The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer.
Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing (POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.


Comparison of the efficacy and safety between dezocine injection and morphine injection for persistence of pain in Chinese cancer patients: a meta-analysis.
The association between the efficacy and safety of dezocine injection and morphine injection for persistence of pain in patients with cancer had yielded controversial results. Therefore, we conduct a meta-analysis of existing observational published studies to assess the relationship between them among Chinese. We conducted a comprehensive research from the databases of PubMed, Web of Science, and Wan Fang Med Online for the related studies up to October 2016. Summary odds ratio (OR) with 95% confidence interval (95% CI) were calculated with the random effects model. Nine published studies comprising 333 dezocine injection patients and 321 morphine injection patients were included in this meta-analysis. Our results suggested that there was no statistical significance between dezocine injection and morphine injection at the case number of effective pain relief (EPR) [OR = 0.97, 95% CI (0.77-1.22), I2 = 0.0, P for heterogeneity = 1.000]. However, the rate of adverse drug reaction (ADR) caused by dezocine injection was 56% less than that caused by morphine injection, the difference was statistically significant [OR = 0.44, 95% CI (0.30-0.65), I2 = 0.0, P for heterogeneity = 0.980]. No between-study heterogeneity and publication bias were found. In conclusions, this meta-analysis indicates that there is no significant association on the efficacy of persistence of pain in patients with cancer between dezocine injection and morphine injection among Chinese. However, dezocine injection was with less ADR compared with morphine injection.


Lateral Sesamoid Position Relative to the Second Metatarsal in Feet With and Without Hallux Valgus: A Prospective Study.
We sought to determine whether hallux valgus displaces the sesamoid bones laterally away from a stationary first metatarsal or whether the first metatarsal head is displaced medially from the stationary sesamoids, which remain in position relative to the rest of the forefoot. We reviewed weightbearing radiographs in the dorsal plantar view of 128 consecutive patients (149 feet) seen over 2 months in 2014. Of these, 82 feet (55%) had a hallux valgus angle of >15° (hallux valgus group) and 67 feet (45%) had an angle of no more than 15° (control group). We measured the absolute distances from the center of the lateral sesamoid and the first metatarsal head to the long axis of the second metatarsal. Next, the relative distances, defined as the ratio of these 2 absolute distances to the length of the second metatarsal, were calculated to adjust for foot size. Both the absolute and the relative distances from the center of the first metatarsal head to the second metatarsal differed significantly between the 2 groups and correlated positively with the hallux valgus angle and first intermetatarsal angle. However, neither the absolute nor the relative distance to the lateral sesamoid bone differed significantly between the groups, nor did they correlate with either of the 2 angles. Thus, despite medial shifting of the first metatarsal in hallux valgus, the lateral sesamoid retains its relationship to the second metatarsal in transverse plane. Its apparent lateral movement is a radiographic misinterpretation. Awareness of this misinterpretation should improve the success of corrective surgery.


Escherichia coli deoxyribonucleic acid synthesis mutants: their effect upon bacteriophage P2 and satellite bacteriophage P4 deoxyribonucleic acid synthesis.
Escherichia coli C strains containing different deoxyribonucleic acid (DNA) synthesis mutations have been tested for their support of the DNA synthesis of bacteriophage P2 and its satellite phage P4. Bacteriophage P2 requires functional dnaB, dnaE, and dnaG E. coli gene products for DNA synthesis, whereas it does not require the products of the dnaA, dnaC, or dnaH genes. In contrast, the satellite virus P4 requires functional dnaE and dnaH gene products for DNA synthesis and does not need the products of the dnaA, dnaB, dnaC, and dnaG genes. Thus the P2 and P4 genomes are replicated differently, even though they are packaged in heads made of the same protein.


GLC assay of belladonna extracts.
Samples of belladonna pilular and powdered extract and tincture from two suppliers were analyzed by GLC as a cooperative effort between two laboratories to develop methodology with substantial improvements in sensitivity, specificity, precision, and working time over the present official method. This goal was achieved, but marked differences in response of the individual extracts to different isolation schemes were noted.


[Follow-up studies on model cast prostheses after 4 years wear].
Over a period of 4-1/2 years, patients having model cast dentures that had been inserted in the dental office were checked and submitted to follow-ups. It became evident that the socalled pre-prosthetical measures had been performed in a non-satisfying manner. In 69% of the patients, teeth had been extracted directly before inserting the model cast denture. As a result thereof, a majority of the dentures was sagging after a relatively short time and 70% of the dentures revealed non-occlusion in the final follow-up. 47% of the dentures had to be modified because of necessary tooth extractions, thereby reducing the original number of abutment teeth by 19%. About a third of the inserted model cast dentures showed gross deficiences, the percentage of socalled "collar" constructions was relatively high.


Gensini scores and well-being states among patients with coronary artery disease: A comparison study.
World Health Organization (WHO) considered Mental Health Continuum (MHC) as a good instrument for well-being studies. Moreover, gensini score (GS) is an intensity index for coronary artery disease (CAD). The aim of our study was to compare GSs among patients who had coronary artery disease with different well-being states. This was a cross-sectional study conducted in Tehran Heart Center, Iran, in 2013. The study population consisted of 50 non-depressed patients who were candidates for coronary artery bypass graft (CABG). All of the participants were interviewed according to the Iranian version of Mental Health Continuum (IV-MHC) and were allocated to flourishing, maternal mental health (MMH) and languishing states based on the related classification criteria. GS was calculated for each participant. Data were analyzed by SPSS. Forty one (82%) patients were in flourishing, 9 (18%) in MMH and nobody was in languishing states. The mean (standard deviation) of GS was 90.43 (44.424) and 89.67 (33.378) for flourishing and MMH ones, respectively (P = 0.962). There was no statistically significant correlation between GSs and well-being states (all Ps > 0.050). Considering IV-MHC classification, all of our patients were only allocated to flourishing and MMH states. There was no relationship between intensity of CAD and the states (P > 0.050). We recommend further research with larger sample sizes for better evaluation of the Iranian version of the instrument.


A likely inverse-Compton emission from the Type IIb SN 2013df.
The inverse-Compton X-ray emission model for supernovae has been well established to explain the X-ray properties of many supernovae for over 30 years. However, no observational case has yet been found to connect the X-rays with the optical lights as they should be. Here, we report the discovery of a hard X-ray source that is associated with a Type II-b supernova. Simultaneous emission enhancements have been found in both the X-ray and optical light curves twenty days after the supernova explosion. While the enhanced X-rays are likely dominated by inverse-Compton scatterings of the supernova's lights from the Type II-b secondary peak, we propose a scenario of a high-speed supernova ejecta colliding with a low-density pre-supernova stellar wind that produces an optically thin and high-temperature electron gas for the Comptonization. The inferred stellar wind mass-loss rate is consistent with that of the supernova progenitor candidate as a yellow supergiant detected by the Hubble Space Telescope, providing an independent proof for the progenitor. This is also new evidence of the inverse-Compton emission during the early phase of a supernova.


Central hypoventilation in progressive supranuclear palsy.
Central hypoventilation, also known as Ondine's curse, results from an impairment of the autonomic respiratory drive. It is characterized by an attenuated or absent respiratory response to hypoxemia and hypercapnia with preservation of volitional respiratory function. RJ was a 75-year-old woman with a diagnosis of probably PSP who developed central hypoventilation approximately four years after her initial onset of symptoms. Brain MRI showed no evidence of medullary lesions, one of the more common causes of adult onset central hypoventilation. The respiratory centers in the medulla, especially the ventral respiratory group (VRG) containing Botzinger and pre-Botzinger complex of neurons, appear critical for normal respiratory rhythm generation. RJ was maintained on a portable ventilator after her diagnosis of Central Hypoventilation. Ten month after being placed on ventilation she passed of unclear cause. RJ showed pathological features consistent with a diagnosis of PSP, specifically loss of neurons, secondary demyelination, and tau-positive inclusions in both astrocytes and neurons, chiefly in the globus pallidus, midbrain, and brainstem. RJ showed significant tauopathy in the region of the VRG in particular. We also examined this region in sixteen other cases of PSP and found similar tauopathy in all but one case, which had significantly less involvement of this area. We had limited clinical data on these cases but one had two episodes of unexplained hypoxia shortly before being placed on hospice. Central hypoventilation associated with tauopathy involving the VRG may be more common than often appreciated.


A cross-sectional study of epilepsy in Danish Labrador Retrievers: prevalence and selected risk factors.
The purpose of this study was to investigate the prevalence and selected risk factors of epilepsy, the proportion of dogs with epilepsy in remission, and the types of seizures in Danish Labrador Retrievers. A prospective cross-sectional study of epilepsy was conducted in 1999-2000. The study was carried out in 2 phases in a reference population consisting of 29,602 individuals. In phase 1, 550 dogs were selected by random sampling stratified by year of birth. A telephone interview was used to identify dogs with possible epilepsy. In phase 2, dogs judged during phase 1 as possibly suffering from epilepsy were further subjected to physical and neurologic examination, CBC, blood chemistry, and a questionnaire on seizure phenomenology. Seventeen dogs were diagnosed with epilepsy, yielding a prevalence of 3.1% (95% CI 1.6-4.6%) in the Danish population of Labrador Retrievers. A diagnosis of epilepsy was 6 times more probable in dogs >4 years (born before 1995) than in younger dogs (born between 1995 and 1999) (P = .004, relative risk = 6.5). No significant difference in risk between genders was observed, nor could any effect of neutering be proven statistically. The frequencies of primary generalized seizures and partial seizures (with or without secondary generalization) were 24 and 70%, respectively. The type of seizures could not be classified in 6%. In conclusion, the 3.1% prevalence of epilepsy in Danish Labrador Retrievers is higher than the 1% prevalence of epilepsy described in the general canine population, establishing that this breed is at increased risk.


