Perineal wound outcome was categorized as infectious complications, non-infectious complications, and primary perineal wound healing. From a total of 582 articles, eight studies published between 1988 and 2012 were included: four randomized controlled trials (RCTs), three comparative cohort studies, and one cohort study without control group. Gentamicin was administered using sponges (n = 3), beads (n = 4), and by local injection (n = 1). There was substantial heterogeneity regarding underlying disease, definition of outcome parameters and timing of perineal wound evaluation among the included studies, which precluded meta-analysis with pooling. Regarding infectious complications, three of six evaluable studies demonstrated a positive effect of local application of gentamicin: one of four RCTs and both comparative cohort studies. Only two RCTs reported on non-infectious complications, showing no significant impact of gentamicin sponge. All three comparative cohort studies demonstrated a significantly higher percentage of primary perineal wound healing after local application of gentamicin beads, but only one out of three evaluable RCTs did show a positive effect of gentamicin sponges. Currently available evidence does not support perineal gentamicin application after APR.


Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11.
Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFβ-smooth muscle myosin heavy chain (SMMHC; encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain helicase DNA-binding protein-7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. These results suggest that CHD7 is also critical for CBFB-MYH11-induced leukemogenesis. To test this hypothesis, we generated Chd7f/fMx1-CreCbfb+/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with polyinosinic-polycytidylic acid. The Lin-Sca1-c-Kit+ (LK) population was significantly lower in Chd7f/fMx1-CreCbfb+/56M mice than in Mx1-CreCbfb+/56M mice. In addition, there were fewer 5-bromo-2'-deoxyuridine-positive cells in the LK population in Chd7f/fMx1-CreCbfb+/56M mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7f/fMx1-CreCbfb+/56M and Mx1-CreCbfb+/56M leukemic cells. In vitro studies showed that CHD7 interacted with CBFβ-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBFβ-SMMHC on Csf1r, a RUNX1 target gene. Moreover, RNA sequencing of c-Kit+ cells showed that CHD7 functions mostly through altering the expression of RUNX1 target genes. Most importantly, Chd7 deficiency delayed Cbfb-MYH11-induced leukemia in both primary and transplanted mice. These data indicate that Chd7 is important for Cbfb-MYH11-induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.


Performance of High-Layer-Thickness Ti6Al4V Fabricated by Electron Beam Powder Bed Fusion under Different Accelerating Voltage Values.
The electron beam powder bed fusion (EB-PBF) process is typically carried out using a layer thickness between 50 and 100 μm with the accelerating voltage of 60 kV for the electron beam. This configuration ensures forming accuracy but limits building efficiency. The augmentation of the accelerating voltage enlarges the molten pool due to the rise in penetrability, suggesting that a higher layer thickness can be used. Therefore, the effects of layer thickness and accelerating voltage were investigated simultaneously in this study to explore the feasibility of efficiency improvement. Ti6Al4V was fabricated by EB-PBF using layer thicknesses of 200 and 300 μm. Two accelerating voltage values of 60 and 90 kV were used to study their effects under expanded layer thickness. The results reveal that dense parts with the ultimate tensile strength higher than 950 MPa and elongation higher than 9.5% could be fabricated even if the layer thickness reached 300 μm, resulting in a building rate of up to 30 mm3/s. The expansion of the layer thickness could decrease the minimum bulk energy density needed to fabricate dense parts and increase the α platelet thickness, which improved the energy efficiency. However, expanding layer thickness had a significant negative effect on surface roughness, but it could be improved by applying augmented accelerating voltage.


Long-period grating and its application in laser beam shaping in the 1.0 microm wavelength region.
Laser beam shaping is an important subject for industrial and medical applications since different applications may require different laser intensity distributions. We present an all-fiber beam-shaping device that could transform a Gaussian-shaped laser beam into an intensity uniform beam in the 1.0 microm wavelength region using a long-period grating (LPG). The device can be used to shape the beam of a Yb-doped high-power fiber laser. The mode structure of the LPGs made of HI1060 fiber is analyzed. The design parameters that affect the beam shaping are discussed, and the results of the beam shaping using two cladding modes, LP(03) and LP(04), are presented.


Oligomerization-dependent folding of the membrane fusion protein of Semliki Forest virus.
The spikes of alphaviruses are composed of three copies of an E2-E1 heterodimer. The E1 protein possesses membrane fusion activity, and the E2 protein, or its precursor form, p62 (sometimes called PE2), controls this function. Both proteins are, together with the viral capsid protein, translated from a common C-p62-E1 coding unit. In an earlier study, we showed that the p62 protein of Semliki Forest virus (SFV) dimerizes rapidly and efficiently in the endoplasmic reticulum (ER) with the E1 protein originating from the same translation product (so-called heterodimerization in cis) (B.-U. Barth, J. M. Wahlberg, and H. Garoff, J. Cell Biol. 128:283-291, 1995). In the present work, we analyzed the ER translocation and folding efficiencies of the p62 and E1 proteins of SFV expressed from separate coding units versus a common one. We found that the separately expressed p62 protein translocated and folded almost as efficiently as when it was expressed from a common coding unit, whereas the independently expressed E1 protein was inefficient in both processes. In particular, we found that the majority of the translocated E1 chains were engaged in disulfide-linked aggregates. This result suggests that the E1 protein needs to form a complex with p62 to avoid aggregation. Further analyses of the E1 aggregation showed that it occurred very rapidly after E1 synthesis and could not be avoided significantly by the coexpression of an excess of p62 from a separate coding unit. These latter results suggest that the p62-E1 heterodimerization has to occur very soon after E1 synthesis and that this is possible only in a cis-directed reaction which follows the synthesis of p62 and E1 from a common coding unit. We propose that the p62 protein, whose synthesis precedes that of the E1 protein, remains in the translocon of the ER and awaits the completion of E1. This strategy enables the p62 protein to complex with the E1 protein immediately after the latter has been made and thereby to control (suppress) its fusion activity.


Consistent, small effects of treefall disturbances on the composition and diversity of four Amazonian forests.
Understanding the resilience of moist tropical forests to treefall disturbance events is important for understanding the mechanisms that underlie species coexistence and for predicting the future composition of these ecosystems. Here, we test whether variation in the functional composition of Amazonian forests determines their resilience to disturbance.We studied the legacy of natural treefall disturbance events in four forests across Amazonia that differ substantially in functional composition. We compared the composition and diversity of all free-standing woody stems 2-10 cm diameter in previously disturbed and undisturbed 20 × 20 m subplots within 55, one-hectare, long-term forest inventory plots.Overall, stem number increased following disturbance, and species and functional composition shifted to favour light-wooded, small-seeded taxa. Alpha-diversity increased, but beta-diversity was unaffected by disturbance, in all four forests.Changes in response to disturbance in both functional composition and alpha-diversity were, however, small (2 - 4% depending on the parameter) and similar among forests. Synthesis. This study demonstrates that variation in the functional composition of Amazonian forests does not lead to large differences in the response of these forests to treefall disturbances, and overall, these events have a minor role in maintaining the diversity of these ecosystems.


Serum neopterin levels in spontaneous urticaria and atopic dermatitis.
Serum neopterin may be considered a diagnostic marker of the degree of activation of the immune system. This preliminary study was performed to measure serum neopterin levels in patients with acute spontaneous urticaria (ASU), chronic spontaneous urticaria (CSU) and atopic dermatitis (AD). In total, 180 patients [96 men, 84 women; mean age 23.1 years; 41 with spontaneous urticaria (13 ASU and 28 CSU), 48 with AD] and 96 healthy controls were enrolled in the study. Patients with ASU had the highest neopterin levels, and all three groups of patients (ASU, CSU and AD) had higher values than normal subjects. This preliminary study demonstrates that serum neopterin could be a biomarker of immune activation in patients with SU or AD.


