Synthesis and antiulcer activity evaluation of conjugates of amino acids with N-aroyl- N, N'-dicyclohexyl urea.
Amino acids are safe molecules with variable efficacy against ulceration. Considering the good antioxidant potential of N-aroyl- N, N'-dicyclohexyl urea and antiulcer activities of amino acids, a series of amino acid conjugates of N-aroyl- N, N'-dicyclohexyl urea was synthesized and the effect against ulceration in albino rats induced by pyloric ligation was screened. All these compounds were found to be safe and active. Reduction of ulcer index was significant for all compounds. Conjugates of methionine and histidine exhibited enhanced antiulcer activity comparable to omeprazole in terms of inhibition of release of gastric juice, hydrochloric acid and neutralization activity. The promising efficacy and safety of these compounds is interesting for further investigation.


Degradation products of resin-based materials detected in saliva in vivo.
Dental composites remain under scrutiny regarding their (long-term) safety. In spite of numerous studies on the release of monomers both in vitro and in vivo, only limited quantitative data exist on the in vivo leaching of degradation products from monomers and additives. The aim of this observational study was for the first time to quantitatively and qualitatively monitor the release of parent compounds and their degradation products in saliva from patients undergoing multiple restorations. Five patients in need of multiple large composite restorations (minimally 5 up to 28 restorations) due to wear (attrition, abrasion, and erosion) were included in the study, and they received adhesive restorative treatment according to the standard procedures in the university clinic for Restorative Dentistry. Saliva was collected at different time points, starting before the restoration up until 24 h after the treatment with composite restorations. Saliva extracts were analyzed by liquid chromatography-mass spectrometry. Leaching of monomers and degradation products was highest within 30 min after the placement of the restorations. The highest median concentrations of monomers were recorded for UDMA, BisEMA-3, and TEGDMA; yet, besides BisEMA-3 and TEGDMA, no monomers could be detected after 24 h. Mono- and demethacrylated degradation products remained present up to 24 h and concentrations were generally higher than those of monomers. In patients with multiple restorations, degradation products were still present in the sample taken before the next operation, several weeks after the previous operation. Exposure to residual monomers and degradation products occurs in the first hours after restoration. Monomers are present in saliva shortly after restoration, but degradation products can be detected weeks after the restoration confirming a long-term release. Future research should focus more on the release of degradation products from monomers and additives from resin-based materials given their prolonged presence in saliva after restoration.


Platelet-rich plasma injection for tennis elbow: did it ever work?
Platelet-rich plasma (PRP) is a commonly used treatment for tendinopathies such as tennis elbow despite the questionable evidence of its efficacy. A recent Cochrane review suggests that it likely does not provide clinically meaningful benefits in people with tennis elbow. In this viewpoint, we discuss how lack of regulation allowed aggressive marketing and clinical use without normal phases of drug development and approval process or rigorous evidence of benefits. Since several phases of development were bypassed, we still do not know the optimal preparation method and dosing of PRP for tendinopathies. Furthermore, several clinical trials compared PRP with other interventions although it was unclear if PRP was better than placebo and these comparisons created distraction rather than improved understanding of its effects.


Electrospun composite nanofiber yarns containing oriented graphene nanoribbons.
The graphene nanoribbon (GNR)/carbon composite nanofiber yarns were prepared by electrospinning from poly(acrylonitrile) (PAN) containing graphene oxide nanoribbons (GONRs), and successive twisting and carbonization. The electrospinning process can exert directional shear force coupling with the external electric field to the flow of the spinning solution. During electrospinning, the well-dispersed GONRs were highly oriented along the fiber axis in an electrified thin liquid jet. The addition of GONRs at a low weight fraction significantly improved the mechanical properties of the composite nanofiber yarns. In addition, the carbonization of the matrix polymer enhanced not only the mechanical but also the electrical properties of the composites. The electrical conductivity of the carbonized composite yarns containing 0.5 wt % GONR showed the maximum value of 165 S cm(-1). It is larger than the maximum value of the reported electrospun carbon composite yarns. Interestingly, it is higher than the conductivities of both the PAN-based pristine CNF yarns (77 S cm(-1)) and the monolayer GNRs (54 S cm(-1)). These results and Raman spectroscopy supported the hypothesis that the oriented GONRs contained in the PAN nanofibers effectively functioned as not only the 1-D nanofiller but also the nanoplatelet promoter of stabilization and template agent for the carbonization.


Granulosa cell tumor of the ovary: tumor review.
Granulosa cell tumors of the ovary are rare neoplasms that originate from sex-cord stromal cells. The long natural history of granulosa cell tumors and their tendency to recur years after the initial diagnosis are the most prominent of their characteristics. The secretion of estradiol is the reason for signs at presentation such as vaginal bleeding and precocious puberty. Abdominal pain and hemoperitoneum, which occasionally can occur, are attributable to tumor rupture. The most common finding in pelvic examination is a tumor mass, which is subsequently confirmed with imaging techniques. Surgery is the mainstay of initial management for histological diagnosis, appropriate staging, and debulking. A more conservative unilateral salpingo-oophorectomy is indicated in patients with stage I disease and patients of reproductive age. Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment for postmenopausal women and those with more advanced disease. The stage of disease is the most important prognostic factor associated with the risk of relapse. There are no clear conclusions regarding the role of postoperative chemotherapy or radiotherapy in stage I disease and in those with completely resected tumor. The use of adjuvant chemotherapy or radiotherapy has sometimes been associated with prolonged disease-free survival and possibly overall survival. Chemotherapy is the treatment of choice for patients with advanced, recurrent, or metastatic disease, and BEP (bleomycin, etoposide, and cisplatin) is the preferred regimen. Although the overall rate of response to treatment is high, the impact of treatment on disease-free or overall survival is unknown. Prolonged surveillance is mandatory because tumors tend to recur years after the initial diagnosis.


Efficacy of Venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine.
This study evaluated the anxiolytic efficacy, safety and tolerability of a flexible dose of venlafaxine extended release (ER) compared with placebo and paroxetine in the short-term treatment of generalized social anxiety disorder (SAD). Adult outpatients with generalized SAD (n = 434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks. The primary efficacy variable was the Liebowitz social anxiety scale total score. Secondary efficacy variables included the patient-rated social phobia inventory and the proportion of responders in each group (a responder was defined as having a clinical global impression-improvement score of 1 or 2). Treatment with venlafaxine ER was associated with significantly greater improvement than treatment with placebo for all primary and secondary efficacy variables (p < 0.05). No significant differences in primary or secondary efficacy variables were observed between the venlafaxine ER and paroxetine groups. The week 12 response rates were 69%, 66% and 36% for the venlafaxine ER, paroxetine and placebo groups, respectively. Both active treatments were generally well tolerated and were associated with a similar incidence of adverse events. This study shows that venlafaxine ER is an effective, safe and well-tolerated drug treatment for SAD.


Marseillevirus adenitis in an 11-month-old child.
A Marseillevirus (giant virus of amoeba) has been found in the blood and stool samples of individuals who otherwise appear to be healthy. During an attempt to define a serological cutoff for Marseillevirus by enzyme-linked immunosorbent assay (ELISA) in children, we serendipitously detected high antibody responses to Marseillevirus in an 11-month-old boy suffering from adenitis. Marseillevirus DNA was then found in his blood using PCR and with a unique sequence. We identified Marseillevirus in a lymph node using fluorescence in situ hybridization (FISH) and immunohistochemistry, and the lymph node was removed surgically. The child was declared to be cured 1 year later. We conclude that adenitis during early childhood may be caused by Marseillevirus.


Quantum and all-atom molecular dynamics simulations of protonation and divalent ion binding to phosphatidylinositol 4,5-bisphosphate (PIP2).
Molecular dynamics calculations have been used to determine the structure of phosphatidylinositol 4,5 bisphosphate (PIP2) at the quantum level and to quantify the propensity for PIP2 to bind two physiologically relevant divalent cations, Mg(2+) and Ca(2+). We performed a geometry optimization at the Hartree-Fock 6-31+G(d) level of theory in vacuum and with a polarized continuum dielectric to determine the conformation of the phospholipid headgroup in the presence of water and its partial charge distribution. The angle between the headgroup and the acyl chains is nearly perpendicular, suggesting that in the absence of other interactions the inositol ring would lie flat along the cytoplasmic surface of the plasma membrane. Next, we employed hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to investigate the protonation state of PIP2 and its interactions with magnesium or calcium. We test the hypothesis suggested by prior experiments that binding of magnesium to PIP2 is mediated by a water molecule that is absent when calcium binds. These results may explain the selective ability of calcium to induce the formation of PIP2 clusters and phase separation from other lipids.