Outcomes of Isolated Varus Derotational Osteotomy in Children With Cerebral Palsy Hip Dysplasia and Predictors of Resubluxation.
The appropriate intervention for hip subluxation or dislocation in children affected by cerebral palsy (CP) remains controversial. The purpose of this retrospective study was to report radiographic and clinical outcomes following isolated femoral varus derotational osteotomy (VDRO) in children with CP hip dysplasia. Risk factors for resubluxation and avascular necrosis (AVN) were also examined. A cohort of 100 patients (199 hips) with CP treated with isolated VDRO between 2003 and 2009 was reviewed. All but 1 patient received bilateral surgery. Patients were followed for an average of 5.4 years (range, 1.03 to 10.20 y). Anteroposterior pelvic radiographs were used to assess migration percentage (MP), Shenton's line, and presence of AVN. Resubluxation was defined as a postoperative break in Shenton's line. Radiographic outcomes and risk analysis was performed in the 91 subjects (179 hips) with radiographic follow-up >1 year. Significant improvement was observed in MP, and all hips had a reconstituted Shenton's line following surgery. Over the course of follow-up, 16% of hips were noted to have a repeat break in Shenton's line. Univariate risk analysis showed preoperative MP, Gross Motor Function Classification System (GMFCS) level, and age at surgery were risk factors for a recurrent line break. Preoperative MP and GMFCS level were found to be predictors of resubluxation in multivariate analysis. AVN was detected in 10 hips (5.7%). GMFCS level V patients were more at risk for resubluxation, but less at risk for AVN when compared with ambulatory (GMFCS I/II/II) patients and GMFCS level IV patients. Performing a VDRO without additional procedures provided a stable and concentrically reduced hip joint in this population of children with CP. Attention should be paid to initial ambulatory status during the postoperative period. Concomitant procedures such as pelvic osteotomy should be considered for patients of GMFCS level IV and V, as these patients were more at risk for recurrent subluxation. Level III-retrospective comparative study.


A hybrid Zeeman slower for lithium.
Zeeman slowers come in two commonly used types: electromagnet-based slowers and permanent-magnet slowers. Both have characteristic advantages and disadvantages. The electric currents required to create strong magnetic fields lead to heat dissipation that limits the achievable fields, while permanent-magnet slowers cause bias magnetic fields at the position of the magneto-optical trap. Here, we combine both approaches and their advantages at our lithium-6 triangular-lattice quantum gas microscope and extend the field of an electromagnet-based Zeeman slower using permanent magnets. We observe nearly doubled loading rates of the magneto-optical trap and no significant stray fields in the trapping region. Our approach allows for a stronger magnetic field in places where geometric constraints prevent the use of coils, and it provides a low-cost upgrade to the loading rate at established experiments.


Characteristics of Different Types of Childhood Violence and the Risk of Revictimization.
This study investigates the relationship between the characteristics of different types of childhood violence and adult victimization using two waves of data from a community telephone survey (T1) and a follow-up survey, including 505 cases and 506 controls, aged 17-35 years (T2). The logistic regression analyses showed that exposure to childhood abuse, regardless of type, was associated with adult victimization. Exposure to multiple types of abuse, victimization both in childhood and in young adulthood, and recency of abuse increased these odds. Our findings emphasize the importance of assessing multiple forms of violence when studying revictimization. Practitioners working with children and young adults should be attentive to the number of victimization types experienced and recent victimization to prevent further abuse.


Basic musculoskeletal assessment: tips for the home health nurse.
Home care clients typically present with functional deficits that are frequently attributable to musculoskeletal abnormalities. This article teaches the home care nurse how to conduct a basic musculoskeletal assessment and how to use the findings to develop a thorough plan of care for the home care client.


Assessment of the importance of alpha-amylase inhibitor-2 in bruchid resistance of wild common bean.
Both alpha-amylase inhibitor-2 (alphaAI-2) and arcelin have been implicated in resistance of wild common bean (Phaseolus vulgaris L.) to the Mexican bean weevil (Zabrotes subfasciatus Boheman). Near isogenic lines (NILs) for arcelin 1-5 were generated by backcrossing wild common bean accessions with a cultivated variety. Whereas seeds of a wild accession (G12953) containing both alphaAI-2 and arcelin 4 were completely resistant to Z. subfasciatus, those of the corresponding NIL were susceptible to infestation, suggesting that the principal determinant of resistance was lost during backcrossing. Three independent lines of transgenic azuki bean [Vigna angularis (Willd.) Ohwi and Ohashi] expressing alphaAI-2 accumulated high levels of this protein in seeds. The expression of alphaAI-2 in these lines conferred protection against the azuki bean weevil (Callosobruchus chinensis L.), likely through inhibition of larval digestive alpha-amylase. However, although the seed content of alphaAI-2 in these transgenic lines was similar to that in a wild accession of common bean (G12953), it did not confer a level of resistance to Z. subfasciatus similar to that of the wild accession. These results suggest that alphaAI-2 alone does not provide a high level of resistance to Z. subfasciatus. However, alphaAI-2 is an effective insecticidal protein with a spectrum of activity distinct from that of alphaAI-1, and it may prove beneficial in genetic engineering of insect resistance in legumes.


Centre variation in cost and outcomes for congenital heart surgery.
Although overall outcomes for children undergoing heart surgery have improved, there is a significant variation in outcomes across hospitals. This review discusses the variation in cost and outcomes across centres performing congenital heart surgery, potential underlying mechanisms, and efforts to reduce variation and improve outcome.


Hsa_circ_0134111 promotes osteoarthritis progression by regulating miR-224-5p/CCL1 interaction.
Mechanical, metabolic, inflammatory, and immune factors contribute to the development of osteoarthritis (OA), a joint disease characterized by cartilage destruction. The circular RNA (circRNA) hsa_circ_0134111 is upregulated in the cartilage of OA patients; however, its potential role in OA pathogenesis and progression remains unexplored. In this study, the effects of hsa_circ_0134111 knockdown were evaluated in primary human chondrocytes treated with IL-1β to simulate OA, as well as in a rat model of OA. Hsa_circ_0134111 expression was upregulated in IL-1β-stimulated chondrocytes. CCK-8 and flow cytometry assays showed that hsa_circ_0134111 knockdown reversed IL-1β-induced cell decline by inhibiting apoptosis. Following prediction analysis of circRNA and miRNA targets, dual-luciferase reporter and silencing/overexpression assays suggested that a regulatory network composed of hsa_circ_0134111, miR-224-5p, and CCL1 modulates IL-1β-mediated OA-like effects in chondrocytes. Accordingly, CCL1 overexpression abrogated the prosurvival effects of hsa_circ_0134111 knockdown in vitro. Moreover, hsa_circ_0134111 silencing in vivo alleviated cartilage destruction in an OA rat model, decreased IL-6 and TNF-α levels in synovial fluid, and downregulated CCL1 expression in the affected joints. These results suggest that hsa_circ_0134111 contributes to OA development by binding to miR-224-5p, thereby releasing the inhibition that miR-224-5p exerts over CCL1.


Nursing consultation software for hypertensive users of the Family Health Strategy.
To report the development of a nursing consultation software for hypertensive users of the Family Health Strategy. Applied methodological research based on Roger Pressman's Software Engineering, developed in three cycles: planning, composed of the definition of the database prototyping and modelling; development of the navigation interface; and development of functional expressions and programming. The software consists of administrative and nursing consultation screens. In the history, there is the option of undertaking the first and next consultation; nursing diagnoses are suggested by the system after entering information and can be selected by nurses. Interventions for diagnoses are suggested and can be chosen by nurses after structuring the medical plan. It is believed that the introduction of computer technology for nursing consultation brings several contributions, such as standardization, integration with different information systems, and continuous update.


Noninvasive sample collection for the genotyping of neonatal rats using adhesive tape.
To develop a noninvasive sample collection method for genotyping, we compared PCR products from samples collected from neonates using five different brands of adhesive tape. Next, the youngest application age to distinguish genotypes was established. The tapes were applied on the backs of rats on postnatal day (PND) 10. DNA extracts from two brands provided clear PCR products that enabled genotype identification. The youngest age for distinguishing genotypes was PND 5; however, the youngest age that provided accurate results was PND 7. Thus, the present method allows for genotyping during the neonatal period without invasive burden and may improve animal welfare by refining.


[Simultaneous determination of 76 pesticide residues in the traditional Chinese medicine by magnetic hydrophilic-lipophilic-balanced materials assisted matrix solid phase dispersion extraction-high performance liquid chromatography-tandem mass spectrometry].
Traditional Chinese medicine (TCM) is gaining popularity worldwide, but its quality is often affected by excessive pesticide residues during cultivation and production. A sensitive and reliable method for the simultaneous determination of multi-residue pesticides in TCMs is the key to guarantee the quality and safety of TCMs. In this study, broad-spectrum hydrophilic-lipophilic balanced magnetic adsorbents were prepared for the magnetic matrix solid phase dispersion (MMSPD) extraction of 76 pesticides from three different TCMs before their detection by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Unlike the traditional matrix solid phase dispersion (MSPD), which required tedious SPE column packing, an external magnetic field was employed in our method for magnetic isolation and extraction from TCM samples, followed by grounding adsorption. First, broad-spectrum hydrophilic-lipophilic balanced magnetic adsorbents, Fe3O4@PLS, were successfully fabricated by the swelling polymerization of divinyl benzene (DVB) and N-vinyl pyrrolidone (NVP) on the surface of Fe3O4 magnetic particles. The prepared materials were systematically characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffractometry (XRD) for their morphologies, chemical structure, and crystalline structure. Then, the obtained magnetic particles (Fe3O4@PLS) were applied to MMSPD for the simultaneous extraction and analysis of the 76 pesticides in honeysuckle, chrysanthemum, and pseudo-ginseng root (dry) prior to detection by HPLC-MS/MS. In order to establish the optimal extraction conditions, the key parameters affecting the MMSPD extraction efficiency were optimized, including the amount of magnetic materials Fe3O4@PLS (5, 10, 12, 15, 20 mg), volume fractions of methanol in water for matrix purification (0%, 5%, 10%, 20%, 25%), grinding adsorption time for dispersion (2, 3, 4, 5, 6 min), type (methanol, methanol containing 0.1% (v/v) formic acid, acetonitrile, acetonitrile containing 0.1% (v/v) formic acid) and volume (0.5, 1, 2, 2.5, 5 mL) of elution solvent, and vortex time for desorption (1, 2, 3, 4, 5 min). Finally, the optimal conditions were set as follows: 10 mg of the magnetic adsorbent Fe3O4@PLS, 10 mL 20% (v/v) of methanol in water with a vortex time of 1 min for matrix purification, grinding time of 5 min for dispersion and adsorption, 0.5 mL acetonitrile containing 0.1% (v/v) formic acid as the elution solvent, and vortex time of 1 min for desorption. Then, the 76 pesticides were separated on an Agilent ZORBAX Eclipse Plus C18 column (100 mm×3.0 mm, 1.8 μm) with gradient elution and analyzed in multiple reaction monitoring (MRM) mode by positive electrospray ionization (ESI+). Under the optimal conditions, good linearities were obtained for the 76 pesticides in the concentration ranges of 10 to 200 μg/kg, with correlation coefficients (r 2)≥0.9965. The limits of detection (LODs, S/N=3) were in the range of 0.6-3.0 μg/kg, and the limits of quantification (LOQs, S/N=10) ranged from 2.0 to 10.0 μg/kg. The proposed method was successfully applied to 76 pesticide residue analysis in honeysuckle, chrysanthemum, and pseudo-ginseng root (dry). At three spiked levels, the recoveries were 69.1%-112.2%, 67.1%-102.8% and 70.1%-105.1%, with RSDs of 2.0%-12.4%, 2.1%-13.2% and 2.0%-13.5% for honeysuckle, chrysanthemum, and pseudo-ginseng root(dry), respectively. The prepared magnetic material Fe3O4@PLS has the characteristics of both strong magnetic responsibility and high broad-spectrum adsorption property for hydrophilic (e. g., carbendazim) and lipophilic (e. g., edifenphos) pesticides. The implementation of the MMSPD method before the analysis of the 76 pesticides by HPLC-MS/MS has the following advantages: less consumption of the magnetic materials, sample, and organic solvent; simple operation; high sensitivity; and satisfactory accuracy and precision. Hence, this is a potential method for the simultaneous determination of multiple pesticide residues in complex non-liquid TCM samples.