Nightmare Disorder, Psychopathology Levels, and Coping in a Diverse Psychiatric Sample.
Nightmares are associated with psychopathology and impaired coping in the general population. However, little is known about this association in a psychiatric population. In this study, we investigate whether patients with diverse psychiatric disorders have increased symptomatology and different coping styles if they suffer from comorbid nightmare disorder. Participants were 498 patients with diverse moderate to severe psychiatric disorders. As part of a standard assessment procedure, they filled out questionnaires regarding nightmares, psychopathology, personality pathology, and coping. A multivariate analysis of covariance and post hoc tests showed that patients with nightmare disorder scored higher on psychopathology (ηp2 = .03; p = .001) and personality pathology (ηp2 = .01-.03; p < .05). No significant differences were found with regards to coping strategies. Nightmare disorder is associated with higher levels of psychopathology and personality pathology in a sample of patients with diverse psychiatric disorders.


Arresting and convicting the innocent: the potential role of an "inappropriate" emotional display in the accused.
Research from both simulated and actual jurors has demonstrated that the defendant's emotional display can influence legal decisions. The purpose of this paper is to review the evidence regarding the influence of the defendant's emotional display, and to consider the potential role of suspect and defendant emotion in wrongful convictions. It is possible that the lack of "appropriate" emotion during questioning or interrogation may lead investigators to create a mind-set that the suspect is the guilty party; as a result, they may be less inclined to investigate other leads. During a trial, the defendant's perceived level of emotion can potentially mislead jurors (e.g. a defendant displaying a low level of emotion leading people to believe, inappropriately, that he is guilty). After a review of the pertinent literature and examples of relevant cases, reasons are provided regarding why one's emotional display may be of limited diagnostic value. Future research ideas are proposed in an effort to determine more definitively the impact of the emotional display of the accused on legal decisions.


Umbelliferone prevents oxidative stress, inflammation and hematological alterations, and modulates glutamate-nitric oxide-cGMP signaling in hyperammonemic rats.
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that occurs as a result of liver failure. Umbelliferone (UMB; 7-hydroxycoumarin) is a natural product with proven hepatoprotective activity; however, nothing has yet been reported on its protective effect against hyperammonemia, the main culprit behind the symptoms of HE. Here, we evaluated the effect of UMB against ammonium chloride (NH4Cl)-induced hyperammonemia, oxidative stress, inflammation and hematological alterations in rats. We demonstrated the modulatory role of UMB on the glutamate-nitric oxide (NO)-cGMP pathways in the cerebrum of rats. Rats received intraperitoneal injections of NH4Cl (3 times/week) for 8 weeks and concomitantly received 50 mg/kg UMB. NH4Cl-induced rats showed significantly elevated blood ammonia and liver function markers. Lipid peroxidation and NO were increased in the liver and cerebrum of rats while the antioxidant defenses were declined. UMB significantly reduced blood ammonia, liver function markers, lipid peroxidation and NO, and enhanced the antioxidant defenses in NH4Cl-induced rats. UMB significantly prevented anemia, leukocytosis, thrombocytopenia and prolongation of PT and aPTT. Hyperammonemic rats showed elevated levels of cerebral TNF-α, IL-1β and glutamine as well as increased activity and expression of Na+/K+-ATPase, effects that were significantly reversed by UMB. In addition, UMB down-regulated nitric oxide synthase and soluble guanylate cyclase in the cerebrum of hyperammonemic rats. In conclusion, this study provides evidence that UMB protects against hyperammonemia via attenuation of oxidative stress and inflammation. UMB prevents hyperammonemia associated hematological alterations and therefore represents a promising protective agent against the deleterious effects of excess ammonia.


Increased mortality in turkeys selected for increased body weight following vaccination with a live Newcastle disease virus vaccine.
Candidate male and female breeders from nine genetic lines of turkeys that were reared intermingled, with the sexes housed in different buildings on the same farm, were vaccinated with a live Newcastle disease virus vaccine (B1 type, LaSota) just prior to the commencement of egg production. In 1999, an average mortality for all lines of 5.8% occurred during the 10 days immediately following vaccination and the level of mortality varied among lines. Mortality was, in general, greater in large-bodied lines than in small-bodied lines. Affected birds exhibited gross multiple areas of focal necrosis in the liver and spleen and congestion of the heart and lungs. The percentage mortality occurring following similar vaccination in 2000 averaged 2.6 for the 10 days following vaccination and mortality was greater (P < or = 0.05) in one line (F line) than the other genetic groups and higher in females than in males. Mortality in the F line, selected for increased body weight and known to be susceptible to various diseases, averaged 15.1% for both years. Attempts failed in both years to isolate Pasteurella multocida or other bacteria. There was a positive correlation between increased body weight and increased mortality following vaccination with the live LaSota vaccine.


[Clinical importance of the determination of intestinal dipeptidase and enterokinase activity in patients with chronic enteritis].
The activity of enterokinase and some dipeptidases (glycylalanine, glycylleucine, glycylvaline and glycylglycine) was studied in the intestinal mucosa biopsy specimens of 52 patients with chronic enteritis. Hydroxyproline excretion in the urine was defined before and after gelatin tolerance testing which showed a decrease in hydrolysis and protein absorption in the small intestine in chronic enteritis. A decrease in the level of dipeptidases and enterokinase involved in membranous digestion was noted whereas the level of glycylglycine acting intracellularly was practically unchanged. A decrease in the enzymatic activity correlated with a degree of gravity of disease and a degree of change in a morphological picture of the intestinal mucosa.


Immunosuppressive C₂₁ steroidal glycosides from the root of Cynanchum atratum.
Six new C21 steroidal glycosides (1-6) and one dideoxysaccharide (7), named atratcynosides A-F and atratcynose A, were isolated from the 80% ethanol extract of the root of Cynanchum atratum, together with three known compounds (8-10). The structures of the new compounds were determined on the basis of extensive spectral analyses and qualitative chemical methods. All compounds were subjected to detect the immunosuppressive activities by an in vitro model of concanavalin A-induced proliferation of T-lymphocytes from mice. Compounds 1-3 showed significant immunosuppressive activities in dose-dependent manners with the IC50 values from 3.3 to 7.0 μM. Moreover, the structure-activity relationship of the steroidal glycosides on the immunosuppression was analyzed.


A case of primary intracranial hemangiopericytoma with hepatic metastases: successful treatment with radiofrequency ablation and transcatheter arterial chemoembolization.
Intracranial hemangiopericytoma is an uncommon soft tissue sarcoma. We report a case of a 54-year-old Japanese female with hepatic metastasis from primary intracranial hemangiopericytoma. At age 44 years the patient underwent primary resection of the intracranial tumor, followed by no adjuvant therapy. At age 53 years she underwent resection of bone metastases in her left upper arm and tenth right rib. The following year, three hepatic tumors with high vascularity were detected by ultrasonography, computed tomography scans, and magnetic resonance imaging. An ultrasound-guided liver biopsy specimen confirmed the diagnosis of hepatic metastases from the primary intracranial hemangiopericytoma. A combination therapy of transcatheter arterial chemoembolization and radiofrequency ablation was performed against the hepatic metastasis. After 5 years, there has been no local recurrence in the liver.


Induction of leukemia inhibitory factor secretion by interleukin-1 in a human T lymphoma cell line.
The control of leukemia inhibitory factor (LIF) secretion by interleukin-1 (IL-1) was studied in the HSB2 human T lymphoma cell line. We show that in the presence of phytohemagglutinin (PHA), the addition of IL-1 in the culture medium induced a strong increase in the level of secreted LIF, as detected with the DA1.a test cell line. Subclones of the HSB2 cell line obtained by limiting dilution, and selected for their high level of LIF secretion, after phorbol myristate acetate (PMA) treatment, were more carefully analyzed. In the same conditions of stimulation, a 50X increase in the amount of secreted LIF was observed with the 2B3 subclone, whereas the 3C2 subclone gave a very weak signal in response to the stimulation. Several other chemical reagents and a panel of recombinant cytokines including IL-2, -3, -4, -5, and -6, granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte-CSF (M-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were tested for their induction of LIF secretion. None of the other tested components was as potent as IL-1 (100 U/ml) and 1% PHA. A half maximal response was obtained with a concentration of 15-20 pM IL-1.