New Faces at the Bedside: Death Doulas, Vigilers, and Companions.
A growing number of nonmedical caregivers seek to improve dying in the United States. They call themselves end-of-life doulas, death midwives, soul guides, compassionate companions, and vigilers, among other names. These new faces at the bedside share a common goal of comforting the dying and their loved ones. Their work is both humanitarian and spiritual as they bring compassionate presence into the sacred space of dying. Thousands of individuals provide end-of-life caregiving through volunteer programs in hospitals, hospices, and community non-profits; hundreds more provide their services to clients for a fee. Using in-depth interviews and analysis of print and online materials, this article traces the development of nonmedical end-of-life caregiving from volunteer vigiling and companioning programs to the professionalization of end-of-life doulaing. Though professional doulas are in the media spotlight, this work began with volunteers who continue to provide most of the nonmedical end-of-life care support for the dying in the United States.


The Role of Manual Aspiration Thrombectomy in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI.
In STEMI, primary PCI restores macrovascular coronary blood flow effectively but microvascular perfusion remains a challenge. Thrombus has the potential to embolize to the microvasculature limiting effective coronary blood flow. Thrombus burden is associated with a higher mortality and manual aspiration thrombectomy has the potential to reduce thrombus burden. The first large trial of routine aspiration thrombectomy (TAPAS, N = 1071) showed an improvement in myocardial blush and an unexpected reduction in mortality. Reinforcing the enthusiasm for this finding meta-analysis of small trials also showed a reduction in mortality, which led to routine manual thrombectomy becoming a class IIa recommendation in the American and European Guidelines for STEMI. Subsequently; however, large trials such as TOTAL (N = 10,732) and TASTE (N = 7244) and meta-analysis showed an increase in the risk of stroke with routine manual thrombectomy but no improvement in mortality, myocardial infarction, stent thrombosis, or severe heart failure. As such, manual thrombectomy should not be routinely used instead saving it as a bailout procedure as indicated.


Initial plasma HIV-1 RNA levels and progression to AIDS in women and men.
It is unclear whether there are differences between men and women with human immunodeficiency virus type 1 (HIV-1) infection in the plasma level of viral RNA (the viral load). In men, the initial viral load after seroconversion predicts the likelihood of progression to the acquired immunodeficiency syndrome (AIDS), but the relation between the two has not been assessed in women. Currently, the guidelines for initiating antiretroviral therapy are applied uniformly to women and men. From 1988 through 1998, the viral load and the CD4+ lymphocyte count were measured approximately every six months in 156 male and 46 female injection-drug users who were followed prospectively after HIV-1 seroconversion. The median initial viral load was 50,766 copies of HIV-1 RNA per milliliter in the men but only 15,103 copies per milliliter in the women (P<0.001). The median initial CD4+ count did not differ significantly according to sex (659 and 672 cells per cubic millimeter, respectively). HIV-1 infection progressed to AIDS in 29 men and 15 women, and the risk of progression did not differ significantly according to sex. For each increase of 1 log in the viral load (on a base 10 scale), the hazard ratio for progression to AIDS was 1.55 (95 percent confidence interval, 0.97 to 2.47) among the men and 1.43 (95 percent confidence interval, 0.76 to 2.69) among the women. The median initial viral load was 77,822 HIV-1 RNA copies per milliliter in the men in whom AIDS developed and 40,634 copies per milliliter in the men in whom it did not; the corresponding values in the women were 17,149 and 12,043 copies per milliliter. Given the recommendation that treatment should be initiated when the viral load reaches 20,000 copies per milliliter, 74 percent of the men but only 37 percent of the women in our study would have been eligible for therapy at the first visit after seroconversion (P<0.001). Although the initial level of HIV-1 RNA was lower in women than in men, the rates of progression to AIDS were similar. Treatment guidelines that are based on the viral load, rather than the CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex.


Diagnostic value of compression ultrasonography and fibrinogen-related parameters for the detection of postoperative deep vein thrombosis following elective hip replacement: a pilot study.
To determine their ability to diagnose postoperative deep vein thrombosis (DVT) D-dimer - by three methods -, fibrinogen degradation products (FgDP) and fibrinogen levels were measured in 68 consecutive patients before elective surgery for hip replacement and on postoperative day 1, 3, 6, and 10. All patients received prophylaxis and underwent compression real-time B-mode ultrasonography (C-US) on postoperative day 5 and 9, and bilateral ascending venography on day 10. Twenty-two out of 68 patients developed asymptomatic postoperative DVT, which was limited to the calf veins in 14 and involved the proximal veins in 8 patients. C-US was negative in all patients on day 5. On day 9, C-US sensitivity and specificity for proximal DVT were 63% (95% confidence interval: 26%-90% and 98% (89%-100%) respectively. Postoperative changes in the laboratory parameters evaluated were not different in patients with or without DVT until day 10. On day 10, mean D-dimer, FgDP and fibrinogen levels were significantly higher in patients with DVT than in those without DVT (p values between 0.006 and 0.032), but only D-dimer was higher with DVT involving two or more venous segments than with thrombosis involving one venous segment only (p < 0.05). Stepwise logistic regression analysis identified D-dimer and fibrinogen on day 10 as predictors of postoperative DVT. In a receiver operator curve and after weighing for the coefficients generated by logistic regression analysis, the combination of a latex photometric immuno-assay and of PT-derived fibrinogen yielded-at a cut-off value of 7.0 a sensitivity of 100% (73%-100%) and a specificity of 58% (39%-75%) for DVT, with a negative predictive value of 100% (78%-100%), a positive predictive value of 52% (32%-71%) and an overall accuracy of 71% (55%-83%). These results suggest that two simple, fast and reproducible tests may permit the identification of patients at low risk of having postoperative DVT and that a combination of sensitive laboratory assays and of the highly specific C-US may select patients requiring anticoagulant treatment. Efficacy and cost-effectiveness of this approach should be evaluated in large clinical management studies.


Effect of irradiation on early enzymatic changes in healing mandibular periosteum and bone. A histochemical study on rats.
The influence of irradiation was studied histochemically in healing mandibular periosteum and bone. After a cut line had been made on both sides of the mandible the rats were exposed to roentgen ray irradiation. The single doses were 15, 20, 30, 35 or 40 Gy. The animals were killed 1, 2, 4, 8, 10, 12, 16 and 24 hours after irradiation, for histochemical analysis. All enzymes, acid phosphatase, cytochrome oxidase, lactate, isocitrate, glucose-6-phosphatase and succinate dehydrogenase, showed a greater increase in enzyme staining in the irradiated cut lines than in the non-irradiated control lines. The intensity of the staining increased with time and dose over 24 hours. The observation time included an inflammatory phase with vascular, enzymatic and cellular responses to periosteal and bone injury. The increase in staining was dependent on the time after surgical trauma and radiation dose. The increase in enzyme staining probably represents the initial cell damage after irradiation.


CPR and AEDs save lives: insuring CPR--AED education and CPR--AED access in schools.
Sudden cardiac arrest and sudden cardiac death are less common in children and adolescents than in the adult population. The outcomes from sudden cardiac arrest are generally quite poor in all ages and some data suggest that they are worse in the child and adolescent age group. In addition, the incidence of bystander cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) use is generally quite low although it is somewhat variable across communities. This review has been written in order to review the data for pediatric bystander CPR and AED use as it relates to out-of-hospital cardiac arrest (OHCA) survival. The purpose of this article is also to review endeavors at CPR--AED education in the context of improving both community bystander CPR/AED interventions and OHCA survival. Finally, this review will attempt to suggest some potential educational interventions in order to increase both bystander CPR-AED use and OHCA survival in local communities. Findings from several recent studies suggest that the incidence of bystander CPR--AED intervention is relatively low and that OHCA survival is also quite low in most communities. Several studies also suggest that community educational efforts can increase bystander CPR--AED interventions. The increase in OHCA survival may be attributed to the community educational efforts, yet that increase in survival is relatively small. A prospective high-school study has shown that in this very specific environment, a high incidence of CPR--AED use can be achieved, and that as a result the OHCA survival can be relatively high. It would be beneficial to attempt to ensure that all schools have a CPR--AED program along with a group of individuals trained to do CPR and use an AED. Not only should all schools have a cardiac emergency response plan (CERP) but all schools should have CPR--AED programs and all students should learn CPR and AED use prior to graduation. This strategy will ensure that we will have a community of individuals who would perform CPR and use an AED in the community and that in so doing we could increase the incidence of bystander CPR/AED use and increase the OHCA survival rate.