Competition and niche separation of pelagic bacteria in freshwater habitats.
Freshwater bacterioplankton assemblages are composed of sympatric populations that can be delineated, for example, by ribosomal RNA gene relatedness and that differ in key ecophysiological properties. They may be free-living or attached, specialized for particular concentrations or subsets of substrates, or invest a variable amount of their resources in defence traits against protistan predators and viruses. Some may be motile and tactic whereas others are not, with far-reaching implications for their respective life styles and niche partitioning. The co-occurrence of competitors with overlapping growth requirements has profound consequences for the stability of community functions; it can to some extent be explained by habitat factors such as the microscale complexity and spatiotemporal variability of the lacustrine environments. On the other hand, the composition and diversity of freshwater microbial assemblages also reflects non-equilibrium states, dispersal and the stochasticity of community assembly processes. This review synoptically discusses the competition and niche separation of heterotrophic bacterial populations (defined at various levels of phylogenetic resolution) in the pelagic zone of inland surface waters from a variety of angles, focusing on habitat heterogeneity and the resulting biogeographic distribution patterns, the ecophysiological adaptations to the substrate field and the interactions of prokaryotes with predators and viruses.


Separation of representative lipid compounds of biological membranes and lipid derivatives from peroxidized polyunsaturated fatty acids by reversed phase high-performance liquid chromatography.
A complex mixture of different lipid compounds, including phosphatidylcholine, phosphatidylserine, all trans-retinol, 15(S)-hydroperoxyeicosatetraenoic acid, D-alpha-tocopherol, saturated and unsaturated fatty acids can be separated by reversed phase HPLC by using a C-18, 120 mm x 4 mm, 3 microns particle size column and a step gradient from acetonitrile/water (1:1; v:v) to 100% acetonitrile at a flow rate of 0.8 ml/min. By applying this elution condition, separation of various groups of lipid hydroperoxides and lipid derivatives, each one originating from a different in vitro peroxidized polyunsaturated fatty acid, can be obtained. Simultaneous detection is carried out by a diode array detector at a wavelength accumulation range set up between 195 and 400 nm. The possibility of simultaneously having such a large number of measurements renders this chromatographic method particularly suitable in studies concerning lipid peroxidation where, in addition to the detection of free radical-induced lipid hydroperoxides, data on some key antioxidant molecules, i.e. vitamin A and E, as well as that of structural compounds of biological membranes, i.e. phosphatidylcholine and phosphatidylserine, can be achieved.


HEAVEN Criteria: Derivation of a New Difficult Airway Prediction Tool.
Airway management is vitally important in the management of critically ill and injured patients. Current tools to predict the difficult airway have limited application in the emergency airway situation. The aim of this study was to derive a novel difficult airway prediction tool for emergency intubation. A retrospective descriptive analysis was performed in a population of air medical rapid sequence intubation patients requiring more than 1 attempt. The Delphi technique was used to classify the etiology for airway failure as reported by providers as part of a performance improvement database. Etiologies were organized into 6 categories, and an acronym was derived for ease of recall. A total of 504 patients were screened, with 63 (12%) patients identified in whom the initial intubation attempt was unsuccessful. All 63 patients (100%) were placed into 1 or more categories (HEAVEN criteria = Hypoxemia, Extremes of size, Anatomic challenges, Vomit/blood/fluid, Exsanguination/anemia, and Neck mobility issues). The database was relatively modest in size, and many patients had more than 1 criterion present, limiting our ability to perform prevalence calculations. The HEAVEN criteria represent a set of difficult airway predictors that may be applied prospectively by emergency airway personnel, facilitating airway decision making. These criteria should be validated prospectively.


[Effect and mechanism of lipopolysaccharides-induced myeloid-derived suppressor cells on airway inflammation in asthmatic mice].
To explore the effect and mechanism of lipopolysaccharides (LPS)-induced CD11b⁺Gr-1⁺ myeloid-derived suppressor cells (MDSCs) on airway inflammation in asthmatic mice. A total of 34 female BALB/c mice were selected. Among them, 4 mice received an intraperitoneal injection of LPS for inducing the accumulation of MDSCs. And the MDSCs were separated with CD11b immunomagnetic beads from spleen extract. Another 30 mice were randomly divided into normal control, asthmatic and cell treatment groups. The mice in the asthmatic and cell treatment groups were sensitized with ovalbumin by a combination of intraperitoneal injection and challenges to establish the murine asthmatic model. At Days 14 and 21 post-sensitization, the mice in cell treatment group received an intravenous injection of LPS-induced MDSCs. At 24 hours after the last allergen challenge, the number of inflammatory cells were counted and morphological identification of leucocytes in bronchoalveolar lavage fluid (BALF) was performed to analyze the degree of airway inflammation in conjunctions with pathological sections. The BALF and serum levels of interleukin-13 were measured by enzyme-linked immunosorbent assay (ELISA). The number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) in peripheral blood was measured by flow cytometry. The total number of cells, the percentage of neutrophils and eosinophils of BALF in the cell treatment group [(17.0 ± 8.3)×10⁴/ml, 11.1% ± 2.0%, 9.8% ± 2.9%] were significantly lower than those in the asthmatic group [(36.0 ± 15.9)×10⁴/ml, 20.8% ± 4.0%, 14.1% ± 4.2%] (P = 0.000, 0.000, 0.011). Compared to the asthmatic group, the BALF and serum levels of IL-13 were significantly lower [(34.7 ± 7.1) vs (105.0 ± 9.0) ng/L, (34.0 ± 4.7) vs (48.1 ± 6.1) ng/L] (both P = 0.000) and the number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells increased in peripheral blood (8.0% ± 1.3% vs 5.1% ± 2.1%, P = 0.002) and airway inflammation was significantly relieved in the cell treatment group. LPS-induced MDSCs may improve airway inflammation through up-regulating Tregs in peripheral blood and suppressing Th2 effector function in asthmatic mice.


Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns.
Anatomically separate fat depots differ in size, function, and contribution to pathological states, such as the metabolic syndrome. We isolated preadipocytes from different human fat depots to determine whether the basis for this variation is partly attributable to differences in inherent properties of fat cell progenitors. We found that genome-wide expression profiles of primary preadipocytes cultured in parallel from abdominal subcutaneous, mesenteric, and omental fat depots were distinct. Interestingly, visceral fat was not homogeneous. Preadipocytes from one of the two main visceral depots, mesenteric fat, had an expression profile closer to that of subcutaneous than omental preadipocytes, the other main visceral depot. Expression of genes that regulate early development, including homeotic genes, differed extensively among undifferentiated preadipocytes isolated from different fat depots. These profiles were confirmed by real-time PCR analysis of preadipocytes from additional lean and obese male and female subjects. We made preadipocyte strains from single abdominal subcutaneous and omental preadipocytes by expressing telomerase. Depot-specific developmental gene expression profiles persisted for 40 population doublings in these strains. Thus, human fat cell progenitors from different regions are effectively distinct, consistent with different fat depots being separate mini-organs.


Monitoring the molecular composition of live cells exposed to electric pulses via label-free optical methods.
The permeabilization of the live cells membrane by the delivery of electric pulses has fundamental interest in medicine, in particular in tumors treatment by electrochemotherapy. Since underlying mechanisms are still not fully understood, we studied the impact of electric pulses on the biochemical composition of live cells thanks to label-free optical methods: confocal Raman microspectroscopy and terahertz microscopy. A dose effect was observed after cells exposure to different field intensities and a major impact on cell peptide/protein content was found. Raman measurements reveal that protein structure and/or environment are modified by the electric pulses while terahertz measurements suggest a leakage of proteins and other intracellular compounds. We show that Raman and terahertz modalities are a particularly attractive complement to fluorescence microscopy which is the reference optical technique in the case of electropermeabilization. Finally, we propose an analytical model for the influx and efflux of non-permeant molecules through transiently (electro)permeabilized cell membranes.