Genome-Wide Investigation of the Phospholipase C Gene Family in Zea mays.
Phospholipase C (PLC) is one of the main hydrolytic enzymes in the metabolism of phosphoinositide and plays an important role in a variety of signal transduction processes responding to plant growth, development, and stress. Although the characteristics of many plant PLCs have been studied, PLC genes of maize have not been comprehensively identified. According to the study, five phosphatidylinositol-specific PLC (PI-PLC) and six non-specific PLC (NPC) genes were identified in maize. The PI-PLC and NPC genes of maize are conserved compared with homologous genes in other plants, especially in evolutionary relationship, protein sequences, conserved motifs, and gene structures. Transient expression of ZmPLC-GFP fusion protein in Arabidopsis protoplast cells showed that ZmPLCs are multi-localization. Analyses of transcription levels showed that ZmPLCs were significantly different under various different tissues and abiotic stresses. Association analysis shown that some ZmPLCs significantly associated with agronomic traits in 508 maize inbred lines. These results contribute to study the function of ZmPLCs and to provide good candidate targets for the yield and quality of superior maize cultivars.


Heme Pocket Structure and Its Functional Implications in an Ancestral Globin Protein.
Proteins have undergone evolutionary processes to achieve optimal stability, increased functionality, and novel functions. Comparative analysis of existent and ancestral proteins provides insights into the factors that influence protein stability and function. Ancestral sequence reconstruction allows us to deduce the amino acid sequences of ancestral proteins. Here, we present the structural and functional characteristics of an ancestral protein, AncMH, reconstructed to be the last common ancestor of hemoglobins and myoglobins. Our findings reveal that AncMH harbors heme and that the heme binds oxygen. Furthermore, we demonstrate that the ferrous heme in AncMH is pentacoordinated, similar to that of human adult hemoglobin and horse myoglobin. A detailed comparison of the heme pocket structure indicates that the heme pocket in AncMH is more similar to that of hemoglobin than that of myoglobin. However, the autoxidation of AncMH is faster than that of both hemoglobin and myoglobin. Collectively, our results suggest that ancestral proteins of hemoglobins and myoglobins evolved in steps, including the hexa- to pentacoordination transition, followed by stabilization of the oxygen-bound form.


Short-Term Health Impact Assessment of Urban PM10 in Bejaia City (Algeria).
We used Health Impact Assessment (HIA) to analyze the impact on a given population's health outcomes in terms of all-causes mortality and respiratory and cardiovascular hospitalizations attributable to short-term exposure to particulate matter less than 10 μm diameter (PM10) in Bejaia city, for which health effects of air pollution have never been investigated. Two scenarios of PM10 reduction were considered: first, a scenario where the PM10 annual mean is decreased by 5 µg/m(3), and then a scenario where this PM10 mean is decreased to 20 µg/m(3) (World Health Organization annual air quality guideline (WHO-AQG)). Annual mean level of PM10 (81.7 µg/m(3)) was calculated from objective measurements assessed in situ. Each year, about 4 and 55 deaths could be postponed with the first and the second scenarios successfully. Furthermore, decreasing PM10 annual mean by 5 µg/m(3) would avoid 5 and 3 respiratory and cardiac hospitalizations, respectively, and not exceeding the PM10 WHO-AQG (20 µg/m(3)) would result in a potential gain of 36 and 23 per 100000 respiratory and cardiac hospitalizations, respectively. Lowering in current levels of PM10 has a nonnegligible impact in terms of public health that it is expected to be higher in the case of long-term effects.


Influence of ganglioside treatment on acrylamide neuropathy in mice. A morphometric study.
Female CBA/J mice were given oral doses of 40 mg/kg acrylamide 3 times weekly for 7 or 11 weeks in order to induce peripheral neuropathy. Half the animals were concurrently treated with 20 mg/kg, subcutaneously, of a ganglioside mixture (Cronassial). The other half received physiological saline and served as control. At the end of 7 or 11 weeks, the tibial nerves were removed and examined histomorphometrically. Every animal had developed a neuropathy. However, the mice treated with the ganglioside mixture showed on both the examination dates a substantially larger proportion of small sprouting nerve fibres than the control. It was concluded from this that treatment with gangliosides stimulated the regenerative potential of the damaged nerves.


Health literacy and current CD4 cell count in a multiethnic U.S. sample of adults living with HIV infection.
Hispanic and Black adults are disproportionately affected by HIV and experience poorer HIV-related health outcomes relative to non-Hispanic White adults. The current study adopted Sørensen's integrated model to test the hypothesis that lower functional and critical health literacy competencies contribute to poorer HIV-related health and CD4 cell count for Hispanic and Black individuals. Eighty-one non-Hispanic White, Hispanic, and Black HIV seropositive individuals from a large, Southwestern metropolitan area were administered measures of health literacy, including the Expanded Numeracy Scale, Newest Vital Sign, Rapid Estimate of Adult Literacy in Medicine, Test of Functional Health Literacy (TOHFLA)-numeracy, and TOHFLA-reading. Hispanic and Black individuals demonstrated less HIV knowledge than non-Hispanic White individuals. Black participants demonstrated fewer health literacy appraisal skills. Importantly, lower levels of health literacy were linked to poorer CD4 cell count (an index of immune functioning) for Hispanic and Black individuals and not for non-Hispanic White individuals. These findings suggest race group differences for health literacy on current CD4 cell count such as very specific dimensions of low health literacy (e.g. poorer judgment of health-related information), but not other presumed deficits (e.g. motivation, access), play an important role in clinical health outcomes in HIV.


Alterations of p16INK4A and p15INK4B genes in gastric carcinomas.
It has been suggested that cyclin-dependent kinase inhibitors (CDKIs), including p16 and p15, are tumor suppressor genes. Alterations of CDKIs have been found in most types of cancer. However, little is known about the status of p16 and p15 genes, including methylation of the promoter region, in gastric carcinoma. Thirty-six primary gastric tumors and 9 gastric carcinoma cell lines were examined for alterations of the p16 and p15 genes. Deletion of the p16 and p15 genes was assessed by Southern blot analysis, expression by Northern blot analysis, and mutation by polymerase chain reaction-single strand conformation polymorphism followed by direct sequencing. The methylation status of the 5' CpG island of the p16 gene was evaluated using methylation-sensitive restriction enzymes, and reversal of the transcriptional block of the p16 gene was determined by Northern blot analysis after treatment with 5-aza-2'-deoxycytidine. Homozygous deletions of the p16 and 15 genes from 2 of 9 gastric carcinoma cell lines were found. In contrast, no deletions were detected in 36 primary gastric tumors, and one primary tumor showed rearrangements of the p16 and p15 genes. Two gastric carcinoma cell lines showed a point mutation and an insertional mutation of the p16 gene, respectively; however, no point mutations were noted for the p16 and p15 genes in any of the primary gastric tumors. Constitutive levels of p16 mRNA expression in gastric carcinoma cell lines were quite heterogeneous; four gastric carcinoma cell lines had no detectable p16 mRNA and 6 gastric carcinoma cell lines had negligible expression of p15 mRNA. Of 10 primary gastric tumors, only 1 tumor expressed p16 mRNA. Furthermore, abnormal DNA methylation patterns of the p16 gene were found in 2 gastric carcinoma cell lines through the use of methylation-sensitive restriction enzymes. These cell lines lacked expression of p16 mRNA without deletions of the p16 gene. These transcriptional blocks were reversed by treatment with 5-aza-2'-deoxycytidine. Deletions or mutations of the p16 and p15 genes are uncommon in primary gastric carcinomas. However, defective mRNA transcription, sometimes by aberrant DNA methylation, might be one of the pathways of inactivation of the p16 gene that leads to the development of gastric carcinoma.