Local delivery of tobramycin and vancomycin in primary total knee arthroplasty achieves minimum inhibitory concentrations for common bacteria causing acute prosthetic joint infection.
The aim of this study was to determine if the local delivery of vancomycin and tobramycin in primary total knee arthroplasty (TKA) can achieve intra-articular concentrations exceeding the minimum inhibitory concentration thresholds for bacteria causing acute prosthetic joint infection (PJI). Using a retrospective single-institution database of all primary TKAs performed between January 1 2014 and May 7 2019, we identified patients with acute PJI that were managed surgically within 90 days of the initial procedure. The organisms from positive cultures obtained at the time of revision were tested for susceptibility to gentamicin, tobramycin, and vancomycin. A prospective study was then performed to determine the intra-articular antibiotic concentration on postoperative day one after primary TKA using one of five local antibiotic delivery strategies with tobramycin and/or vancomycin mixed into the polymethylmethacrylate (PMMA) or vancomycin powder. A total of 19 patients with acute PJI after TKA were identified and 29 unique bacterial isolates were recovered. The mean time to revision was 37 days (6 to 84). Nine isolates (31%) were resistant to gentamicin, ten (34%) were resistant to tobramycin, and seven (24%) were resistant to vancomycin. Excluding one Fusobacterium nucleatum, which was resistant to all three antibiotics, all isolates resistant to tobramycin or gentamicin were susceptible to vancomycin and vice versa. Overall, 2.4 g of tobramycin hand-mixed into 80 g of PMMA and 1 g of intra-articular vancomycin powder consistently achieved concentrations above the minimum inhibitory concentrations of susceptible organisms. One-third of bacteria causing acute PJI after primary TKA were resistant to the aminoglycosides commonly mixed into PMMA, and one-quarter were resistant to vancomycin. With one exception, all bacteria resistant to tobramycin were susceptible to vancomycin and vice versa. Based on these results, the optimal cover for organisms causing most cases of acute PJI after TKA can be achieved with a combination of tobramycin mixed in antibiotic cement, and vancomycin powder. Cite this article: Bone Joint J 2020;102-B(6 Supple A):163-169.


Oxidative metabolic responses of rabbit pulmonary alveolar macrophages.
During phagocytosis of opsonized lipopolysaccharide-coated paraffin oil droplets, rabbit alveolar macrophages reduced nitroblue tetrazolium, which effect was in part inhibitable with the use of superoxide dismutase. Exposure of cytochalasin-B-treated rabbit alveolar macrophages to opsonized zymosan led to the generation of superoxide, as quantitated by ferricytochrome C reduction. It was found that nitroblue tetrazolium in the presence of ferricytochrome C could in turn serve as scavenger of superoxide during stimulation of cytochalasin-B-treated rabbit alveolar macrophages. Following challenge with either opsonized zymosan or the membrane perturbant digitonin, rabbit alveolar macrophages released hydrogen peroxide into the extracellular medium. Employment of the surface membrane stimulant phorbol myristrate acetate led to activation of the hexose monophosphate shunt, which activity could be further enhanced in the presence of superoxide dismutase or attenuated in the presence of catalase. These studies demonstrate that rabbit alveolar macrophages release superoxide and hydrogen peroxide during surface membrane perturbation. In turn, hydrogen peroxide generation can stimulate the hexose monophosphate shunt.


Stable isotope ratios indicate diet and habitat use in New World monkeys.
This paper demonstrates the use of stable isotope ratios of carbon and nitrogen in animal tissue for indicating aspects of species behavioral strategy. We analyzed hair from individuals representing four species of New World monkeys (Alouatta palliata, the mantled howler; Ateles geoffroyi, the spider monkey; Cebus capucinus, the capuchin; and Brachyteles arachnoides, the woolly-spider monkey or muriqui) for delta 13C and delta 15N using previously developed methods. There are no significant differences in either carbon or nitrogen ratios between sexes, sampling year, or year of analysis. Seasonal differences in delta 13C reached a low level of significance but do not affect general patterns. Variation within species was similar to that recorded previously within single individuals. The omega 13C data show a bimodal distribution with significant difference between the means. The two monkey populations living in an evergreen forest were similar to each other and different from the other two monkey populations that inhabited dry, deciduous forests. This bimodal distribution is independent of any particular species' diet and reflects the level of leaf cover in the two types of forest. The delta 15N data display three significantly different modes. The omnivorous capuchins were most positive reflecting a trophic level offset. The spider monkeys and the muriquis were similar to one another and significantly more positive than the howlers. This distribution among totally herbivorous species correlates with the ingestion of legumes by the howler monkey population. In combination, these data indicate that museum-curated primate material can be analyzed to yield information on forest cover and diet in populations and species lacking behavioral data.


Anxiolytic Effect of Exogenous Ketone Supplementation Is Abolished by Adenosine A1 Receptor Inhibition in Wistar Albino Glaxo/Rijswijk Rats.
Anxiety disorders are one of the most common mental health problems worldwide, but the exact pathophysiology remains largely unknown. It has been demonstrated previously that administration of exogenous ketone supplement KSMCT (ketone salt/KS + medium chain triglyceride/MCT oil) by intragastric gavage for 7 days decreased the anxiety level in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. To investigate the potential role of the adenosinergic system in the pathomechanism of anxiety we tested whether the inhibition of adenosine A1 receptors (A1Rs) influence the anxiolytic effect of the exogenous ketone supplement. As A1Rs may mediate such an effect, in the present study we used a specific A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine) to test whether it modulates the anxiolytic effect of sub-chronically (7 days) applied KSMCT in the previously tested animal model by using elevated plus maze (EPM) test. We administered KSMCT (2.5 g/kg/day) alone by intragastric gavage and in combination with intraperitoneally (i.p.) injected of DPCPX in two doses (lower: 0.15 mg/kg, higher: 0.25 mg/kg). Control groups represented i.p saline and water gavage with or without i.p. DPCPX administration (2.5 g/kg/day). After treatments, the level of blood glucose and beta-hydroxybutyrate (βHB), as well as body weight were recorded. KSMCT alone significantly increased the time spent in the open arms and decreased the time spent in the closed arms, supporting our previous results. Injection of lower dose of DPCPX decreased, while higher dose of DPCPX abolished the effect of KSMCT administration on EPM. Blood βHB levels were significantly increased after administration of KSMCT, while DPCPX did not change the KSMCT induced increase in blood βHB levels. These results demonstrate that A1R inhibition modified (decreased) the anti-anxiety effect of KSMCT administration implying that the adenosinergic system, likely via A1Rs, may modulate the exogenous ketone supplement induced anxiolytic influence.


Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide.
Tuberculosis (TB) is one of the major health challenge in the world. The current treatment of TB needs daily administration of combined drug therapy for six or more months. Sometime non-adherence and less bioavailability from current therapy develops multidrug resistance, as a result, high dose requirement and subsequent intolerable toxicity are seen. Therefore, nanotechnology gained special attention as it has potential to improve patient compliance, bioavailability and reduction in dosing frequency. The aim of this study is to fabricate alginate-chitosan nanoparticles (AL-CS NPs) under appropriate conditions using ionic gelation method. The use of natural polymers in nanoparticle fabrication has a vast application due to their biodegradability, biocompatibility and nontoxic nature. Ionic gelation method involves the interaction between macromolecules with opposite charged ionizable groups forming polyelectrolyte complex. Hence, it is rational to formulate natural polymerbased sustained release nano-particulate matrix to improve patient adherence, reducing dose frequency and drug toxicity. The formulations were based on 32 factorial designs. Nanoparticles of combined drug (Isoniazid- INH and Pyrazinamide-PYZ) were fabricated using natural polymer. Formulation process involved the use of pregelated sodium alginate followed by ionic gelation with chitosan. Pregelation of sodium alginate included calcium chloride. The effects of sodium alginate concentration and chitosan concentration on particle size, zeta potential, entrapment efficiency and in vitro drug release were studied. Optimized Batch-3s showed particle size 539.7 ± 2.33 nm, zeta potential -26.4 ± 0.55 mV, and entrapment efficiency is 70.21 ± 0.24% and 73.45 ± 0.21% of INH and PYZ, respectively. Dissolution release study of Batch-3s in 7.4 pH phosphate buffer exhibited the initial burst of 5.04 ±0.45% and 19.68 ± 0.87% at 0.25 hrs followed by slow, sustained release of drug 74.53 ± 2.53 and 57.87 ± 2.04% at 10 hrs of INH and PYZ, respectively. It concluded that chitosan (CS) and sodium alginate (AL) concentration are rate-limiting factors in formulation development. Natural polymer based combined drug nano-particulate system could be an innovative and optimistic approach in the treatment of TB.