Identification of plasma antifibrin/fibrinogen antibodies in a patient with hemolytic uremic syndrome.
We investigated a patient with atypical hemolytic uremic syndrome without diarrhea to determine the presence of antibodies and the specificity of the related antigens. The patient experienced repeated episodes of hemolytic uremic syndrome. She is dialysis dependent. von Willebrand factor (vWF), vWF multimers, platelet aggregation, ADAMTS-13 activity and platelet immunoblots were determined. During acute episodes vWF increased threefold, with unusually large vWF multimers on two occasions. Platelet aggregation was normal but the plasma caused spontaneous aggregation of normal platelets. Reactivity was removed after absorption with protein A. Protein blotting against platelet and microvascular endothelial cells showed strong and persistent reactivity against antigens of 200 and 55 kDa. Two-dimensional immunoblots of the whole platelet proteome and incubation with plasma identified strong immunoreactivity with two target spots in the 55-kDa area. Mass spectroscopy confirmed the target as beta-fibrin, molecular weight 50.73 kDa, isoelectric point 7.95, with MASCOT scores of 859 and 750, Two years after presentation another band was detected at 66 kDa and identified as the alpha subunit of fibrin. This patient's plasma contained a platelet-aggregating factor that was removed by immunoglobulin absorption. She developed antibodies against the alpha and beta subunits of fibrin/fibrinogen.


Targeted Radiofrequency Ablation as an Adjunct in Treatment of Lumbar Facet Cysts.
Lumbar facet cysts are frequently found in patients with facet degeneration and segmental instability. When the facet cyst is localized in the neural foramina and lateral recess or becomes large, it can cause radiculopathy or neurogenic claudication. These symptomatic cysts are typically treated interventionally with drainage and a corticosteroid injection or attempts via overinflation to rupture the cyst; however, these procedures have a significant recurrence rate (up to 50%) and often need to be repeated or lead to lumbar surgery if unsuccessful. This is the first report of using targeted radiofrequency (RF) current as an adjunct to cyst drainage. Although RF has been used for years to treat facet pain indirectly by targeting the medial facet nerve branches, with this technique, under image guidance, the actual cyst is percutaneously drained and then cauterized along with the associated facet capsule, where the original cyst developed. This has improved overall results with less cyst recurrence than previous percutaneous methods and was documented with both intermediate and long-term followup clinically and with magnetic resonance imaging (MRI) scans. This report reviews the underlying anatomy and pathology of the facet joint relating to the development of facet cysts and how current percutaneous treatments for lumbar facet cysts can be supplemented and improved by adding targeted RF ablation to the percutaneous options available to treat a lumbar facet cyst.


Screening of cytokines to enhance vaccine effects of heat shock protein 70-rich tumor cell lysate.
Heat shock proteins (HSPs) have been recognized as significant participants in immune reactions. We have previously reported that heat-treated cells expressing HSP70 can mediate potent antitumor immune responses. As successful immunotherapy is dependent on the host immune system, the present study evaluated whether systemic administration of immunocyte stimulatory and growth promoting cytokines could enhance heat-treated cell lysate vaccine (HCLV) immunization to further promote the antitumor immunity. After heating mouse melanoma B16 cells (43 degrees C, 30 min) to elicit increased HSP70 expression, cells were lysed by freeze thawing to prepare HCLV. In approaches using a poorly immunogenic melanoma B16, the effects of various cytokines (IL-1beta, -2, -4, -6 and -12, IFN-beta and -gamma, GM-CSF and TNF-alpha) were assessed in combination with HCLV. Syngenic C57BL/6 mice were immunized subcutaneously with HCLV twice, on days -14 and -7, while cytokines were injected intraperitoneally on day -7. Subcutaneous B16 cell challenge was performed on day 0. IL-12 significantly enhanced the efficacy of HCLV, compared to non-heated cell lysate vaccine (CLV) and non-vaccination. Systemic administration of recombinant IL-12 augmented the efficacy of HCLV, inducing protective immunity against tumor challenge and enhancing cytotoxicity assessed in primed splenocytes against B16 cells in treated mice. These results suggest that IL-12 represents an important modulator of antitumor immune responses induced by HCLV, and may facilitate further efforts to develop novel cancer immunotherapies based on HSP70-mediated vaccination.


Impaired induction of type II interferon in tumor-bearing mice.
The response of mice to type II interferon inducers such as purified protein derivative of tuberculin or OK-432 was significantly impaired after either the implantation of tumor cells or the injection of cell-free tumor ascitic fluids. Complete inhibition of type II interferon induction occurred in 3 to 5 days. This inhibitory effect persisted until the death of mice implanted with tumors or for 7 days after i.p. injection of 0.2 ml of tumor ascitic fluid. The inhibitory activity was seen even with 0.2 ml of the 10,000-fold dilution of the fluid and with its filtrate passed through a Diaflo UM-10 membrane (greater than 10,000-dalton exclusion), However, such tumor ascitic fluids did not affect the induction of type I interferon in mice by polyriboinosinic-polyribocytidylic acid or tilorone-HCl. Moreover, adjuvant-induced nontumorous ascitic fluid had no inhibitory activity. These results indicate that the in vivo induction of type II interferon is specifically impaired by tumor-mediated factor(s) with molecular weights of less than 10,000.


Countertransference in Dermatology.
The doctor-patient relationship in dermatology, as in all the fields of medicine, is not a neutral relationship, removed from affects. These affects take root in the sociocultural, professional, family and personal history of both persons in the relationship. They underpin the psychic reality of the patients, along with a variety of representations, preconceived ideas, and fantasies concerning dermatology, the dermatologists or the psychiatrists. Practitioners call these "countertransference feelings", with reference to the psychoanalytical concept of "countertransference". These feelings come forward in a more or less conscious way and are active during the follow-up of any patient: in fact they can facilitate or hinder such a follow-up. Our purpose in focusing on this issue is to sensitize the dermatologists to recognizing these countertransference feelings in themselves (and the attitudes generated by them), in order to allow the patients and doctors to build a dynamic, creative, trustful and effective relationship.


Recombinant human progranzyme 3 expressed in Escherichia coli for analysis of its activation mechanism.
Gr3 is reported to play an important role in defense against viral infection. Although it is known that Gr3 is synthesized as a proenzyme and activated in the cytotoxic granules of NK cells and CTL, the activation mechanism is not clearly understood. In an attempt to analyze the activation mechanism of human Gr3, a recombinant pro-Gr3 was expressed in the periplasm of E. coli and purified to homogeneity. On SDS-PAGE the recombinant pro-Gr3 showed a slightly higher molecular weight than the enzymatically active Gr3, because the former possesses a small propeptide at its N-terminal. The recombinant pro-Gr3 was enzymatically inactive. It could be activated by treatment with cathepsin C, which concomitantly decreased the molecular weight to that of active Gr3. The proteolytic reaction of cathepsin C did not continue after one dipeptide had been removed, indicating that the recombinant pro-Gr3 had the native conformation without any refolding process. The recombinant pro-Gr3 would be a valuable tool for analyzing the activation mechanism and exploring other activating enzymes besides cathepsin C.


In vitro study on the effects of silver sulfadiazine on bilirubin binding.
Silver sulfadiazine is a new topical antimicrobial agent with a broad spectrum of activity against most bacterial (both gram-positive and gram-negative) and many fungal species. This broad spectrum of activity suggests that silver sulfiazine may be useful in clinical situations which require the inhibition of cutaneous bacterial and/or fungal colonization. The present study was undertaken to determine the effect of this agent on a bilirubin-protein binding. Using chromatographic procedures on artificially jaundiced sera and human serum albumin solutions, we were unable to detect any releast of protein-bound bilirubin by a saturated suspension of silver sulfadiazine.


Myxofibrosarcoma: a correlative cytologic and histologic study of 13 cases examined by fine needle aspiration cytology.
A correlative cytologic and histologic study of 13 myxofibrosarcomas is presented. The myxofibrosarcomas were grouped histologically into four grades (I to IV) according to the degree of cellularity, atypica and prevalence of mitotic figures. Cytologically, the neoplasms exhibited two types of malignant cells: an elongated, spindle-shaped, fibroblast-like cell and a larger, histocyte-like cell, often embedded in myxoid material. Some aspirates contained small capillary-like fragments. The degree of cellular and nuclear polymorphism and the quantitative distribution between the two types of cells in the different grades corresponded to the histologic classification. The differential diagnosis between myxofibrosarcoma and other myxoid soft tissue neoplasms is discussed. Staining the aspirated material with Alcian blue at different pHs helps to distinguish between myxomatous mesenchymal neoplasms containing nonsulphated glucosaminoglycans, such as myxofibrosarcoma, and those containing sulphated ones, such as myxoid chondrosarcoma and chordoma.


Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress‑mediated cell death in multiple myeloma cells.
The inhibitory effects of macrolide antibiotics including clarithromycin (CAM) on autophagy flux have been reported. Although a macrolide antibiotic exhibits no cytotoxicity, its combination with bortezomib (BZ), a proteasome inhibitor, for the simultaneous blocking of the ubiquitin (Ub)‑proteasome and autophagy‑lysosome pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via stress overloading of the endoplasmic reticulum (ER). As misfolded protein cargo is recruited by histone deacetylase 6 (HDAC6) to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of vorinostat [suberoylanilide hydroxamic acid (SAHA); potently inhibits HDAC6] with CAM and BZ compared with each reagent or a 2‑reagent combination. CAM/BZ treatment induced vimentin positive‑aggresome formation along with the accumulation of autolysosomes in the perinuclear region, whereas they were inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including C/EBP homologous protein (CHOP). Similarly to MM cell lines, enhanced cytotoxicity with CHOP upregulation following SAHA/CAM/BZ treatment was shown by a wild‑type murine embryonic fibroblast (MEF) cell line; however, a CHOP‑deficient MEF cell line almost completely canceled this pronounced cytotoxicity. Knockdown of HDAC6 with siRNA exhibited further enhanced CAM/BZ‑induced cytotoxicity and CHOP induction along with the cancellation of aggresome formation. Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient ER stress‑mediated apoptosis in MM cells.