Psychometric properties of the Spanish version of the Personal Outcomes Scale.
Personal outcomes-related quality of life provides information about the impact of individualized supports and services that are provided to people with intellectual disability. The Personal Outcomes Scale (POS) is a valid and reliable instrument that measures these outcomes using two parts, self-report and report by others. Based on the POS, the aim of this study is to provide a new psychometric study of the instrument that allows the evaluation of the three principal informers involved in the enhancement of individual's quality of life: individual with intellectual disability, professional and family member. This approach overcomes the limitations of the POS. For the self-report were involved 529 people with intellectual disability. A professional (N = 522) and a family member (N = 462) separately participated for the report by others versions to assess personal outcomes for each participant. The reliability study provides appropriate values for the first and second order factors with α values being higher than .82. The construct validity analysis provides an adjustment of the theoretical model, particularly regarding the assessments from professionals. Results show this instrument is adequate to evaluate personal outcomes and giving the guidelines for making policy and practice decisions.


Structure of ferrofluid nanofilms in homogeneous magnetic fields.
We report molecular dynamics simulations results for model ferrofluid films subject to an external, homogeneous magnetic field directed parallel or perpendicular to the film surfaces. The interactions between the magnetic nanoparticles are modeled via the Stockmayer potential. In a previous study [J. Jordanovic and S. H. L. Klapp, Phys. Rev. Lett. 101, 038302 (2008)] we have shown that an external field can control the number and internal structure of the layers characterizing the fluid films, in qualitative agreement with experiments. Here we explore the dependence of the layering effects on thermodynamic conditions, and we analyze the results from an energetic (microscopic and macroscopic) perspective. As a special case we investigate a monolayer to bilayer transition induced via a perpendicular field.


Left atrium: no longer neglected.
Left atrial evaluation is strongly linked to the history of cardiac imaging. In the past, the importance of this chamber has been largely downplayed because cineangiography could not visualize it directly. Nowadays echocardiography can easily assess left and right atrial size and function. Left atrial enlargement is frequent in many cardiac diseases. A main determinant of left atrial volume is ventricular diastolic function. It has recently been suggested that left atrial volume might be the morphophysiologic expression of chronic diastolic function. In fact the left atrium is exposed directly to left ventricular diastolic pressure through the open mitral valve and because of its thin wall structure it tends to dilate with increasing pressure. Other important determinants of atrial volume are the degree of ventricular remodeling, mitral regurgitation and the presence of atrial fibrillation. The degree of left atrial enlargement is associated with adverse prognosis in different clinical settings. Patients with dilated cardiomyopathy and with a left atrial volume > 68 ml/m2 have a 3.8-fold risk compared with those with smaller left atrial volume. The predictive value of left atrial volume is independent of left ventricular systolic and diastolic function, mitral regurgitation and atrial fibrillation. This is noteworthy because these factors are both determinant of left atrial volume and have a strong impact on outcome. It might be concluded that left atrial volume represents a powerful predictive marker because it is a window allowing comprehensive evaluation of several factors associated with bad prognosis, which are often difficult to document separately.


[Indications for lymphography in uterine cancer].
The analysis of the clinicoroentgenological findings in 98 patients with corpus uteri cancer has shown the frequency and volume of lymphogenic metastasis depending on the histological structure and degree of tumor local dissemination. Predominant metastatic sites have been defined:external and general iliac lymph nodes. Indications to lymphography depending on primary tumor spreading have been worked out. The authors managed to show the value of x-ray observation over time and repeated lymphography in the evaluation of the therapeutic efficacy and metastasis detection.


[Bonding of resin cement to bleached dental enamel].
The effects of bleaching times, types of etching agent and storage period of bleached bovine tooth on the shear bond strength of resin cement to the enamel were examined. Bovine teeth were repeatedly bleached 0, 1, 3, and 5 times then stored in 37 degrees C water for 1 week. The effect of bleaching number of the bovine tooth on the bond strength of resin cement to the enamel was investigated using 40% phosphoric acid (EG) etching technique. Next, the effects of types of etching agent and of storage period of bleached bovine tooth with three times in 37 degrees C water on the bond strength were studied using 10% citric acid-3% ferric chloride (10-3) or 10% citric acid (10-0) solution. The bleaching of bovine tooth allowed for a dramatic decrease in the bond strength from 18.3 MPa to 9.8 MPa (1 time), and 3.9 MPa (3 times), even though the bovine enamel was etched by EG. However, when 10-3 or 10-0 solution was applied to the three times bleached enamel, bond strengths were 13.9 and 10.0 MPa, respectively. Furthermore, prolonging of the storage period of the three times bleached bovine tooth in water to 2 months resulted in a increase in the bond strength from 3.9 to 10.1 MPa, even if bovine enamel was etched by EG, and close to that obtained from the 10-3 etching. To obtain the expected bond strength to bleached enamel, it is better to wait for 2 months for a restoration and use the 10-3 etching.


Comparison of production-related responses to hyperinsulinemia and hypoglycemia induced by clamp procedures or heat stress of lactating dairy cattle.
Hyperinsulinemia concurrent with hypoglycemia is one of a myriad of physiological changes typically experienced by lactating dairy cows exposed to heat stress, the consequences of which are not yet well defined or understood. Therefore, the objective of this experiment was to separate the production-related effects of hyperinsulinemia with hypoglycemia from those of a hyperthermic environment. Multiparous lactating Holstein cows (n = 23; 58 ± 4 d in milk, 3.1 ± 0.3 lactations) were housed in temperature-controlled rooms and all were subjected to 4 experimental periods as follows: (1) thermoneutral (TN; temperature-humidity index of 65.1 ± 0.2; d 1-5), (2) TN + hyperinsulinemic-hypoglycemic clamp (HHC; insulin infused at 0.3 µg/kg of BW per h, glucose infused to maintain 90 ± 10% of baseline blood glucose for 96 h; d 6-10), (3) heat stress (HS; temperature-humidity index of 72.5 ± 0.2; d 16-20), and (4) HS + euglycemic clamp (EC; glucose infused to reach 100 ± 10% of TN baseline blood glucose for 96 h; d 21-25). Cows were fed and milked twice daily. Feed refusals were collected once daily for calculation of daily dry matter intake, and milk samples were collected at the beginning and end of each period for component analyses. Circulating insulin concentrations were measured in daily blood samples, whereas glucose concentrations were measured more frequently and variably in association with clamp procedures. Rectal temperatures and respiration rates were greater during HS than TN, as expected, and states of hyperinsulinemia and hypoglycemia were successfully induced by the HHC and high ambient temperatures (HS and EC). Feed intake differed based upon thermal environment as it was similar during TN and HHC periods, and declined for HS and EC. Milk production was not entirely reflective of feed intake as it was greatest during TN, intermediate during HHC, and lowest during HS and EC. All milk components differed with the experimental period, primarily in response to the thermal environment. Interestingly, TN baseline glucose concentrations were highly correlated with the change in glucose from TN to HS, and were related to glycemic status during HS. Furthermore, although few in number, those cows that failed to become hypoglycemic during HS tended to have a greater reduction in milk yield. The work presented here addresses a critical knowledge gap by broadening our understanding of the physiological response to heat stress and the related changes in glycemic state. This broadened understanding is fundamental for the development of novel, innovative management strategies as the dairy industry is compelled to become increasingly efficient in spite of global warming.