NF-κB-inducing kinase contributes to normal development of cortical thymic epithelial cells: its possible role in shaping a proper T-cell repertoire.
Nuclear factor (NF)-κB-inducing kinase (NIK) is known to be a critical regulator of multiple aspects of the immune response. Although the role of NIK in the development of medullary thymic epithelial cells (mTECs) has been well documented, the impact of NIK on the differentiation and function of cortical thymic epithelial cells (cTECs) remains ambiguous. To investigate the possible involvement of NIK in cTEC differentiation, we have compared the gene expression and function of cTECs from a NIK-mutant mouse, alymphoplasia (aly/aly) with those of cTECs from wild-type (WT) mice. Flow cytometric analyses revealed that expression levels of MHC class II, but not MHC class I or other TEC markers, were higher in aly/aly cells than in WT cells. Notably, the proportion of MHC class IIhi+ cTECs was elevated in aly/aly mice. We also demonstrated that expression of Ccl5 mRNA in the MHC class IIhi+ subset of aly/aly cTECs was decreased compared with that in WT cells, implying an abnormal pattern of gene expression in aly/aly cTECs. Analyses of bone marrow chimera using aly/aly or aly/+ mice as hosts suggested that Vβ usage and CD5 expression on WT T-cells were altered when they matured in aly/aly thymi. These results collectively indicate that NIK may be involved in controlling the function of cTEC in selecting a proper T-cell repertoire.


Conceptual Models and Mechanisms of Action that Underpin End-of-Life Care Interventions to Improve Spiritual Well-Being.
Background: Understanding the conceptual models that underpin interventions, and the linkage between mechanisms of action and their intended outcomes, makes replication possible. Aim: To identify and appraise conceptual models and mechanisms of action underpinning end-of-life care interventions to improve spiritual well-being. Design: A systematic review following the Preferred Reporting Items for Systematic Review and Meta-Analysis was conducted. Data sources: A comprehensive search was performed in eight databases from inception to January 12, 2021. Results: A logic model was developed and potential mechanisms of action were identified from the seven included studies. Conclusion: First, conceptual models that have relevance and appropriateness to cultural setting are required to underpin future intervention development and implementation. Second, careful intervention development should articulate the link between concept, mechanisms, and outcomes. Third, selection of valid outcome measured must have a strong justification of how the construct being measured relates to the intervention goals.


Calcium transport in intact human erthrocytes.
Intact human erythrocytes can be readily loaded with calcium by incubation in hypersomotic media at alkaline pH. Erythrocyte calcium content increases from 15-20 to 120-150 nmol/g hemoglobin after incubation for 2 h at 20 degree C in a 400 mosmol/kg, pH 7.8 solution containing 100 mM sodium chloride, 90 mM tetramethylammonium chloride, 1 mM potassium chloride, and 10 mM calcium chloride. Calcium uptake is a time-dependent process that is associated with an augmented efflux of potassium. The ATP content in these cells remains at more than 60% of normal and is not affected by calcium. Calcium uptake is influenced by the cationic composition of the external media. The response to potassium is diphasic. With increasing potassium concentrations, the net accumulation of calcium initially increases, becoming maximal at 1 mM potassium, then diminishes, falling below basal levels at concentrations above 3 mM potassium. Ouabain inhibits the stimulatory effect of low concentrations of potassium. The inhibitory effects of higher concentrations of potassium are ouabain insensitive and independent of the external calcium concentration. Sodium also inhibits calcium uptake but this inhibition can be modified by altering the external concentration of calcium. The effux of calcium from loaded erythrocytes is not significantly altered by changes in osmolality, medium ion composition, or ouabain. It is concluded that hypertonicity increases the net uptake of calcium by increasing the influx of calcium and that some part of the sodium potassium transport system is involved in this influx process.


Comparative core fucosylation analysis of some major therapeutic antibody N-glycans by direct infusion ESI-MS and CE-LIF detection.
The analysis of carbohydrate moieties of glycoprotein biopharmaceuticals is of high importance, especially because glycosylation changes can impact the biological effect of the drugs. In the case of monoclonal antibody therapeutics, the degree of core fucosylation significantly influences its effector function, thus should be closely monitored during the clone selection, development and manufacturing processes. MS analysis of labile sugar residues such as core fucosylation and terminal silylation may be misleading as such residues can break off during the ionization process or alter the ionization efficiency, both of which affect the results. In the case of monoclonal antibody therapeutics tailored for antibody-dependent cellular cytotoxicity function, core fucosylation should be kept minimal; therefore, close attention should be paid to the prevalence of this particular sugar residue. This paper reports on the core fucosylation analysis of some major immunoglobulin G N-glycans by direct infusion ESI-MS and CE-LIF. In comparison to the industry standard of CE-LIF, a lower degree of core fucosylated structures was found by ESI-MS analysis, emphasizing the need to use orthogonal quantitative separation methods in addition to MS.


Dual-transmitter systems regulating arousal, attention, learning and memory.
An array of neuromodulators, including monoamines and neuropeptides, regulate most behavioural and physiological traits. In the past decade, dramatic progress has been made in mapping neuromodulatory circuits, in analysing circuit dynamics, and interrogating circuit function using pharmacogenetic, optogenetic and imaging methods This review will focus on several distinct neural networks (acetylcholine/GABA/glutamate; histamine/GABA; orexin/glutamate; and relaxin-3/GABA) that originate from neural hubs that regulate wakefulness and related attentional and cognitive processes, and highlight approaches that have identified dual transmitter roles in these behavioural functions. Modulation of these different neural networks might be effective treatments of diseases related to arousal/sleep dysfunction and of cognitive dysfunction in psychiatric and neurodegenerative disorders.


Expression, purification, reconstitution and inhibition of Ustilago maydis sterol 14 alpha-demethylase (CYP51; P450(14DM)).
Triadimenol and tebuconazole are potent inhibitors of the sterol 14 alpha-demethylation reaction in fungi which is catalysed by CYP51, a haem-thiolate containing enzyme belonging to the cytochrome P450 monooxygenase superfamily. Using CYP51 from the phytopathogen Ustilago maydis, a comparison of the sensitivity of the fungal enzyme to triadimenol and tebuconazole has been carried out. U. maydis CYP51 was purified to homogeneity as determined by SDS-PAGE and specific haem content. Catalytic activity was investigated following reconstitution with its respective NADPH cytochrome P450 reductase and proposed endogenous substrate, 24-methylenedihydrolanosterol. Addition of the triadimenol and tebuconazole induced type II spectral changes in the enzyme, with saturation occurring at equimolar azole concentrations. Inhibition of reconstituted activities showed a one-to-one sensitivity of the fungal CYP51 as judged by IC50 values. The implications for fungicide mode of action and treatment are discussed.