Robotic Surgical System for Radical Prostatectomy: A Health Technology Assessment.
Prostate cancer is the second most common type of cancer in Canadian men. Radical prostatectomy is one of the treatment options available, and involves removing the prostate gland and surrounding tissues. In recent years, surgeons have begun to use robot-assisted radical prostatectomy more frequently. We aimed to determine the clinical benefits and harms of the robotic surgical system for radical prostatectomy (robot-assisted radical prostatectomy) compared with the open and laparoscopic surgical methods. We also assessed the cost-effectiveness of robot-assisted versus open radical prostatectomy in patients with clinically localized prostate cancer in Ontario. We performed a literature search and included prospective comparative studies that examined robot-assisted versus open or laparoscopic radical prostatectomy for prostate cancer. The outcomes of interest were perioperative, functional, and oncological. The quality of the body of evidence was examined according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also conducted a cost-utility analysis with a 1-year time horizon. The potential long-term benefits of robot-assisted radical prostatectomy for functional and oncological outcomes were also evaluated in a 10-year Markov model in scenario analyses. In addition, we conducted a budget impact analysis to estimate the additional costs to the provincial budget if the adoption of robot-assisted radical prostatectomy were to increase in the next 5 years. A needs assessment determined that the published literature on patient perspectives was relatively well developed, and that direct patient engagement would add relatively little new information. Compared with the open approach, we found robot-assisted radical prostatectomy reduced length of stay and blood loss (moderate quality evidence) but had no difference or inconclusive results for functional and oncological outcomes (low to moderate quality evidence). Compared with laparoscopic radical prostatectomy, robot-assisted radical prostatectomy had no difference in perioperative, functional, and oncological outcomes (low to moderate quality evidence). Compared with open radical prostatectomy, our best estimates suggested that robot-assisted prostatectomy was associated with higher costs ($6,234) and a small gain in quality-adjusted life-years (QALYs) (0.0012). The best estimate of the incremental cost-effectiveness ratio (ICER) was $5.2 million per QALY gained. However, if robot-assisted radical prostatectomy were assumed to have substantially better long-term functional and oncological outcomes, the ICER might be as low as $83,921 per QALY gained. We estimated the annual budget impact to be $0.8 million to $3.4 million over the next 5 years. There is no high-quality evidence that robot-assisted radical prostatectomy improves functional and oncological outcomes compared with open and laparoscopic approaches. However, compared with open radical prostatectomy, the costs of using the robotic system are relatively large while the health benefits are relatively small.


HER2-targeted therapy in breast cancer: a systematic review of neoadjuvant trials.
Targeting human epidermal growth factor receptor 2 (HER2) during or in sequence with chemotherapy improves overall survival in metastatic and early HER2-overexpressing breast cancer. In this paper we systematically review neoadjuvant clinical trial data in HER2-positive breast cancer and discuss key unanswered clinical questions. All trials of HER2-targeted neoadjuvant therapy were identified through non-date-limited searches of PubMED® and Biosis® and congress abstract book searches from 2000-2011. Eligible trials were prospective, had at least 10 patients and a clear definition of pathological complete response (pCR) rate. A total of 50 trials fulfilled the eligibility criteria; 41 single-arm phase II studies were identified, 37 with trastuzumab and 4 with lapatinib, with significant variability in baseline tumour characteristics and pCR rates (range 12-66.7%). Of 9 randomised phase II/III trials, 4 assessed the addition of trastuzumab to chemotherapy and a further 5 randomised trials assessed different HER2-targeting approaches. Four of these studies assessed dual HER2-targeting approaches, which universally increased pCR at the expense of increased non-cardiac toxicity when lapatinib, but not pertuzumab, was added to trastuzumab. Significant advances have been made in HER2 targeting, resulting in a marked increase in the number of breast cancer patients experiencing tumour pCR. Mature data from randomised neoadjuvant and adjuvant studies are awaited for survival outcomes with combination targeted approaches. Unanswered questions centre on the individualisation of therapy and include; which, if any, chemotherapy backbone should be used, and which patients need dual HER2 blockade?


Reduced bioaccumulation of PAHs by Lactuca satuva L. grown in contaminated soil amended with sewage sludge and sewage sludge derived biochar.
The influence of sewage sludge (SS) and sewage sludge biochar (SSBC) upon biomass yield and the bioaccumulation of PAHs into lettuce plants grown in contaminated soil (∑16PAH 20.2 ± 0.9 mg kg(-1)) is presented. All SSBC amendments (2, 5 and 10%) and the 2% SS amendment significantly (P < 0.01) increased lettuce biomass. Both SS and SSBC amendments significantly reduced (P < 0.01) the bioaccumulation of PAHs at all application levels; with reduction in ∑16PAH concentration ranging between 41.8 and 60.3% in SS amended treatments and between 58.0 and 63.2% in SSBC amended treatments, with respect to the control. Benefits in terms of biomass production and PAHs bioaccumulation reduction were greatest where SSBC was used as a soil amendment. At high application rates (10%) SSBC reduced bioaccumulation of PAHs by between 56% and 67%, while SS reduced bioaccumulation of PAHs by less than 44%.


Preparation and Characterization of Protein-Loaded Electrospun Fiber Mat and Its Release Kinetics.
For the enhancement of protein's bioavailability, a specific delivery system was developed by coaxial electrospinning. Bovine serum albumin (BSA) was used as protein model, and the core-sheath fiber mat was fabricated using sodium alginate as shell layer and the BSA-loaded chitosan nanoparticle that was prepared previously as core layer. By optimizing electrospinning parameters, uniform fibers with diameters ranging from 200-600 nm were obtained, and transmission electron microscopy and confocal laser scanning microscopy revealed their core-sheath structures. Fourier transform infrared spectroscopy (FTIR) analysis demonstrated that there existed molecular interaction between components, which enhanced the mat's thermal stability and mechanic property. It was found that the predominant release mechanism of BSA from fiber mat was erosion, and little change occurred in the secondary structure of encapsulated BSA indicated by FTIR and circular dichroism analysis. The study shows that the obtained fiber mat is a potential delivery system for protein.


Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity.
Long-term side effects of antiretroviral therapy are attributed to the mitochondrial (mt) toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their ability to deplete mtDNA. Studies in hepatocytes suggest that uridine is able to prevent and treat mtDNA depletion by pyrimidine NRTls [zalcitabine (ddC) and stavudine (d4T)] and to fully abrogate hepatocyte death, elevated lactate production and intracellular steatosis. Uridine was also found to improve the liver and haematopoietic toxicities of zidovudine (AZT), which are unrelated to mtDNA depletion, and to prevent neuronal cell death induced by ddC. Most recently, uridine was found to prevent the onset of a lipoatrophic phenotype (reduced intracellular lipids, increased apoptosis, mtDNA depletion and mt depolarization) in adipocytes incubated long-term with d4T and AZT. Various steps of mt nucleoside utilization may be involved in the protective effect, but competition of uridine metabolites with NRTIs at polymerase y or other enzymes is a plausible explanation. Pharmacokinetic studies suggest that uridine serum levels can be safely increased in humans to achieve concentrations which are protective in vitro (50-200 microM). Uridine was not found to interfere with the antiretroviral activity of NRTIs. Mitocnol, a sugar cane extract which effectively increases uridine in human serum, was beneficial in individual HIV patients with mt toxicity and is now being tested in placebo-controlled randomized trials. Until these data become available, the risk-benefit calculation of using uridine should be individualized. The current safety data justify the closely monitored use of uridine in individuals who suffer from mt toxicity but who cannot be switched to less toxic NRTIs.


Orientation and molecular map position of the complement genes in the mouse MHC.
Over the past few years six gene clusters have been isolated from the major histocompatibility complex (MHC) of the BALB/c mouse encompassing a total of 1600 kb of DNA and 48 genes. The molecular distances between these gene clusters and the orientation of four of the six clusters on chromosome 17 is not known. Here we use pulse-field gradient gels and Southern blot hybridization to establish large-scale genomic restriction maps covering several hundreds of kb surrounding the three gene clusters located in the K, I, S, and D regions of the MHC. Comparison of the maps orients the complement gene clusters in the S region with the 21-OHB gene pointing towards the K end and the C2 gene pointing towards the D end of the MHC. The distances between the E alpha and 21-OHB genes is 430 kb and between the C2 and TNF-alpha genes at least 420 kb.


Comparison of unmet health care needs in children with intellectual disability, autism spectrum disorder and both disorders combined.
The purpose of this study was to assess the unmet health care needs of children with intellectual disability (ID) compared with children with autism spectrum disorder (ASD) and whether access to health insurance coverage is a contributing factor. Children with ID may be masked in the health care system due to increased diagnosis and awareness of ASD. The needs, unmet needs and insurance coverage of children with ID alone, ASD alone, and co-occurring ID and ASD were assessed in this study. The 2016 to 2019 United States' Census Bureau National Survey of Children's Health was used to determine differences in unmet needs, care not received and health insurance coverage during the past year for children with ID and/or ASD. Adjusted odds ratios and 95% confidence intervals for care not received were determined controlling for sex, insurance, race, age and parents' highest education level. Children with ID were nearly four times more likely not to receive needed medical care as children with ASD. Results were similar for unmet hearing and mental health care. Children with both ID and ASD were more likely to have unmet health care but less likely to have unmet medical care compared with children with ASD alone. There were no significant differences for unmet dental or vision care. Children with ID were 3.58 (95% confidence interval: 1.6-8.0) times more likely to have inconsistent health insurance compared with children with ASD. Children with ID alone are more likely to have unmet medical, hearing and mental health care needs than children with ASD alone. Children with co-occurring ID and ASD have a large amount of general unmet health care needs but less unmet medical needs. Children with ID are less likely to have consistent health insurance than children with ASD. This hinders the ability of children with ID to receive quality care. Further research is needed to determine if the diagnosis of ASD in children in the United States is negatively affecting children with ID alone.


hydra Mutants of Arabidopsis are defective in sterol profiles and auxin and ethylene signaling.
The hydra mutants of Arabidopsis are characterized by a pleiotropic phenotype that shows defective embryonic and seedling cell patterning, morphogenesis, and root growth. We demonstrate that the HYDRA1 gene encodes a Delta8-Delta7 sterol isomerase, whereas HYDRA2 encodes a sterol C14 reductase, previously identified as the FACKEL gene product. Seedlings mutant for each gene are similarly defective in the concentrations of the three major Arabidopsis sterols. Promoter::reporter gene analysis showed misexpression of the auxin-regulated DR5 and ACS1 promoters and of the epidermal cell file-specific GL2 promoter in the mutants. The mutants exhibit enhanced responses to auxin. The phenotypes can be rescued partially by inhibition of auxin and ethylene signaling but not by exogenous sterols or brassinosteroids. We propose a model in which correct sterol profiles are required for regulated auxin and ethylene signaling through effects on membrane function.