Stabilization of platelet-fibrinogen interactions: modulation by divalent cations.
The binding of fibrinogen to its GPIIb-IIIa receptor is divalent-cation dependent. In addition to Ca+2 and Mg+2, Mn+2 has been shown to modulate adhesive protein interactions with integrins. This study examined the effect of Mn+2 on fibrinogen interactions with intact platelets. Compared with that of control platelets in buffer containing 1 mmol/L Mg+2, fibrinogen binding to adenosine diphosphate- or thrombin-stimulated platelets decreased 23% +/- 12% and 15% +/- 9% (mean +/- SD, n = 4), respectively, after addition of 1 mmol/L Mn+2. No change in binding affinity was noted, but the stability of platelet-fibrinogen interactions was diminished markedly. Ethylenediaminetetraacetic acid dissociated 68% +/- 8% of fibrinogen bound to ADP-treated platelets (p < 0.05) during a 60-minute incubation with fibrinogen and 1 mmol/L Mn+2, compared with 40% +/- 13% of fibrinogen bound to control platelets and 29% +/- 8% of fibrinogen bound in the presence of Ca+2 (mean +/- SD, n = 6). Mn+2 also diminished the stabilization of fibrinogen interaction with thrombin-stimulated platelets and inhibited the recovery of bound fibrinogen with the Triton X-100 (Union Carbide Corp., Danbury, Conn.) insoluble cytoskeleton. Only 31% +/- 10% of fibrinogen bound to thrombin-stimulated platelets for 60 minutes in the presence of Mn+2 associated with the cytoskeleton (p < 0.05), compared with 61% +/- 14% and 75% +/- 20% of fibrinogen bound to control platelets incubated with and without Ca+2, respectively. Mn+2 further inhibited large adenosine diphosphate- or thrombin-induced platelet aggregate formation and reduced the ability of platelets to retract fibrin clots. These data suggest that Mn+2 alters GPIIb-IIIa function relative to native fibrinogen and support a role for the stabilization of platelet-fibrinogen interactions in platelet aggregation and clot retraction.


Small cell carcinoma of the pyriform sinus successfully treated with concurrent chemo-radiotherapy: A case report.
Primary small cell carcinomas (SCCs) are uncommon in extrapulmonary sites and account for only 2.5% to 5.0% of all SCCs. SCCs in the pyriform sinus are rare and there is little information regarding this disease, especially on therapeutics. Herein, we present a case of successfully treated SCC in the right pyriform sinus that occurred in a patient with small cell lung carcinoma (SCLC) that completely resolved 4 years prior. A 1.5 × 1.5-cm mass in the right pyriform sinus was detected on imaging studies in a 71-year-old male at a regular check-up visit after being in remission from SCLC. Based on histologic examination and immunohistochemistry, the tumor in the right pyriform sinus was diagnosed as an extrapulmonary SCC. Chemo-radiotherapy was applied to the SCC of the pyriform sinus with a regimen of etoposide and cisplatin. The patient exhibited complete response to treatment and has been disease free for 11 months. This interesting case shows that chemotherapy with concurrent radiation may be an effective therapeutic modality for localized extrapulmonary SCC similar to localized SCLC, which is treated with concurrent chemo-radiotherapy as the standard therapeutic option.


[Pyloric hypertrophic stenosis in the premature child. A clinical case].
Hypertrophic pyloric stenosis (HPS) is rare in premature infants. We report a case of HPS in an extremely low birth weight neonate (28 weeks of gestation, 622 gr), discovered on the 10th week of life. Although the diagnosis and treatment of pyloric stenosis has ben well established for many years, the presentation in preterm babies is atypical and the diagnosis often delayed. A brief review of literature is included.


Total ovarian volume before human chorionic gonadotrophin administration for ovulation induction may predict the hyperstimulation syndrome.
Total ovarian volumes were measured before the administration of HCG in 42 women undergoing treatment for infertility by in-vitro fertilization (IVF) and embryo transfer and considered to have an exaggerated response to stimulation ( > 20 follicles). Seven women who subsequently developed moderate or severe ovarian hyperstimulation syndrome (OHSS) (n = 7; group 1) were compared with 35 matched controls (five matched controls per case; n = 35; group 2) of similar age, number of follicles and duration of infertility who underwent follicular stimulation, oocyte recovery, in-vitro fertilization and embryo transfer during the same period but did not develop moderate or severe OHSS. The mean age, duration of infertility and total number of follicles were similar but the mean total ovarian volume was significantly higher in the group of women who developed moderate or severe OHSS compared with controls (271.00 +/- 87.00 versus 157.30 +/- 54.20 ml; P < 0.01). We conclude that total ovarian volume measured before HCG administration is higher in women who develop moderate or severe OHSS compared with controls and may therefore be used as an additional parameter in the preventative strategy for the ovarian hyperstimulation syndrome.


There's no such thing as a healthy glow: cutaneous malignant melanoma--the case against suntanning.
One of the objectives of the 1992 United Kingdom Government White Paper 'Health of the Nation', is to reduce ill health and death caused by skin cancers by the year 2005. The Europe Against Cancer Programme shares those aims for the entire European population. Skin cancer was the first cancer demonstrated to have a chemical cause, with Percival Pott's 1775 description of squamous cell carcinoma of the scrotum induced by chimney soot, and skin cancers were also the first to be linked with ionising radiation. Currently there is a general consensus amongst researchers which acknowledges solar ultraviolet radiation as the major carcinogenic agent for the development of skin cancers. Changing attitudes and lifestyles affecting sun exposure is deemed responsible for the upward trends in incidence and mortality from skin cancers. The recognition of skin cancer as a preventable malignancy has implications for the health promotion role of nurses and of their multidisciplinary colleagues throughout Europe. This paper reviews the literature relating to sunlight as a risk factor for cutaneous malignant melanoma, and considers the behavioural issues which need to be addressed by healthcare professionals generally, and by nurses specifically, when establishing or participating in health promotion initiatives.


Targeting of repeated sequences unique to a gene results in significant increases in antisense oligonucleotide potency.
A new strategy for identifying potent RNase H-dependent antisense oligonucleotides (ASOs) is presented. Our analysis of the human transcriptome revealed that a significant proportion of genes contain unique repeated sequences of 16 or more nucleotides in length. Activities of ASOs targeting these repeated sites in several representative genes were compared to those of ASOs targeting unique single sites in the same transcript. Antisense activity at repeated sites was also evaluated in a highly controlled minigene system. Targeting both native and minigene repeat sites resulted in significant increases in potency as compared to targeting of non-repeated sites. The increased potency at these sites is a result of increased frequency of ASO/RNA interactions which, in turn, increases the probability of a productive interaction between the ASO/RNA heteroduplex and human RNase H1 in the cell. These results suggest a new, highly efficient strategy for rapid identification of highly potent ASOs.


Enhanced resistance of adriamycin-treated MCR-5 lung fibroblasts by increased intracellular glutathione peroxidase and extracellular antioxidants.
Considerable evidence indicates that reactive oxygen species play an etiological role in both cardiotoxicity and the skin necrosis induced by adriamycin (ADM). An increase in glutathione peroxidase activity on addition of selenium to cultured MCR-5 lung fibroblasts was observed; this increase was accompanied by enhanced cellular resistance to ADM toxicity. Moreover, the presence of exogenous antioxidant systems, such as superoxide dismutase, catalase, vitamin E, dimethylsulfoxide, and desferroxamine, an iron chelating agent, resulted in significant protection from ADM-mediated damage.