Semi-supervised incremental learning with few examples for discovering medical association rules.
Association Rules are one of the main ways to represent structural patterns underlying raw data. They represent dependencies between sets of observations contained in the data. The associations established by these rules are very useful in the medical domain, for example in the predictive health field. Classic algorithms for association rule mining give rise to huge amounts of possible rules that should be filtered in order to select those most likely to be true. Most of the proposed techniques for these tasks are unsupervised. However, the accuracy provided by unsupervised systems is limited. Conversely, resorting to annotated data for training supervised systems is expensive and time-consuming. The purpose of this research is to design a new semi-supervised algorithm that performs like supervised algorithms but uses an affordable amount of training data. In this work we propose a new semi-supervised data mining model that combines unsupervised techniques (Fisher's exact test) with limited supervision. Starting with a small seed of annotated data, the model improves results (F-measure) obtained, using a fully supervised system (standard supervised ML algorithms). The idea is based on utilising the agreement between the predictions of the supervised system and those of the unsupervised techniques in a series of iterative steps. The new semi-supervised ML algorithm improves the results of supervised algorithms computed using the F-measure in the task of mining medical association rules, but training with an affordable amount of manually annotated data. Using a small amount of annotated data (which is easily achievable) leads to results similar to those of a supervised system. The proposal may be an important step for the practical development of techniques for mining association rules and generating new valuable scientific medical knowledge.


BODIPY-embedded electrospun materials in antimicrobial photodynamic inactivation.
Drug-resistant pathogens, particularly those that result in hospital acquired infections (HAIs), have emerged as a critical priority for the World Health Organization. To address the need for self-disinfecting materials to counter the threat posed by the transmission of these pathogens from surfaces to new hosts, here we investigated if a cationic BODIPY photosensitizer, embedded via electrospinning into nylon and polyacrylonitrile (PAN) nanofibers, was capable of inactivating both bacteria and viruses via antimicrobial photodynamic inactivation (aPDI). Materials characterization, including fiber morphology and the degree of photosensitizer loading, was assessed by scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and UV-visible diffuse reflectance spectroscopy (UV-Vis DRS), and demonstrated that the materials were comprised of nanofibers (125-215 nm avg. diameter) that were thermostable to >300 °C. The antimicrobial potencies of the resultant Nylon-BODIPY(+) and PAN-BODIPY(+) nanofiber materials were evaluated against four strains of bacteria recognized by the World Health Organization as either critical or high priority pathogens: Gram-positive strains methicillin-resistant S. aureus (MRSA; ATCC BAA-44) and vancomycin-resistant E. faecium (VRE; ATCC BAA-2320), and Gram-negative strains multidrug-resistant A. baumannii (MDRAB; ATCC BAA-1605) and NDM-1 positive K. pneumoniae (KP; ATCC BAA-2146). Our results demonstrated the detection limit (99.9999%; 6 log units reduction in CFU mL-1) photodynamic inactivation of three strains upon illumination (30-60 min; 40-65 ± 5 mW cm-2; 400-700 nm): MRSA, VRE, and MDRAB, but only minimal inactivation (47-75%) of KP. Antiviral studies employing PAN-BODIPY(+) against vesicular stomatitis virus (VSV), a model enveloped virus, revealed complete inactivation. Taken together, the results demonstrate the potential for electrospun BODIPY(+)-embedded nanofiber materials as the basis for pathogen-specific anti-infective materials, even at low photosensitizer loadings.


Aortic valve replacement for aortic stenosis with severe left ventricular dysfunction. Prognostic indicators.
Aortic valve replacement for aortic stenosis (AS) carries an increased risk in the presence of left ventricular (LV) systolic dysfunction. Few data are available on the outcome of such patients. Between 1985 and 1992, 154 consecutive patients (107 men and 47 women) with LV systolic dysfunction (ejection fraction [EF] < or = 35%) underwent aortic valve replacement for AS. The mean preoperative characteristics included EF, 27 +/- 6%; aortic valve mean gradient, 44 +/- 18 mm Hg; aortic valve area, 0.6 +/- 0.2 cm2; and cardiac output, 4.1 +/- 1.5 L/min. Simultaneous coronary artery bypass graft surgery was performed in 78 patients (51%). Perioperative (30-day) mortality was 9% (14 of 154 patients). Fifty patients died during follow-up. Coronary artery disease (P = .002) and a reduced preoperative cardiac output (P = .03) were significantly related to reduced overall survival rate by multivariate analysis. Postoperative improvement occurred in most patients; 88% were New York Heart Association class III or IV before surgery versus 7% after surgery. Postoperative EF was assessed in 76% of survivors; 76% of these demonstrated improvement. By multivariate analysis, change in EF was inversely related to coronary disease (P = .002) and preoperative aortic valve area (P = .03). Despite LV dysfunction, the risk of aortic valve replacement for AS was acceptable and related to coronary artery disease and mean aortic gradient, and long-term survival was related to coronary disease and cardiac output. Improvement in symptoms and EF occurred in most patients.


Prospective study of serum vitamin D and cancer mortality in the United States.
Vitamin D has been hypothesized to reduce cancer mortality through its effects on incidence and/or survival. Epidemiologic studies of the association of 25-hydroxyvitamin D [25(OH)D] and the risk of cancer, however, have been largely limited to incident cancers at a few sites. A total of 16,818 participants in the Third National Health and Nutrition Examination Survey who were 17 years or older at enrollment were followed from 1988-1994 through 2000. Levels of serum 25(OH)D were measured at baseline by radioimmunoassay. Cox proportional hazards regression models were used to examine the relationship between serum 25(OH)D levels and total cancer mortality (in the entire population or according to race/ethnicity, sex, age, and retinol status) and mortality from specific cancers. Because serum was collected in the south in cooler months and the north in warmer months, we examined associations by collection season. All statistical tests were two-sided. We identified 536 cancer deaths in 146,578 person-years. Total cancer mortality was unrelated to baseline vitamin D status in the entire population, men, women, non-Hispanic whites, non-Hispanic blacks, Mexican Americans, and in persons younger than 70 or 70 years or older. We found no interaction between vitamin D and season or vitamin D and serum retinol. Colorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/L or higher associated with a 72% risk reduction (95% confidence interval = 32% to 89%) compared with lower than 50 nmol/L, P(trend) = .02. Our results do not support an association between 25(OH)D and total cancer mortality, although there was an inverse relationship between 25(OH)D levels and colorectal cancer mortality.


Prevalence of the extensor digitorum, extensor digiti minimi and extensor indicis tendons and their variations.
We aimed to investigate tendon variations of the extensor digitorum (ED), extensor digiti minimi (EDM), and extensor indicis proprius (EIP) muscles. Our study was performed on 43 fetal cadavers (86 extremities), aged between 17 and 40 weeks of gestation. The number of ED tendons varied from three to six, proximal to the extensor retinaculum (ER), and from three to eight, distal to the ER. The ED most often had four tendons, both proximally and distally from the ER. The ED tendons of the fourth finger were observed to be most frequently duplicated. The most common juncturae tendinum (JT) was type 1 in the second intermetacarpal space (IMCS), type 2 in the third IMCS, and type 3r in the fourth IMCS according to von Schroeder classification. The number of EIP and EDM tendons varied from one to two and from one to five, respectively. The EIP double tendons inserted both into the ulnar and palmar sides of the extensor digitorum of the second finger, which had not been reported in the literature. In our study, 7% of hands had variant muscles. In 4.7% of hands, the extensor indicis et medii communis was observed, while the extensor medii proprius and the extensor digitorum brevis manus were observed in 1.2% and 1.2% of hands, respectively. Knowing the prevalence of the ED, EDM and EIP tendons and their variations in the fetal period should help to treat partial loss of hand function or injury after birth and to correct congenital hand deformities.


Effect of the somatostatin analog, octreotide, and of other hormones on the release of the acid-labile subunit of the 150 kDa complex by rat hepatocyte in primary culture.
In normal subjects, the major form of circulating IGF is the GH-dependent 150 kDa complex. The liver appears to be the main source of the three components of the 150 kDa complex and, in particular, hepatocytes synthesize the insulin-like growth factor (IGF) peptide and the acid-labile subunit (ALS), whereas Kupffer and sinusoidal endothelial cells produce IGF-binding protein-3 (IGFBG-3). We have studied the effects of the somatostatin analog octreotide, IGF-II des(1-3)IGF-I, transforming growth factor (TGF)-beta 1 and tri-iodothyronine (T3) on ALS secretion into the medium conditioned by rat hepatocytes in primary culture. The regulation of ALS release was evaluated in the conditioned medium of adult rat hepatocytes exposed to increasing concentrations of test substances or to vehicle alone (control), after gel filtration in basic conditions, by immunoblot using an antiserum generated against the N-terminal 34 amino acids of human ALS. The results demonstrate that: 1) octreotide in vitro produces a dose-dependent inhibition of both basal and GH-stimulated ALS secretion into the hepatocyte conditioned medium; 2) the release of ALS by adult rat hepatocytes is not affected by the presence during the incubation of des(1-3)IGF-I or IGF-II; 3) an inhibitory effect, although only with very high doses, can be observed after treatment with TGF-beta 1; and 4) a small but significant increase of ALS released into the medium can be seen when hepatocytes are treated with T3. Evaluation of the effect of substances known to affect the production of IGF peptides, the IGFBPs, or both, on adult rat hepatocytes in primary culture revealed no powerful stimulator, but instead a potent inhibitor of ALS release/synthesis. Our data suggest that the effect of somatostatin on the 150 kDa complex is mediated not only by the reduction in GH concentration, but also by a direct inhibition of ALS release or synthesis.