Treatment of acute septic arthritis.
Acute septic arthritis is a rare, but potentially devastating disease. The treatment is initiated intravenously, but can be safely switched to oral after 2-4 days providing large doses of a well-absorbing antibiotic and, for time-dependent antibiotics, 4 times-a-day administration are used. Empiric treatment should always cover Staphylococcus aureus and common respiratory pathogens, whereas Kingella kingae and Salmonella are important only regionally. Studies conducted by our group have shown that a total course of 10 days may suffice for previously healthy children in a Western setting. Treatment of neonates, patients with immunodeficiency or cases caused by methicillin-resistant S. aureus, may deserve a different approach.


[Agranulocytosis caused by dapsone. Apropos of 3 cases. Review of the literature].
Authors describe three cases of agranulocytosis in patients with giant cell (temporal) arterities treated with Dapsone and corticosteroids. The culture in vitro of CFU.GM. cells of two patients, four healthy subject and two patients treated with Dapsone with out granulopenia, demonstrates no any toxic effect of Dapsone. A review of the literature finds 59 cases of agranulocytosis in patients treated with Dapsone alone or in combination with other drugs. Doses of Dapsone ranged from 25 mg to 300 mg a day. Agranulocytosis occurred between the 4th and the 12th week, more often near the 8th week. Agranulocytosis occurred suddenly without previous granulocytopenia. These facts argue for immunoallergic mechanism. This Dapsone side effect requires to restrict its use and to reserve it to serious diseases or failures of other therapeutic drugs. It needs too to keep a close eye on the patients between the 6th and 12th week.


Characterization of VAMP isoforms in 3T3-L1 adipocytes: implications for GLUT4 trafficking.
The fusion of GLUT4-containing vesicles with the plasma membrane of adipocytes is a key facet of insulin action. This process is mediated by the formation of functional soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes between the plasma membrane t-SNARE complex and the vesicle v-SNARE or VAMP. The t-SNARE complex consists of Syntaxin4 and SNAP23, and whereas many studies identify VAMP2 as the v-SNARE, others suggest that either VAMP3 or VAMP8 may also fulfil this role. Here we characterized the levels of expression, distribution, and association of all the VAMPs expressed in 3T3-L1 adipocytes to provide the first systematic analysis of all members of this protein family for any cell type. Despite our finding that all VAMP isoforms form SDS-resistant SNARE complexes with Syntaxin4/SNAP23 in vitro, a combination of levels of expression (which vary by >30-fold), subcellular distribution, and coimmunoprecipitation analyses lead us to propose that VAMP2 is the major v-SNARE involved in GLUT4 trafficking to the surface of 3T3-L1 adipocytes.


Variability in nasal resistance measurements.
By means of computer-aided posterior rhinometry, nasal airflow resistance was measured in subjects with normal and abnormal noses. Variations were less than obtained by other methods. Subjects were exposed to several common stimuli which have been reported to induce nasal mucosal changes: exercise, mechanical irritation, air pollutants, and climatic extremes. Any resistive effects were of short duration in that they could no be detected 30 minutes after exposure, but a commonly used decongestant reduced nasal resistance for several hours. Computer-aided rhinometry provides a basal level of nasal patency. Its clinical usefulness, now being tested, will be reported later.


Diffusion tensor imaging analysis of long association bundles in the presence of an arteriovenous malformation.
Conventional imaging demonstrates intertwined fibers of the cerebral white matter as a homogeneous substrate. Recently, diffusion tensor imaging has allowed 3D reconstruction of these fiber bundles. The goal of this study was to analyze the modifications of the association fibers induced by an arteriovenous malformation (AVM) in the parietotemporooccipital (PTO) associative area and their clinical significance. The authors analyzed the long association fibers in seven patients harboring an AVM in or near the PTO region in relation with the fibers' clinical manifestation. The fibers include the arcuate fasciculus (AF), the occipitofrontal fasciculus (OFF), and the inferior longitudinal fasciculus (ILF). These structures were compared with the contralateral bundles. The modification of the tracts could establish a pattern signature depending on the specific location of the vascular malformation. There was a positive correlation between the degree of modifications of OFF and ILF fiber tracts and visual deficits. Alteration of the AF correlated with a speech disorder and the risk of postoperative deficits. Diffusion tensor imaging enables in vivo dissection of fiber tracts coursing through the PTO area. Depending on the location of the AVMs, long association fibers are variously modified. These findings correlate with clinical manifestations and may predict outcome after surgery.


Performance profiles: the influence of patient satisfaction data on physicians' practice.
Health maintenance organizations and other payers increasingly use patient satisfaction data to profile physician performance. Little is known about physicians' use of patient satisfaction information or how profiles affect individual physician behaviors. The objective of this study was to examine primary care physicians' perceptions of performance profiles based on patient satisfaction data, whether physicians use profiles to change practice behaviors, and which profile components physicians think are important for assessing quality of care. A written survey was conducted in 1998 in Massachusetts with 810 primary care physicians (304 pediatricians, 201 family practitioners, 305 internists) who had at least 100 patients in a large managed care plan and had received 1 or more profiles based on patient satisfaction data. Physicians in training were excluded. Physicians' perceptions of profiles and their reported use to change practice behaviors were measured. The response rate was 68%. Twenty-three percent reported that profiles were very or extremely useful for improving care. Only 7% reported using profiles often or always to change care. Although specific profile components related to interpersonal aspects of care were rated more useful, <11% reported using profiles often or always to make changes on any individual component. A majority, 67% to 89%, reported making no or minor changes on profile components. Responses did not vary by specialty, demographics, or practice characteristics. Physicians rated interpersonal factors (eg, ability to communicate with patients, ability to show caring and empathy) as the most important indicators of quality of care; they report having the most control over these factors. Office factors (eg, staying on schedule, ease of scheduling appointments) were ranked as least important for assessing quality of care. Although health maintenance organizations and other payers increasingly use patient satisfaction reports to profile individual physicians and guide physician compensation and health plan participation, <25% of primary care physicians find profiles useful for improving patient care and even fewer report using profiles to change practice. Profiles likely have limited influence on behavior changes. Payers who invest in profiles may find it advantageous to focus on health plans and practice facilities rather than on individual physicians.


Considerations for the development of health-based surface dust cleanup criteria for beryllium.
The exposure-response patterns with beryllium sensitization (BeS), chronic beryllium disease (CBD) and lung cancer are influenced by a number of biological and physicochemical factors. Recent studies have suggested dermal exposure as a pathway for BeS. In light of the current non-health-based DOE Beryllium Rule surface criteria, the feasibility of deriving a human health-based surface dust cleanup criteria (SDCC) for beryllium was assessed based on toxicology and health risk factors via all potential routes of exposure. Beryllium-specific and general exposure factors were evaluated, including (1) beryllium physicochemical characteristics, bioavailability and influence on disease prevalence, and (2) chemical dissipation, resuspension and transfer. SDCC for non-cancer (SDCC) and cancer (SDCC) endpoints were derived from a combination of modern methods applied for occupational, residential and building reentry surface dust criteria. The most conservative SDCC estimates were derived for dermal exposure (5-379 μg/100 cm for 0.1-1% damaged skin and 17-3337 μg/100 cm for intact skin), whereas the SDCC for inhalation exposure ranged from 51 to 485 μg/100 cm. Considering this analysis, the lowest DOE surface criterion of 0.2 μg/100 cm is conservative for minimizing exposure and potential risks associated with beryllium-contaminated surfaces released for non-beryllium industrial or public sector use. Although methodological challenges exist with sampling and analysis procedures, data variability and interpretation of surface dust information in relation to anthropogenic and natural background concentrations, this evaluation should provide useful guidance with regard to cleanup of manufacturing equipment or remediation of property for transfer to the general public or non-beryllium industrial facilities.


Conflicting relationship between age-dependent disorders, valvular heart disease and coronary artery disease by covariance structure analysis: Possible contribution of natriuretic peptide.
It is conceivable that contemporary valvular heart disease (VHD) is affected largely by an age-dependent atherosclerotic process, which is similar to that observed in coronary artery disease (CAD). However, a comorbid condition of VHD and CAD has not been precisely examined. The first objective of this study was to examine a possible comorbid condition. Provided that there is no comorbidity, the second objective was to search for the possible reasons by using conventional risk factors and plasma B-type natriuretic peptide (BNP) because BNP has a potentiality to suppress atherosclerotic development. The study population consisted of 3,457 patients consecutively admitted to our institution. The possible comorbid condition of VHD and CAD and the factors that influence the comorbidity were examined by covariance structure analysis and multivariate analysis. The distribution of the patients with VHD and those with CAD in the histograms showed that the incidence of VHD and the severity of CAD rose with seniority in appearance. The real statistical analysis was planned by covariance structure analysis. The current path model revealed that aging was associated with VHD and CAD severity (P < 0.001 for each); however, as a notable result, there was an inverse association regarding the comorbid condition between VHD and CAD (Correlation coefficient [β]: -0.121, P < 0.001). As the second objective, to clarify the factors leading to this inverse association, the contribution of conventional risk factors, such as age, gender, hypertension, smoking, diabetes, obesity and dyslipidemia, to VHD and CAD were examined by multivariate analysis. However, these factors did not exert an opposing effect on VHD and CAD, and the inverse association defied explanation. Since different pathological mechanisms may contribute to the formation of VHD and CAD, a differentially proposed path model using plasma BNP revealed that an increase in plasma BNP being drawn by VHD suppressed the progression of CAD (β: -0.465, P < 0.001). The incidence of VHD and CAD showed a significant conflicting relationship. This result supported the likely presence of unknown diverse mechanisms on top of the common cascade of atherosclerosis. Among them, the continuous elevation of plasma BNP due to VHD might be one of the explicable factors suppressing the progression of CAD.