Wave intensity analysis of para-aortic counterpulsation.
Wave intensity analysis (WIA) was used to delineate and maximize the efficacy of a newly developed para-aortic blood pump (PABP). The intra-aortic balloon pump (IABP) was employed as the comparison benchmark. Acute porcine experiments using eight pigs, randomly divided into IABP (n = 4) and PABP (n = 4) groups, were conducted to compare the characteristics of intra- and para-aortic counterpulsation. We measured pressure and velocity with probes installed in the left anterior descending coronary artery and aorta, during and without PABP assistance. Wave intensity for aortic and left coronary waves were derived from pressure and flow measurements with synchronization correction applied. To achieve maximized support efficacy, deflation timings ranging from 25 ms ahead of to 35 ms after the R-wave were tested. Similar to those associated with IABP counterpulsation, the PABP-generated backward-traveling waves predominantly drove aortic and coronary blood flows. However, in contrast with IABP counterpulsation, the nonocclusive nature of the PABP allowed systolic unloading to be delayed into early systole, which resulted in near elimination of coronary blood steal without diminution of systolic left ventricular ejection wave intensities. WIA can elucidate subtleties among different counterpulsatile support means with high sensitivity. Total accelerating wave intensity (TAWI), which was defined as the sum of the time integration of accelerated parts of the positive and negative wave intensities, was used to quantify counterpulsation efficacy. In general, the larger the TAWI gain, the better the counter-pulsatile support efficacy. However, when PABP deflation timings were delayed to after the R-wave, the TAWI was found to be inversely correlated with coronary perfusion. In this delayed deflation timing setting, greater wave cancellation occurred, which led to decreased TAWI but increased coronary perfusion attributed to blood regurgitation reduction.


Updated classification and therapy of vascular malformations in pediatric patients.
Vascular malformations (VMs) comprise a diverse group of diagnoses. They are classified by the type of vessel involved, including capillaries, veins, arteries, lymphatic vessels, or combinations of these. Complex VMs, although benign, can impair vital structures, cause deformations, or even threaten the child's life. Although multimodal treatment of VMs in children with disease include a wide variety of options such as observation, laser therapy, sclerotherapy, surgical resection, radiofrequency ablation, and medical therapy, the management of VMs necessitates a multifocal and multidisciplinary method with the patient's quality of life as the priority.


[Relationship between expression of MMP-2 and prognosis in human laryngeal squamous cell carcinoma].
In order to evaluate the potential of matrix metalloproteinase 2(MMP-2) as a prognostic factor for human laryngeal squamous cell carcinoma (HLSCC). Seventy-three surgical specimens from patients with HLSCC were reviewed retrospectively regarding MMP-2 expression via immunohistochemistry. Immunostaining was performed using a streptavidin-biotin peroxidase complex technique. The patients were followed-up till June 2014 and the relationship between MMP-2 and clinical data including age, gender, metastasis, clinical type, pathological type, lymph node metastasis and prognosis were analyzed using SPSS 19.0. The positive expression rate of MMP-2 in 73 patients was 57.53% (42/73). Kaplan-Meier analysis demonstrated statistically significant difference for 5-year overall survival rate between the group with positive and negative MMP-2 expression,the 5-year overall survival rate were 76.0% and 57.5% respectively in the group with negative and positive MMP-2 expression. The site of the primary tumor, clinical stage, lymph node metastasis and T grade were related to the prognosis of HLSCC (P were 0.002, 0.009, 0.034 and 0.001 respectively), and there was no significant correlation between age, sex, pathological differentiation and prognosis of HLSCC. MMP-2 was related with worse overall disease survival and could be considered as a potential marker of poor prognosis.


Freeze-fracture electron microscope study of lipid systems. The cubic phase of space group Pm3n.
The cubic phase Q223 (space group Pm3n) of lipid-water systems has been studied by freeze-fracture electron microscopy. Four types of fracture planes were identified; all display highly ordered two-dimensional domains, each subdivided into subdomains related to each other by displacements and rotations connected to the symmetry of the space group. The images were filtered using cross-correlation averaging techniques and the filtered images were compared with the corresponding planar sections of the electron density map. The similarity of the two distributions was assessed via a mathematical parameter, the matching index, whose values were determined as a function of the apodization of the electron density map and of the position of the plane in the direction normal to the fracture. By definition, the best coincidence corresponds to an extremum of the matching index. Several conclusions were drawn. (1) The structure of the sample is well preserved in the replicas. (2) The "resolution" of the electron microscope experiments is remarkably close to that of the X-ray scattering study. (3) Of the two types of models that have been envisaged for phase Q223, the micellar is found to be in better agreement with the electron micrographs than the cagelike. (4) The symmetry of the space group is faithfully reflected in the electron microscope images; in particular, the presence of mirror planes rules out the non-centric of the two space groups that are compatible with the crystallographic data. (5) The crystallographic orientations of the fracture planes that are most frequently identified coincide with those of the most intense X-ray reflections; this observation was interpreted as an indication that the fracture propagates differently in the hydrocarbon and in the water volumes. (6) The thinner metal deposits in the replicas were found to coincide with the hydrocarbon regions of the fractures. (7) The fracture seems to be planar across the water matrix and the micelles seem to be removed from the replica and replaced by dips.


Assessing pesticides exposure effects on the reproductive performance of a declining aerial insectivore.
In the context of increasing global environmental changes, it has become progressively important to understand the effects of human activity on wildlife populations. Declines in several avian populations have been observed since the 1970s, especially with respect to many farmland and grassland birds, which also include some aerial insectivores. Changes in farming practices referred to as agricultural intensification coincide with these major avian declines. Among those practices, increased pesticide use is hypothesized to be a key driver of avian population declines as it can lead to both toxicological and trophic effects. While numerous laboratory studies report that birds experience acute and chronic effects upon consuming pesticide treated food, little is known about the effects of the exposure to multiple pesticides on wildlife in natural settings. We monitored the breeding activities of Tree Swallows (Tachycineta bicolor) on 40 farms distributed over a gradient of agricultural intensification in southern Québec, Canada, to evaluate the presence of pesticides in their diet and quantify the exposure effects of those compounds on their reproductive performance between 2013 and 2018. We first assessed the presence of 54 active agents (or derivatives) found in pesticides in 2,081 food boluses (insects) delivered to nestlings by parents and documented their spatial distribution within our study area. Second, we assessed the effect of pesticide exposure through food (number of active agents detected and number of contaminated boluses on a given farm for a given year, while controlling for sampling effort) on clutch size as well as hatching and fledging successes and nestling's mass upon fledging. Pesticides were ubiquitous in our study system and nearly half (46%) of food boluses were contaminated by at least one active agent. Yet we found no relationship between our proxies of food contamination by pesticides and Tree Swallow reproductive performance. More studies are needed to better understand the putative role of pesticides in the decline of farmland birds and aerial insectivores as potential sublethal effects of pesticides can carry over to later life stages and impact fitness.


Primary angiosarcoma of the oral cavity in a young adult.
Angiosarcoma is a rare neoplasm, constituting only 2% of all the soft tissue tumors and most frequently involves the skin of the head and neck region in elderly males. They are extremely aggressive tumors with high rates of metastasis and poor outcomes. We report a unique case of angiosarcoma involving an unusual site - upper alveolus and maxilla in a young patient highlighting the diagnostic challenges in such a scenario. A 29 years old female presented with a non-healing wound of the oral cavity, which had progressed to the current maximum size of 6.4 cm within one month. Magnetic resonance imaging (MRI) scan revealed the involvement of maxilla up to the floor of the orbit and adjacent soft tissue. However, no distant metastasis was detected on Positron Emission Tomography (PET) scan. Biopsy of the lesion showed an irregular, highly pleomorphic, and mitotically active epithelioid soft tissue tumor conclusively diagnosed as angiosarcoma.


Effect of photoperiod on the metabolism of deuterium-labeled gibberellin a(53) in spinach.
Application of gibberellin A(53) (GA(53)) to short-day (SD)-grown spinach (Spinacia oleracea L.) plants caused an increase in petiole length and leaf angle similar to that found in plants transferred to long days (LD). [(2)H] GA(53) was fed to plants in SD, LD, and in a SD to LD transition experiment, and the metabolites were identified by gas chromatography with selected ion monitoring. After 2, 4, or 6 SD, [(2)H]GA(53) was converted to [(2)H]GA(19) and [(2)H]GA(44). No other metabolites were detected. After 2 LD, only [(2)H] GA(20) was identified. In the transition experiment in which plants were given 4 SD followed by 2 LD, all three metabolites were found. The results demonstrate unequivocally that GA(19), GA(20), and GA(44) are metabolic products of GA(53), and strongly suggest that photoperiod regulates GA metabolism, in part, by controlling the conversion of GA(19) to GA(20).