Transplantation as an abstract good: practising deliberate ignorance in deceased organ donation in Denmark.
This article investigates valuations of organ transfers that are currently seen as legitimising increasingly aggressive procurement methods in Denmark. Based on interviews with registered donors and the intensive care unit staff responsible for managing organ donor patients we identify three types of valuation: the needs of recipients, respect for donors' autonomy and support of donors' relatives in their grieving process. Sometimes these modes of valuation conflict with each other, and we show how our informants then respond with a form of deliberate ignorance. We suggest that deliberate ignorance has a more general salience in the organ transplant field by way of facilitating a perception of organ transplantation as an abstract moral good rather than a specific good for specific people. Furthermore, we suggest that multiple forms of ignorance sustain each other: a desire for ignorance with respect to the prioritisation of recipients sustains pressure for more organs; this pressure necessitates more aggressive measures in organ procurement and these measures increase the need for ignorance in relation to the actual procedures as well as the actual recipients. These attempts to avoid knowledge are in remarkable contrast to the otherwise widespread policy emphasis on education and information in this medical domain.


Bilateral Cervical Pilomatricoma: A Diagnostic Dilemma for the Pediatric Otolaryngologist.
Pilomatricomas are benign skin tumors often encountered by otolaryngologists but frequently misdiagnosed. Although they can occur at any age, they commonly present in children as a discolored superficial lesion adhered to the overlying skin. Accurate preoperative diagnosis is crucial for appropriate management, which is surgical in most cases. Here, we present bilateral pilomatricomas mimicking features of several other diagnoses in a pediatric patient. The patient was successfully treated with surgical excision. This case presented a unique diagnostic challenge, as the lesions exhibited features of several common diagnoses. In general, surgical management of pilomatricoma is curative, and recurrence is rare.


Genome-wide association, RNA-seq and iTRAQ analyses identify candidate genes controlling radicle length of wheat.
The radicle, present in the embryo of a seed, is the first root to emerge at germination, and its rapid growth is essential for establishment and survival of the seedling. However, there are few studies on the critical mechanisms underlying radicle and then radicle length in wheat seedlings, despite its importance as a food crop throughout the world. In the present study, 196 wheat accessions from the Huanghuai Wheat Region were screened to measure radicle length under 4 hydroponic culture environments over 3 years. Different expression genes and proteins (DEGs/DEPs) between accessions with extremely long [Yunong 949 (WRL1), Zhongyu 9,302 (WRL2)] and short roots [Yunong 201 (WRS1), Beijing 841 (WRS2)] were identified in 12 sets of root tissue samples by RNA-seq and iTRAQ (Isobaric tags for relative and absolute quantification). Phenotypic results showed that the elongation zone was significantly longer in root accessions with long roots compared to the short-rooted accessions. A genome-wide association study (GWAS) identified four stable chromosomal regions significantly associated with radicle length, among which 1A, 4A, and 7A chromosomes regions explained 7.17% to12.93% of the phenotypic variation. The omics studies identified the expression patterns of 24 DEGs/DEPs changed at both the transcriptional and protein levels. These DEGs/DEPs were mainly involved in carbon fixation in photosynthetic organisms, photosynthesis and phenylpropanoid biosynthesis pathways. TraesCS1A02G104100 and TraesCS2B02G519100 were involved in the biosynthesis of tricin-lignins in cell walls and may affect the extension of cell walls in the radicle elongation zone. A combination of GWAS and RNA-seq analyses revealed 19 DEGs with expression changes in the four accessions, among which, TraesCS1A02G422700 (a cysteine-rich receptor-like protein kinase 6, CRK6) also showed upregulation in the comparison group by RNA-seq, iTRAQ, and qRT-PCR. BSMV-mediated gene silencing also showed that TaCRK6 improves root development in wheat. Our data suggest that TaCRK6 is a candidate gene regulating radicle length in wheat.


Intrinsic charge-mobility in benzothieno[3,2-b][1]benzothiophene (BTBT) organic semiconductors is enhanced with long alkyl side-chains.
Recent measurements show that organic materials with a conjugated benzothieno-benzothiophene (BTBT) core exhibit unprecedented charge-carrier mobilities, dramatically influenced by the size of the side-chains. Using a multitude of computational tools, we, in depth, calculate the molecular ordering and charge-transport of these materials to rationalize the side-chain dependence. The reported experimental hole mobilities typically fall within the range of 1-100 cm2 V-1 s-1, therefore we employ both band transport models using deformation-potential theory based on DFT-D3 methodology and hopping transport using kinetic Monte Carlo simulations employing Marcus-Levich-Jortner charge-transfer theory. Band transport calculations are performed in a perfect lattice, considered as a structurally ordered morphology, while hopping transport calculations are performed for both ordered and disordered morphologies based on molecular dynamics simulations. We find that intrinsic mobility in BTBTs is critically controlled by the alkyl chain length; typically, longer alkyl side-chains regulate intrinsic disorder, cause improved balance between different transport directions and, ultimately, lead to enhanced charge-carrier mobility.


Optimized synthesis of art patterns and layered textures.
Line drawings and digital arts appear everywhere, from simple icons and logos to cartoons, maps, and illustrations. We define art patterns as the subset of line drawings and digital arts that are comprised of repeated elements. There exist textures that share characteristics with art patterns. Examples of such textures include piled discrete elements with curved contours. Inspired by recent success of exemplar-based texture synthesis, in this paper, we focus on synthesizing art patterns and textures with curvilinear features from exemplars, which we cast as a global optimization problem. Our energy function for this problem measures both the appearance similarity of color patterns and shape similarity of curvilinear features between an input exemplar and a synthesized image. We develop an overall expectation-maximization-style algorithm for minimizing this energy function. The shape similarity part of the energy is minimized through an innovative application of the level set method. We further generalize our energy function and optimization algorithm to multilayer pattern and texture synthesis. Our generalized optimization can effectively handle multiple layers and synthesize valid instances of interaction.


[Primary dermatology--who is the gate keeper?].
For several years health funds in Israel have allowed patients to see dermatologists, gynecologists, orthopedic surgeons and ENT specialists without being referred by their primary care physician. There is heated debate about whether this practice is justified and if it is cost effective. Is it better medicine for the patient? What are the roles of the primary care physician and of the primary dermatologist in the care of skin diseases? What do patients want? We examined the practices of 4 dermatology clinics and discuss the issues involved.


Thrombotic disorders: diagnosis and treatment.
Hematologists are increasingly involved in the diagnosis and management of patients with venous and arterial thromboembolic disorders. There have been major advances in recent years in our understanding of the central role of hypercoagulability in the pathogenesis of thrombosis. This has led to new approaches to the diagnosis of patients at risk for thrombosis and the development of more rational antithrombotic strategies. In Section I, Dr. Andrew Schafer reviews current concepts of acquired and inherited hypercoagulable states. It is now recognized that most, if not all, patients with venous thromboembolism have a genetic basis for the disorder ("thrombophilia"). The level of lifelong, baseline hypercoagulability in any individual may be determined by the type(s) and number of thrombophilia(s) that are inherited. Clinical episodes of thrombosis are precipitated by acquired thrombogenic triggers, which may be overt (e.g., pregnancy) or subclinical. In Section II, Dr. Mark Levine discusses the complex problem of thrombosis in patients with cancer. The goals of treating acute venous thromboembolism in cancer patients are to prevent recurrence, minimize the risk of anticoagulant-induced bleeding, and improve quality of life. New developments have improved treatment of venous thromboembolism in these patients, including outpatient therapy and secondary prevention with low-molecular-weight heparin. In Section III, Dr. Barbara Konkle reviews the diagnosis and management of thrombotic complications associated with pregnancy and hormonal therapy. Patient management is discussed based on data on thrombotic risks associated with hormonal treatment of infertility, pregnancy and the post-partum period in women with and without underlying thrombophilic risk factors. In Section IV, Dr. Clive Kearon discusses the management of anticoagulation before and after elective surgery. In the past, there has been no consensus on the perioperative management of anticoagulation for patients who require long-term warfarin therapy. This review considers the expected risks and benefits of different approaches to anticoagulation in patients who require warfarin because of atrial fibrillation, a mechanical heart valve, or a history of venous thromboembolism.