Impact of Buffer, Protein Concentration and Sucrose Addition on the Aggregation and Particle Formation during Freezing and Thawing.
This study addresses the effect of freezing and thawing on a therapeutic monoclonal antibody (mAb) solution and the corresponding buffer formulation. Particle formation, crystallization behaviour, morphology changes and cryo-concentration effects were studied after varying the freezing and thawing rates, buffer formulation and protein concentration. The impact of undergoing multiple freeze/thaw (FT)-cycles at controlled and uncontrolled temperature rates on mAb solutions was investigated in terms of particle formation. Physicochemical characteristics were analysed by Differential Scanning Calorimetry whereas morphology changes are visualized by cryomicroscopy measurements. Micro Flow Imaging, Archimedes and Dynamic Light Scattering were used to investigate particle formation. Data retrieved in the present study emphasizes the damage caused by multiple FT-cyles and the need for sucrose as a cryoprotectant preventing cold-crystallization specifically at high protein concentrations. Low protein concentrations cause an increase of micron particle formation. Low freezing rates lead to a decreased particle number with increased particle diameter. The overall goal of this research is to gain a better understanding of the freezing and thawing behaviour of mAb solutions with the ultimate aim to optimize this process step by reducing the unwanted particle formation, which also includes protein aggregates.


Outcomes in the management of high-risk gestational trophoblastic neoplasia in trophoblastic disease centers in South America.
South America has a higher incidence of gestational trophoblastic disease than North America or Europe, but whether this impacts chemotherapy outcomes is unclear. The purpose of this study was to evaluate outcomes among women with high-risk gestational trophoblastic neoplasia (GTN) treated at trophoblastic disease centers in developing South American countries. This retrospective cohort study included patients with high-risk GTN treated in three trophoblastic disease centers in South America (Botucatu and Rio de Janeiro, Brazil, and Buenos Aires, Argentina) from January 1990 to December 2014. Data evaluated included demographics, clinical presentation, FIGO stage, WHO prognostic risk score, and treatment-related information. The primary treatment outcome was complete sustained remission by 18 months following completion of therapy or death. Among 1264 patients with GTN, 191 (15.1%) patients had high-risk GTN and 147 were eligible for the study. Complete sustained remission was ultimately achieved in 87.1% of cases overall, including 68.4% of ultra high-risk GTN (score ≥12). Early death (within 4 weeks of initiating therapy) was significantly associated with ultra high-risk GTN, occurring in 13.8% of these patients (p=0.003). By Cox's proportional hazards regression, factors most strongly related to death were non-molar antecedent pregnancy (RR 4.35, 95% CI 1.71 to 11.05), presence of liver, brain, or kidney metastases (RR 4.99, 95% CI 1.96 to 12.71), FIGO stage (RR 3.14, 95% CI 1.52 to 6.53), and an ultra-high-risk prognostic risk score (RR 7.86, 95% CI 2.99 to 20.71). Median follow-up after completion of chemotherapy was 4 years. Among patients followed to that timepoint, the probability of survival was 90% for patients with high-risk GTN (score 7-11) and 60% for patients with ultra-high-risk GTN (score ≥12). Trophoblastic disease centers in developing South American countries have achieved high remission rates in high-risk GTN, but early deaths remain an important problem, particularly in ultra-high-risk GTN.


Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers.
PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platforms that have the potential to control the release, absorption kinetics and lung retention time of conjugated drugs. The clinical application of these systems though, would likely require partial substitution of surface PEG groups with drug molecules that are anticipated to alter their lung clearance kinetics and clearance pathways. In the current study, we therefore evaluated the impact of increased surface hydrophobicity via substitution of 50% surface PEG groups with a model hydrophobic drug (α-carboxyl OtButylated methotrexate) on the lung clearance of a Generation 5 PEGylated polylysine dendrimer in rats. PEG substitution with OtBu-methotrexate accelerated lung clearance of the dendrimer by increasing polylysine scaffold catabolism, improving systemic absorption of the intact dendrimer and low molecular weight products of scaffold catabolism, and enhancing mucociliary clearance. These results suggest that the conjugation of hydrophobic drug on the surface of a PEGylated dendrimer is likely to accelerate lung clearance when compared to a fully PEGylated dendrimer.


Enterobius vermicularis as a Novel Surrogate for the Presence of Helminth Ova in Tertiary Wastewater Treatment Plants.
Significant effort has gone into assessing the fate and removal of viruses, bacteria, and protozoan parasites during wastewater treatment to provide data addressing potential health risks associated with reuse options. Comparatively less is known about the fate of parasitic worm species ova in these complex systems. It is largely assumed that these helminths settle, are removed with the sludge, and consequently represent a relatively low risk for wastewater reuse applications. However, helminths are a highly diverse group of organisms that display a wide range of physical properties that complicate the application of a single treatment for helminth reduction during wastewater treatment. Moreover, their diverse biological and physical properties make some ova highly resistant to both disinfection (i.e., with chlorine or UV treatment) and physical removal (settling) through the wastewater treatment train, indicating that there may be reason to broaden the scope of our investigations into whether parasitic worm eggs can be identified in treated wastewater. The ubiquitous human parasitic nematode Enterobius vermicularis (pinworm) produces small, buoyant ova. Utilizing a novel diagnostic quantitative PCR (qPCR), this study monitored E. vermicularis presence at two full-scale wastewater treatment plants over the course of 8 months and demonstrated incomplete physical removal of E. vermicularis ova through tertiary treatment, with removal efficiencies approximating only 0.5 and 1.6 log10 at the two wastewater treatment plants based on qPCR. These findings demonstrate the need for more-diverse surrogates of helminthic ova to fully assess treatment performance with respect to reclaimed wastewaters.IMPORTANCE Helminths, despite being a diverse and environmentally resistant class of pathogens, are often underestimated and ignored when treatment performance at modern wastewater treatment plants is considered. A one-size-fits-all surrogate for removal of helminth ova may be inappropriate to adequately assess risk and ensure public safety when treated and partially treated wastewaters are encountered. This study argues for the use of human pinworm as a conservative indicator of the presence of helminth ova due to its small size, buoyancy, prevalence in humans, and environmental resistance.


Flame Retardancy and Smoke Suppression of Silicone Rubber Foam with Microencapsulated Sepiolite and Zinc Borate.
The flame-retardant micro-encapsulated sepiolite (MSEP) was successfully prepared by sol-gel method. Fourier transform infrared, X-ray photoelectron spectroscopy, scanning electron microscopy, and energy dispersive spectroscopy were utilized to prove that sepiolite was encapsulated. Then, the mechanical properties, flame retardance, smoke suppression, and pyrolysis characteristics of silicone rubber foam (SiFs) with MSEP and zinc borate (ZB) were analyzed. The results indicated that the tensile and compressive properties of SiFs could evidently improve with the incorporation of MSEP/ZB. SiFs with 3 wt% MSEP and 6 wt% ZB could achieve an limiting oxygen index value of 30.9 vol% and UL-94 V-0 rating, the time to ignition was 64.7% above that of pure SiFs, the peak heat release rate and total heat release were 42.7% and 25.0% lower than that of pure SiFs, respectively. Furthermore, the peak smoke production rate and total smoke production of SiFs with 3 wt% MSEP and 6 wt% ZB were merely 54.22% and 64.10% of pure SiFs. Especially, the thermal stability of SiFs was significantly enhanced, and the carbon residue of SiFs became denser and more complete after adding 3 wt% MSEP and 6 wt% ZB.


Polypropelene-mesh properties and type of anchoring do not influence strength of parietal ingrowth.
In laparoscopic ventral hernia repair, parietal ingrowth of the mesh is of crucial importance. Until significant ingrowth occurs integrity of the repair depends solely on mesh overlap and anchoring device. Relatively few studies have addressed the effect of mesh properties and anchoring device on long-term parietal ingrowth. In 20 sheep, using laparoscopy, we inserted two different polypropylene-based meshes, Physiomesh™ and Ventralight™ ST, anchored with Protack™, SecureStrap™, or Glubran™. After 6 and 12 months, 10 sheep at each time point were euthanized, and we harvested the meshes with corresponding fascia. Mesh with fascia was attached on an Alwetron™ materials testing machine and pulled apart obtaining the peel-off energy (kilojoule (kJ)). The strength of parietal ingrowth at 6 months was 5.99 ± 0.54 kJ (mean ± SEM), 4.94 ± 0.54 kJ and 7.35 ± 0.55 kJ when anchored with Protack™, Glubran™, or SecureStrap™, respectively. At 6 months, the strength of parietal ingrowth of SecureStrap™ was significantly higher than Glubran™ (p = 0.04). No significant difference was seen between any other combinations. Parietal ingrowth at 12 months was 7.05 ± 0.56 kJ, 7.55 ± 0.54 kJ, and 5.73 ± 0.54 kJ when anchored with Protack™, Glubran™, and SecureStrap™, respectively. No significant difference in strength of parietal ingrowth was seen between the three types of anchoring, (p = 1.00, p = 1.00, and p = 0.29). At 12 months, the strength of parietal ingrowth was the same for all comparisons. The two polypropylene meshes showed equal strength of parietal ingrowth independent of mesh properties and anchoring devices used.


Amazoniaseius imparisetosus n. sp., n. g.: an unusual new phytoseiid mite (Acari: Phytoseiidae) from the Amazon forest.
A new genus and species of the subfamily Typhlodrominae are described from the Brazilian Amazon. The main differences between this and all other phytoseiid species are the presence of two unpaired setae on dorsal shield of deutonymphs and adults, and the absence of all ZV setae. It also differs from other typhlodromine species by its relatively long J5 setae, the presence of seta J4 and the broadly rounded posterior margin of the genital shield. Thus, the unique idiosomal setal pattern of this species is here designated as 13A+x:8F+X/JV-3,4:ZV-1-3. Because of the unique characteristics, we here describe this new taxon, Amazoniaseius imparisetosus n. sp., n. g., based on protonymphs, deutonymphs and adult females. This species is accommodated in tribe Paraseiulini Wainstein within Typhlodrominae, due to the presence of the setae z6 and S4. The tribe is redefined and an updated dichotomous key for the separation of the genera of Paraseiulini is provided.