Induction and Impact of Anti-Drug Responses Elicited by a Human Recombinant Coagulation Factor FXaI16L in Preclinical Species.
This paper presents a systemic investigation of ADA development and ADA impact of a human coagulation factor in nonclinical species during drug development and provides insights into potential implications in human if a similar ADA occurs. FXaI16L-induced ADA response was characterized in monkey, mouse, rat, and dog in different studies, and ADA effects on pharmacokinetic and/or pharmacodynamics of FXaI16L were further examined in ADA-negative and ADA-positive animals. After repeated administrations, FXaI16L elicited a dose and exposure day-dependent ADA response which ranged from no response to a transient or persistent response. Increase in exposure day and increase in dose generally enhanced ADA incidence except for a decrease in ADA incidence was observed in monkeys after repeated high-dose administrations. The observable ADA impact on pharmacokinetics was only found in some ADA+ animals and included decrease in clearance and increase in systemic exposure but no increase in half-life. In addition, no or limited effect on pharmacodynamics by ADA was observed. The earliest ADA response was observed after three exposure days, marked elevation of drug exposure was observed in some animals at log titer > 2.0, and the highest antibody titer excited was about 4 (Log10) in all species. A correlation between ADA induction and accumulative exposure after various repeat treatments in different species was found for FXaI16L. In addition, potential immunogenicity risk and mitigation of ADA in clinics are discussed.


Protruding the tongue improves posterior rhinomanometry in obstructive sleep apnoea syndrome.
In posterior rhinomanometry (PRM), oropharyngeal pressure is measured using a tube placed between the tongue and the hard palate. For valid results the patient must position the tongue and soft palate so that both the oropharynx and nasopharynx remain open. A high rate of failure of conventional PRM has been reported in normal individuals. In patients with obstructive sleep apnoea syndrome (OSAS), upper airway abnormalities may further increase the failure rate. This study proposes a modification of the technique in which protrusion of the tongue enhances pressure transmission between the nasopharynx and the mouth. In eight normal subjects, resistance was similar when measured by both methods. Of 24 OSAS patients, conventional PRM was unsuccessful in 11. In the remaining 13 patients, a significant correlation between the two methods was found, but resistance was lower by "tongue-out" than by conventional PRM, consistent with a decrease, during tongue protrusion, in retropalatal resistance, which is a component of the "nasal" resistance measured by PRM. In 26 OSAS patients, unilateral nasal resistance values measured by "tongue-out" PRM were similar to those measured by anterior rhinomanometry. When the "tongue-out" method was used routinely in 541 snorers, failure rates were 1.1% in the 272 non-OSAS patients and 3.7% in the 269 OSAS patients. These results indicate that posterior rhinomanometry with tongue protrusion is a highly effective tool for measuring nasal resistance in snorers.


Electroactive Soft Actuators Based on Columnar Ionic Liquid Crystal/Polymer Composite Membrane Electrolytes Forming 3D Continuous Ionic Channels.
Here, we report low-voltage-driven fast-response nanostructured columnar ionic liquid crystal/polymer composite actuators that form three-dimensional continuous ion channels. A three-component self-assembly of a zwitterionic rod-like molecule (49.5 wt %), an ionic liquid (27.5 wt %), and poly(vinyl alcohol) (23.0 wt %) provided a free-standing stretchable membrane electrolyte. The dissociated ions can move through a continuous 3D ionophilic matrix surrounding the hydrophobic columns formed by the hexagonally organized rod-mesogens. Three-layer actuators composed of the electrolyte film sandwiched between two conductive polymer film electrodes of doped polythiophene exhibited a bending motion with 0.32% strain and moved 2 mm within 220 ms under 1 V at 0.1 Hz in 70% relative humidity due to the formation of electric double layers at the soft solid electrolyte/electrode interfaces. The bending strain of the columnar nanostructured actuator is comparable to those of polymer iongel actuators and block polymer actuators containing 25-80 wt % of ionic liquids. It is noteworthy that a small number of ions organized into the 3D nanochannels can generate the large bending deformation, which can contribute to reduce the risk of leakage of ions and the production cost. In addition, we have demonstrated a low-voltage-driven deformable mirror actuator that is expected to be applied to optical devices.


[Quantitative imaging of the heterogeneity of membrane activation of mammalian neurons and glial cells].
By using quantitative imaging with an ultra-high sensitivity, it was possible to observe the simultaneous action of multiple patches unevenly distributed over the membranes of neurons and glial cells in culture. We used a voltage-sensitive probe to stain vitally the cells. The instrumentation consisted of a liquid-nitrogen cooled matrix of 222,530 photodetectors with a spatial resolution of 0.25 microns 2, a photodynamic range of 10(5), a detection level of a few tens of photons and a maximum time resolution of 500 microseconds. Electrical and pharmacological stimulations were applied to produce the activation of the cells which was accompanied by large variations of the level of fluorescence, giving a precise spatial localization of active domains over the soma-neuritic membranes. These images of fluorescent signals are interpreted as corresponding to the plasmalemmal localization of voltage-dependent channels. This finding, which had not been previously observed with voltage-sensitive probes in fluorescent dye imaging indicates the possibility of measuring the activity of independently functioning domains in single neurons.


Measurement of urinary and fecal steroid metabolites during the ovarian cycle in captive and wild Japanese macaques, Macaca fuscata.
We measured the concentration of steroid hormones from urine, feces, and blood samples of two captive Japanese macaques, Macaca fuscata, during nonconceptive ovarian cycles to compare the patterns of the excreted steroids with those of circulating steroids. Urine and feces were analyzed for estrone conjugates (E1C) and pregnanediol-3-glucronide (PdG) using enzyme immunoassays (EIAs), while plasma was analyzed for estradiol-17beta(E2), progesterone (P), and luteinizing hormone (LH) using radioimmunoassays (RIAs). Urinary and fecal E1C and PdG levels were approximately parallel to plasma E2 and P levels, respectively. The E1C profiles of daily urinary and fecal samples revealed a midcycle peak, followed by a sustained PdG increase lasting up to two weeks from the E1C peak. A fecal E1C peak was one day later than the urinary E1C peak. One of the captive females exhibited a discrete plasma LH peak, one indicator that ovulation has occurred, on the day following the urinary E1C peak, i.e., the same day of fecal E1C peak. We measured excreted steroids in nine wild females and determined the timing of ovulation by comparing fecal steroid profiles to those obtained in captive monkeys. Data from wild females indicated that eight of nine females conceived during their first ovulatory cycle of the sampling period, whereas the remaining female failed to conceive during the sampling period even though she ovulated. In the eight females that conceived, E1C increased again following the detected or estimated E1C peak, with levels comparable to the preovulatory peak levels, and sustained elevations of PdG for over 40 days. These data illustrate that the urinary and fecal profiles of ovarian steroid excretion obtained through the application of these noninvasive techniques provide an accurate approach for monitoring conceptive and nonconceptive ovarian cycle in captive and free-living Japanese macaques.