[Biological and biochemical quality of the Artemia (Anostraca: Artemiidae) population from Real de Salinas saltworks, Calkiní, Campeche, Mexico].
Cysts of Artemia spp. collected from February 1997 to February 2000 in the Real de Salinas solar saltworks, Campeche, Mexico, were compared with Artemia franciscana (batch number 8,131 Microfeast Artemia Cysts, Texas, USA). The variables determined in these two populations were: number of cysts per gram, hatching percentage, hatching efficiency, hatching rate, hatching synchrony and hatching biomass, as well as diameter of the cysts and length of the nauplii (instar I). For Salinas, the average diameters of the encapsulated and decapsulated cysts were 230.5 +/- 4.14 and 221.8 +/- 3.39 microm, respectively. The thickness of the cyst shell was 4.35 +/- 0.68 microm and the length of the nauplii was 388.11 +/- 4.39 microm, this last value is among the smallest reported in the literature. For the commercial population of A. franciscana, the average diameters of the encapsulated and decapsulated cysts were 230.21 +/- 12.49 and 216.96 +/- 13.71, respectively. With respect to the corion thickness and length of the nauplii the values were 6.62 +/- 2.72 and 424.70 +/- 30.08, respectively. The protein value of the cysts (47.91 %) and nauplii (50.5 %) of Artemia population from Real de Salinas, are considered adequate to be used as food in aquaculture. The results indicate that the population from Real de Salinas presents positive features for its use in aquaculture in the region.


Sickle Cell Disease: Considerations for Acute Pain Management in the Hematology-Oncology Ambulatory Setting.
Owing to the lack of specialized care and the unpredictable nature of acute pain episodes in adults with sickle cell disease (SCD), emergency departments have been largely used to provide care for these patients. The lack of specialized care for patients with SCD portends higher healthcare costs and lower health-related quality of life. Although study findings have shown that using multiple models for SCD care is feasible and cost-effective, nurses' awareness of evidence-based guidelines and care models for acute pain management in ambulatory settings is lacking.


Comparative effect of chemical structure of chlorinated N-hydroxy-N-acyl-aminobiphenyl ethers and their related compounds on rat liver cytosol-catalyzed transacylation.
Studies of structure-transacylation relationships for a series of acylhydroxamic acids of chlorinated biphenyl ethers and their related compounds by rat liver N-arylacylhydroxamic acid-dependent N-acyltransferase (AHNAT) are described. In the transacylation of 4-aminoazobenzene catalyzed by AHNAT, 4-substituents (chloro, phenoxy, and mono-, di-, and trichlorophenoxy groups) of N-phenylacetohydroxamic acid enhanced the ability of the unsubstituted hydroxamic acid to serve as acetyl donors. As to the number of chlorines in the phenoxy group, the activity increased with decreasing number from three to zero. Of the monochlorophenoxy compounds, the 4'-chloro compound was the most effective acetyl donor. In 3-substituents (chloro and phenoxy groups) of N-phenylacetohydroxamic acid, the 3-chloro compound was an effective acetyl donor similarly to the 4-chloro compound, whereas the 3-phenoxy compound was 48% as active as the 4-phenoxy compound. None of 2-substituted N-phenylacetohydroxamic acids examined showed transacetylation activity. As to the effect of acyl group structure on the activity, N-propionyl, N-glycoloyl, and N-formyl derivatives of the 4-(4'-chlorophenoxy) compound were only 4, 2, and 0% as active as the corresponding acetyl compound, respectively. Esterification of the N-arylacetohydroxamic acid decreased the activity; O-acetyl, O-methyl, O-glucosyl, and O-glucuronosyl derivatives of the 4-(4'-chlorophenoxy) compound were 35, 7, 0, and 0% as active as the corresponding N-hydroxy compound, respectively.


Cytokine-mediated apoptosis in cardiac myocytes: the role of inducible nitric oxide synthase induction and peroxynitrite generation.
Increased production of nitric oxide (NO) after induction of the cytokine-inducible isoform of nitric oxide synthase (iNOS or NOS2) in cardiac myocytes and other parenchymal cells within the heart may in addition to contributing to myocyte contractile dysfunction also contribute to the induction of programmed cell death (apoptosis). To investigate the mechanism(s) by which increased NO production leads to apoptosis, we examined the role of NO in primary cultures of neonatal rat ventricular myocytes (NRVMs) after induction by the cytokines interleukin-1beta (IL-1beta) and interferon gamma (IFNgamma) or exposure to the exogenous NO donor S-nitroso-N-acetylcysteine (SNAC) or peroxynitrite (ONOO(-)). Both SNAC (1 mmol/L) and ONOO(-) (100 micromol/L), but not their respective controls (ie, N-acetylcysteine and pH-inactivated ONOO(-)), induced apoptosis in confluent, serum-starved NRVMs at 48 hours. Similarly, incubation of NRVMs with IL-1beta and IFNgamma for 48 hours resulted in an increase in iNOS expression, nitrite production, and programmed cell death. Both the cytokine-induced nitrite accumulation and myocyte apoptosis could be completely prevented by the nonselective NOS inhibitor L-nitroarginine (3 mmol/L) or the specific iNOS inhibitor 2-amino-5, 6-dihydro-6-methyl-4H-1,3-thiazine (AMT, 100 micromol/L). NO-mediated myocyte apoptosis was not attenuated by the inhibition of soluble guanylyl cyclase with ODQ, nor could apoptosis be induced by the incubation of NRVMs with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analogue. However, NO-mediated apoptosis was significantly attenuated by the superoxide dismutase mimetic and ONOO(-) scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP, 100 micromol/L). NO/ONOO(-)-mediated apoptosis was associated with increased expression of Bax with no change in Bcl-2 mRNA abundance. Furthermore, apoptotic cell death was also confirmed in adult rat ventricular myocytes (ARVMs) when grown in heteroculture with IL-1beta- and IFNgamma-treated rat cardiac microvascular endothelial cells. Therefore, cytokine-induced apoptosis in NRVMs and ARVMs is mediated by iNOS induction, ONOO(-), and associated with an increase in Bax levels.


Forms of ethnic prejudice: assessing the dimensionality of a Spanish-language version of the Blatant and Subtle Prejudice Scale.
The main purpose of this study was to investigate the dimensionality of a Spanish-language version of the Blatant and Subtle Prejudice Scale via exploratory (EFA) and confirmatory factor analysis (CFA). No research has confirmed the hypothesized factor structure in Latin American countries. Using data from a random and probability survey in population of the northern area of Chile (N= 896), four models were specified: single factor model (global prejudice factor), correlated two-factor model (subtle and blatant prejudice), correlated two-factor second-order model, and single-factor second-order model. The findings indicated that the two-factor second-order model had the best fit. The corresponding alpha coefficients were .82 (subtle prejudice) and .76 (blatant prejudice). Lastly, differences were examined between <<equalitarians>>, <<subtle>>, and <<bigots>> regarding their feelings toward immigrants, their feelings about their beliefs concerning the state aid received by these out-groups, and their feelings about their beliefs regarding future policies for them.