Periplocin induces apoptosis and inhibits inflammation in rheumatoid arthritis fibroblast-like synoviocytes via nuclear factor kappa B pathway.
Apoptotic resistance and excessive proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) stimulated by inflammation could lead to distal joint destruction and bone damage. Periplocin could promote apoptosis, resist proliferation, and reduce inflammation. However, the effect and mechanism toward periplocin in proliferation and inflammation of RA-FLSs remain unclear. The role of tumor necrosis factor (TNF)-α induced proliferation and expression of inflammatory cytokines in RA-FLSs was established. Our studies noted that cell viability of TNF-α-induced RA-FLSs was inhibited in periplocin treatment via dose-response, whereas cell apoptosis of RA-FLSs was triggered by dose-dependent effect of periplocin. Bcl-2 protein, one of the apoptotic regulators, was downregulated, while other regulators of apoptosis, including BAX, cleaved caspase-3, and cleaved caspase-9, were upregulated in RA-FLSs under periplocin treatment. In addition, periplocin decreased the TNF-α-induced mRNA and protein expression levels of interleukin (IL)-1β and IL-6 in RA-FLSs in a dose-dependent way. Finally, the increased levels of phospho (p)-inhibitor of kappa B (IκBα)/IκBα and p-NF (nuclear factor)-κB/nuclear factor kappa B (NF-κB) ratio of RA-FLSs stimulated by TNF-α were decreased by periplocin treatment. Taken together, periplocin treatment decreased cell viability and cytokines expression and promoted cell apoptosis of TNF-α-induced RA-FLSs through inhibition of NF-κB signaling pathway, providing a potential therapeutic approach for RA.


Analyzing the evidence on European health care reforms.
Health system reform, in Europe as elsewhere, has often been influenced as much by theory and conjecture as by fact and experience. In a study published in September 1997, the Regional Office for Europe of the World Health Organization (WHO) drew together the available evidence about the health care systems in the fifty-one countries of the European region. This paper focuses on western European countries. It reviews a variety of policy strategies and then explores implications from this European experience for the formulation of U.S. health care policy.


Xist RNA repeat E is essential for ASH2L recruitment to the inactive X and regulates histone modifications and escape gene expression.
Long non-coding RNA Xist plays a crucial role in establishing and maintaining X-chromosome inactivation (XCI) which is a paradigm of long non-coding RNA-mediated gene regulation. Xist has Xist-specific repeat elements A-F which are conserved among eutherian mammals, underscoring their functional importance. Here we report that Xist RNA repeat E, a conserved Xist repeat element in the Xist exon 7, interacts with ASH2L and contributes to maintenance of escape gene expression level on the inactive X-chromosome (Xi) during XCI. The Xist repeat E-deletion mutant female ES cells show the depletion of ASH2L from the Xi upon differentiation. Furthermore, a subset of escape genes exhibits unexpectedly higher expression in the repeat E mutant cells than the cells expressing wildtype Xist during X-inactivation, whereas the silencing of X-linked non-escape genes is not affected. We discuss the implications of these results to understand the role of ASH2L and Xist repeat E for histone modifications and escape gene regulation during random X-chromosome inactivation.


Rhinophyma's fibrous variant. Histopathology and immunohistochemistry.
Rhinophyma may present with either of two distinct histopathologic appearances. The most common shows histopathologic features of rosacea. The second pattern shows telangiectasia, diffuse dermal fibrosis with abundant mucin, and a virtual absence of pilosebaceous structures. These histopathologic features of the lesser-known fibrous variant of rhinophyma mimic those of fibrous papule of the nose. We report an unusual case that histopathologically resembled the second variant. Immunohistochemically, the dermal fibroblasts in this case showed intense staining with Factor XIIIa in a pattern similar to that demonstrated in fibrous papules. S-100 protein failed to stain these dermal fibroblasts. The presence of Factor XIIIa+ dermal fibroblasts may portend the evolution of fibrosis in rosacea and other inflammatory dermatoses.


Plasmonic Hot Carriers-Controlled Second Harmonic Generation in WSe2 Bilayers.
Modulating second harmonic generation (SHG) by a static electric field through either electric-field-induced SHG or charge-induced SHG has been well documented. Nonetheless, it is essential to develop the ability to dynamically control and manipulate the nonlinear properties, preferably at high speed. Plasmonic hot carriers can be resonantly excited in metal nanoparticles and then injected into semiconductors within 10-100 fs, where they eventually decay on a comparable time scale. This allows one to rapidly manipulate all kinds of characteristics of semiconductors, including their nonlinear properties. Here we demonstrate that plasmonically generated hot electrons can be injected from plasmonic nanostructure into bilayer (2L) tungsten diselenide (WSe2), breaking the material inversion symmetry and thus inducing an SHG. With a set of pump-probe experiments we confirm that it is the dynamic separation electric field resulting from the hot carrier injection (rather than a simple optical field enhancement) that is the cause of SHG. Transient absorption measurement further substantiate the plasmonic hot electrons injection and allow us to measure a rise time of ∼120 fs and a fall time of 1.9 ps. Our study creates opportunity for the ultrafast all-optical control of SHG in an all-optical manner that may enable a variety of applications.


Evaluation and Management of Atherosclerotic Carotid Stenosis.
Medical therapies for the prevention of stroke have advanced considerably in the past several years. There can also be a role for mechanical restoration of the lumen by endarterectomy or stenting in selected patients with high-grade atherosclerotic stenosis of the extracranial carotid artery. Endarterectomy is generally recommended for patients with high-grade symptomatic carotid stenosis. Stenting is considered an option for patients at high risk of complications with endarterectomy. Whether revascularization is better than contemporary medical therapy for asymptomatic extracranial carotid stenosis is a subject of several ongoing randomized clinical trials in the United States and internationally.


Angiographic patterns and the natural history of the vulnerable plaque.
Coronary angiography is the gold standard for the identification of obstructive coronary artery disease (CAD). The use of this diagnostic test in the evaluation of many clinical syndromes of CAD has yielded a wealth of angiographic data relative to the vulnerable atherosclerotic plaque. This chapter reviews these important data including the limitations of the angiogram in vulnerable plaque detection, angiographic patterns of complex plaques or "culprit lesions," and the natural history of the complex angiographic lesion.


Induction of cIAP-2 in human colon cancer cells through PKC delta/NF-kappa B.
Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-kappa B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-kappa B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca2+-independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC delta-selective inhibitor rottlerin or transfection with an antisense PKC delta oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC delta plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC delta in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-kappa B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMA-induced NF-kappa B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC delta-induced cIAP-2 promoter activity and increased NF-kappa B transactivation, suggesting regulation of cIAP-2 expression by a PKC delta/NF-kappa B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-kappa B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC delta/NF-kappa B/cIAP-2 pathway in certain cancers.


Temperature-dependent production of carotovoricin Er and pectin lyase in phytopathogenic Erwinia carotovora subsp. carotovora Er.
The production of pectin lyase (Pnl) and carotovoricin (Ctv), as well as cell lysis in the plant-pathogenic bacterium Erwinia carotovora subsp. carotovora Er are induced by mitomycin C. Here, Pnl and Ctv production and cell lysis were found to be temperature-dependent. The optimal temperature for Pnl production was 30 degrees C. However, the optimal temperature for both Ctv production and cell lysis was 23 degrees C, at which Pnl production was reduced to 47% of the maximum. These data suggest the possible existence of novel regulation system(s) for the production of Pnl and Ctv, and cell lysis, in addition to the well-documented regulation system of recA, rdgA, and rdgB genes.


Angiogenic and lymphangiogenic molecules in hematological malignancies.
In this review, the role of angiogenic and lymphangiogenic growth factors in hematological malignancies is summarized, alongside with possible therapeutic applications. Recent data demonstrate the importance of angiogenesis in hematologic malignancies including leukemia, lymphoma, and multiple myeloma. Expression of angiogenic polypeptides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) associate with clinical characteristics in human leukemia and lymphoma, and their serum concentrations serve as predictors of poor prognosis. VEGF and VEGF-C also act as survival factors on leukemia. Furthermore, certain hematological malignancies both produce angiogenic or lymphangiogenic growth factors including VEGF and VEGF-C, and also express their receptors, resulting in the generation of autocrine loops that may support cancer cell survival and proliferation. Inhibition of the action of key regulators of endothelial cell growth, alone or in combination with other antiangiogenic drugs and/or established chemo- or immunotherapy regimens, is a potential target for therapeutic intervention in hematological malignancies.


The efficacy of early continuous positive airway pressure therapy in patients with acute cardiogenic pulmonary edema.
Although continuous positive airway pressure (CPAP) therapy using a face mask is known to improve oxygenation, the intrapulmonary shunt reduction remains unsettled. Our study was designed to explore this issue. From 1985 to 1987 80 patients with acute cardiogenic pulmonary edema were randomly chosen to receive either serial CPAP therapy or high-flow face mask oxygen therapy without CPAP (control) for the purpose of evaluating the efficacy of CPAP therapy. After screening for exclusion, only 55 patients were included in the first 3-hour investigation period. PaO2 in the CPAP group showed a significant increase by the end of the initial study; whereas intrapulmonary shunt and alveolar-arterial oxygen tension gradient AaDO2 revealed simultaneously a significant reduction. Conversely, neither PaO2 nor intrapulmonary shunt (or AaDO2) in the control group demonstrated any significant beneficial changes. As for cardiovascular function, only the CPAP therapy achieved a significant reduction in rate pressure product in contrast to the control (face mask) therapy alone. In terms of therapeutic failure, 10 patients in the control group failed. However, in the CPAP group only 5 patients had failed at the end of the first 3-hour study period. Overall, the cumulative therapeutic failure rate was 28% in the CPAP group and 60% in the control group during a 6-hour observation study. However, there was no significant difference between the two groups in 24-hour hospital mortality.(ABSTRACT TRUNCATED AT 250 WORDS)