Identification of the active compounds and their mechanisms of medicinal and edible Shanzha based on network pharmacology and molecular docking.
Shanzha (Crataegus pinnatifida Bunge), an edible traditional Chinese medicine (TCM), has an effect on dyspepsia. However, the investigations of the pharmacological effects have not been carried out. This study aimed to identify the potential targets and pharmacological mechanisms of Shanzha in the treatment of dyspepsia by network pharmacology and molecular docking. Five active compounds and 13 key targets were obtained by a set of bioinformatics assays. Vitexin 7-glucoside, suchilactone, and 20-hexadecanoylingenol were the main compounds acting on dyspepsia. The key targets were prostaglandin-endoperoxide synthase 2 (PTGS2), serine/threonine-protein kinase mTOR (MTOR), heat shock protein HSP 90-alpha (HSP90AA1), mitogen-activated protein kinase 1 (MAPK1), MAPK3, E3 ubiquitin-protein ligase Mdm2 (MDM2), receptor tyrosine-protein kinase erbB-2 (ERBB2), caspase-3 (CASP3), matrix metalloproteinase-9 (MMP9), estrogen receptor (ESR1), tumor necrosis factor (TNF), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), and peroxisome proliferator-activated receptor gamma (PPARG), which played the vital roles in TNF, prostate cancer, thyroid hormone, hepatitis B and estrogen signaling pathway. The molecular mechanisms of Shanzha regulating dyspepsia were mainly related to reduction of inflammatory response, controlling cell proliferation and survival, increasing intestinal moisture, and promoting intestinal motility. PRACTICAL APPLICATIONS: Shanzha has been used as an edible TCM to improve digestion for a long time. However, the ingredients and mechanisms of Shanzha in the treatment of dyspepsia are not clear. In this research, network pharmacological analysis integrated with molecular docking was conducted to investigate the molecular mechanism. The results suggested that the core targets alleviated dyspepsia by reducing the intestinal inflammatory response, increasing intestinal movement, controlling cell physiological activities, and reducing constipation. In summary, this study demonstrated the multiple compounds, targets, and pathways characteristics of Shanzha in the treatment of dyspepsia, which may provide guidance and foundations for further application of edible medicine.


First record of Cephenniini on Christmas Island, with updated checklist of world Cephennomicrus species and summary of their distribution (Coleoptera, Staphylinidae, Scydmaeninae).
The tribe Cephenniini is reported for the first time to occur on Christmas Island (external territory of the Commonwealth of Australia). Cephennomicrus lawrencei sp. n. is described and illustrated; the new species shows similarities to several Oriental and Japanese congeners, with the endophallic complex of long flagellum flanked by elongate sclerites especially similar to that of Indonesian C. fesumatranus Jałoszyński. The distribution of world Cephennomicrus species is summarized, ranging from southern and central-eastern Africa, Madagascar, Indian Ocean islands, through Sri Lanka, Southeast Asia, south-eastern China and Taiwan, the Ryukyus and Tsushima Island, eastern Papua New Guinea to Australia and southern Pacific islands. An updated checklist of Cephennomicrus species is provided.


A Framework for Cervical Cancer Elimination in Low-and-Middle-Income Countries: A Scoping Review and Roadmap for Interventions and Research Priorities.
The World Health Organization announced an ambitious call for cervical cancer elimination worldwide. With existing prevention and treatment modalities, cervical cancer elimination is now within reach for high-income countries. Despite limited financing and capacity constraints in low-and-middle-income countries (LMICs), prevention and control efforts can be supported through integrated services and new technologies. We conducted this scoping review to outline a roadmap toward cervical cancer elimination in LMICs and highlight evidence-based interventions and research priorities to accelerate cervical cancer elimination. We reviewed and synthesized literature from 2010 to 2020 on primary and secondary cervical cancer prevention strategies. In addition, we conducted expert interviews with gynecologic and infectious disease providers, researchers, and LMIC health officials. Using these data, we developed a logic model to summarize the current state of science and identified evidence gaps and priority research questions for each prevention strategy. The logic model for cervical cancer elimination maps the needs for improved collaboration between policy makers, production and supply, healthcare systems, providers, health workers, and communities. The model articulates responsibilities for stakeholders and visualizes processes to increase access to and coverage of prevention methods. We discuss the challenges of contextual factors and highlight innovation needs. Effective prevention methods include HPV vaccination, screening using visual inspection and HPV testing, and thermocoagulation. However, vaccine coverage remains low in LMICs. New strategies, including single-dose vaccination could enhance impact. Loss to follow-up and treatment delays could be addressed by improved same-day screen-and-treat technologies. We provide a practical framework to guide cervical cancer elimination in LMICs. The scoping review highlights existing and innovative strategies, unmet needs, and collaborations required to achieve elimination across implementation contexts.


Pharmacokinetics of Ampreloxetine, a Norepinephrine Reuptake Inhibitor, in Healthy Subjects and Adults with Attention-Deficit/Hyperactive Disorder or Fibromyalgia Pain.
Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development. We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2-50 mg. Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30-40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects. The population pharmacokinetic model effectively described the plasma concentration-time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies. ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).


Forensic investigation of 23 autosomal STRs and application in Han and Mongolia ethnic groups.
A forensic validation study of the Early Access Huaxia™ Platinum Polymerase Chain Reaction (PCR) kit was completed to document the performance capabilities and limitations. The genotyping of DNA samples was consistent across a large range of template DNA concentrations, with complete profiles obtained at 0.125 ng; however, no more than 2 mm × 1.2 mm punches of samples would be recommended for direct amplification. The size precision and accuracy test revealed the genotyping ability; while consistent results were obtained when comparing the kit with other commercially available systems. In addition, the whole PCR amplification can finish within approximately 45 min, making the system suitable for fast-detection. However, only partial profiles may be obtained with challenging samples, including DNA stored on Foam-Tipped Applicators (FTA) cards or some case samples. For the forensic application in ethnic groups, a total of 282 and 229 alleles were obtained in Han and Mongolia, respectively. Since the 23 short tandem repeats were independent from each other, the cumulative power of exclusion in duos was 0.999 999 157 188 and the cumulative power of exclusion in trios was 0.999 999 999 859 in the Han group while the cumulative power of exclusion in duos (CPEduo) was 0.999 998 848 26 and cumulative power of exclusion in trios (CPEtrio) was 0.999 999 999 79 in the Mongolia group. And good internal consistency was found between the two investigated groups and the Sichuan Han, Hui, Tibetan and Uygur according to available reference data.


Therapeutic potential of pegylated hemin for reactive oxygen species-related diseases via induction of heme oxygenase-1: results from a rat hepatic ischemia/reperfusion injury model.
Many diseases and pathological conditions, including ischemia/reperfusion (I/R) injury, are the consequence of the actions of reactive oxygen species (ROS). Controlling ROS generation or its level may thus hold promise as a standard therapeutic modality for ROS-related diseases. Here, we assessed heme oxygenase-1 (HO-1), which is a crucial antioxidative, antiapoptotic molecule against intracellular stresses, for its therapeutic potential via its inducer, hemin. To improve the solubility and in vivo pharmacokinetics of hemin for clinical applications, we developed a micellar hemin by conjugating it with poly(ethylene glycol) (PEG) (PEG-hemin). PEG-hemin showed higher solubility in water and significantly prolonged plasma half-life than free hemin, which resulted from its micellar nature with molecular mass of 126 kDa in aqueous media. In a rat I/R model, administration of PEG-hemin significantly elevated HO-1 expression and enzymatic activity. This induction of HO-1 led to significantly improved liver function, reduced apoptosis and thiobarbituric acid reactive substances of the liver, and decreased inflammatory cytokine production. PEG-hemin administration also markedly improved hepatic blood flow. These results suggest that PEG-hemin exerted a significant cytoprotective effect against I/R injury in rat liver by inducing HO-1 and thus seems to be a potential therapeutic for ROS-related diseases, including I/R injury.


Inhibition by somatostatin of the release of growth hormone induced by lysine-vasopressin in normal subjects.
The effect of somatostatin (SRIH) on the release of growth hormone (GH) induced by lysine-vasopressin (LVP) was studied in six normal subjects. They were injected intravenously with 0.06 I. U./kg of LVP alone or in combination with SRIH (an intravenous bolus of 100 micrograms 10 minutes before LVP injection, followed by the constant infusion of 500 micrograms over 90 minutes). LVP strikingly increased serum concentrations of GH; this response was significantly reduced by the treatment with SRIH. This finding provides evidence that the effect of LVP on serum GH levels is sensitive to the inhibition by SRIH; it is proposed that the stimulating action of LVP on GH secretion might be mediated by the inhibition of endogenous SRIH.