Platelet volume analysis for differential diagnosis of thrombocytosis.
The results of the Coulter counter S plus II platelet volume analysis were studied in 100 patients with reactive thrombocytosis (platelet count greater than 500 X 10(9)/l), in 30 patients with myeloproliferative thrombocytosis, and in 32 patients with chronic myeloproliferative disease and a platelet count less than 500 X 10(9)/l. Patients with reactive thrombocytosis had considerably lower mean platelet volumes than those with myeloproliferative thrombocytosis, or normal subjects. The opposite was true for the platelet distribution width. This index for platelet heterogeneity was normal in reactive, but increased in myeloproliferative thrombocytosis. There were no differences in mean platelet volume or platelet distribution width between patients with myeloproliferative disease and a high or normal platelet count. The increased platelet heterogeneity in myeloproliferative disease was caused by an increase of both small and large platelets. The platelet distribution width seemed to be the best variable for the differential diagnosis of thrombocytosis. A platelet distribution width greater than 17 was found in 26 of the 30 patients with myeloproliferative thrombocytosis but in only five of the 100 patients with reactive thrombocytosis. A normal platelet distribution width in a patient with a high platelet count strongly suggests reactive thrombocytosis.


Prevention of cytomegalovirus infection following bone marrow transplantation: a randomized trial of blood product screening.
From 1983 to 1987, cytomegalovirus seronegative allogeneic bone marrow recipients were randomized to receive screened cytomegalovirus (CMV) seronegative or unscreened blood products and 125 patients were available for analysis. CMV infection occurred in 18% of patients in the screened versus 38% in the unscreened blood product group. However, only two of 64 patients in the screened group and seven of 61 in the unscreened group developed culture or biopsy-proven CMV infections. Bone marrow donor CMV seropositivity was associated with an increased risk of developing CMV infection (21% with seronegative and 46% with seropositive donor), and CMV infection was not prevented by blood product screening if the bone marrow donor was sero = positive (62% for screened, 42% for unscreened group, p = 0.80). One year survival censored for relapse was 52% in the screened group versus 68% in the unscreened group (p = 0.08). Gram negative bacteremia complicated bone marrow transplantation (BMT) in 35% of patients receiving screened and 15% of those receiving unscreened blood products (p = 0.02). Relapse did not differ in the screened and unscreened groups. By multivariate analysis, high risk disease (p = 0.0002), CMV infection (p = 0.004), screened blood products group (p = 0.011), recipient age greater than 17 (p = 0.027), chronic graft-versus-host disease (p = 0.014) and gram negative bacteremia (p = 0.004) independently had a negative influence on survival. We conclude that blood product screening was effective in preventing CMV infections following BMT if both the recipient and bone marrow donor were CMV seronegative.(ABSTRACT TRUNCATED AT 250 WORDS)


The Effect of Admission Renal Function on the Treatment and Outcome of Patients with Acute Coronary Syndrome.
Chronic kidney disease is a frequent comorbidity among patients with acute coronary syndrome (ACS). We aimed to evaluate treatment characteristics in ACS patients according to their renal function and to assess the effect of differences in therapy on clinical outcomes. Included were patients with ACS enrolled in the biennial Acute Coronary Syndrome Israeli Surveys (ACSIS) during 2000-2013. Excluded were patients with cardiogenic shock at presentation. The estimated glomerular filtration rate (eGFR) was calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula. The distribution of the eGFRs was divided into 4 categories (<45, 45-59.9, 60-74.9, and ≥75 mL/min/1.73 m2). The primary endpoint was all-cause mortality at 1 year. A total of 13,194 patients with ACS were included. Patients with a reduced eGFR were less likely to be admitted to a coronary care unit and had lower rates of coronary angiograms and subsequent percutaneous coronary interventions. Furthermore, as the eGFR was lower, the patients were less frequently treated with aspirin, clopidogrel, β-blockers, and ACE inhibitors/angiotensin receptor blockers. We demonstrated an inverse association between renal function and 1-year mortality, with the highest mortality rates observed in the group with the lowest eGFR (HR = 3.8, 95% CI 2.9-4.9, p < 0.0001). Differences in mortality remained significant following a multivariate analysis for all the baseline characteristics as well as for invasive and medical treatment (HR = 2.7, 95% CI 1.9-3.7, p < 0.0001). ACS patients with chronic kidney disease represent a high-risk group with an increased mortality risk. Despite this high risk, these patients are less frequently selected for an invasive treatment strategy and are less commonly treated with guideline-based medications. However, reduced renal function was associated with higher mortality regardless of the variations in therapy.


Hypomethylation of p53 in peripheral blood DNA is associated with the development of lung cancer.
Alterations in DNA methylation have been associated with cancers at almost all tumor sites and represent one of the most consistent changes in neoplastic cells. The underlying etiological mechanisms for alteration of DNA methylation patterns are not understood, but experimental studies in animals suggest potential environmental and genetic influences. The purpose of this study was to investigate whether DNA hypomethylation in peripheral blood DNA (potentially representing status at the lung) was associated with increased risk for the development of lung cancer. We evaluated genome-wide and p53 gene-specific hypomethylation in 100 lung cancer cases and controls selected from a large clinical trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Genome-wide methylation status was assessed using the in vitro methyl acceptance capacity assay and p53 gene-specific methylation status using the HpaII quantitative PCR assay. Hypomethylation was evaluated as a risk factor using multivariate conditional logistic regression analyses. Genome-wide methylation status was unrelated to lung cancer risk; the odds ratio was 1.25 and the 95% confidence interval was 0.48-3.21 for those in the highest versus lowest quartile of hypomethylation status. Hypomethylation of the p53 gene in exons 5-8, the hypermutable region, was associated with a 2-fold increased risk for lung cancer (odds ratio, 2.20; 95% confidence interval, 1.04-4.65), whereas there was no risk increase for hypomethylation at exons 2-4, a region of the gene not known for its mutability or functional significance in cancer. Our results indicate that hypomethylation status within exons 5-8 of p53 from peripheral lymphocyte DNA may be a relevant predictor of lung cancer among male smokers.


Examination of two anti-HLA-DR-like monoclonal antibodies.
The cellular distribution of two anti-HLA-DR-like monoclonal antibodies was examined. The reagents showed typical affinity to E- cells, adherent cells and activated T cells. Functionally, they affected the presentation of PPD antigen from APC to T cells in autologous and allogeneic mixed lymphocyte reaction. One of them significantly influenced the proliferation of T helper cells activated polyclonally with PHA.


Nuclear magnetic resonance imaging for studies of flow and transport in porous media.
Nuclear magnetic resonance imaging (NMRI) methods for visualization of fluid flow and transport in porous media are reviewed in this paper. They are illustrated with experiments showing applications of velocity imaging, NMRI measurements of multiphase flow, and NMRI measurements of density flow. The latter two are compared with numerical simulations. The examples show the capacity of NMRI to give structural information both of the medium and the fluid distributions as well as their temporal development. The resulting data can be used in a black box-white box comparison and as benchmarks for numerical models.


Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever.
Dengue shock syndrome is a severe complication of dengue hemorrhagic fever (DHF), characterized by a massive increase in vascular permeability. Plasma cytokine concentrations were prospectively studied in 443 Vietnamese children with DHF, of whom 6 died. Shock was present in 188 children on admission to hospital, and in 71 children it developed later. Contrary to expectations, certain inflammatory markers (interleukin-6 and soluble intercellular adhesion molecule-1) were lower in the group with shock, and this may reflect the general loss of protein from the circulation due to capillary leakage. Only soluble tumor necrosis factor receptor (TNFR) levels showed a consistent positive relationship with disease severity. In patients with suspected DHF without shock, admission levels of sTNFR-75 in excess of 55 pg/mL predicted the subsequent development of shock, with a relative risk of 5.5 (95% confidence interval, 2.3-13.2). Large-scale release of soluble TNFR may be an early and specific marker of the endothelial changes that cause dengue shock syndrome.


A behavioural test to assess daytime sleepiness in obstructive sleep apnoea.
Daytime sleepiness is an important symptom of obstructive sleep apnoea syndrome (OSAS). The standard tests for its objective quantification use EEG recordings, and are time consuming and expensive, which makes them difficult to use for large studies. This study assesses the ability of a simple test of sustained 'wakefulness' to discriminate the excessive somnolence of severe symptomatic obstructive sleep apnoea from normality, and compares its results to the traditional EEG based Maintenance of Wakefulness Test (MWT). Ten subjects (7M 3F) with severe sleep apnoea (> 4% SaO2 dip rate median 32.7 (90% central range 9.7-65.6)) and symptoms of daytime sleepiness, (Epworth Sleepiness Score (ESS)17(10-24)) and 10 normal subjects (4M 6F, ESS 3.5(1-8)) were studied. The MWT and the behavioural test (Oxford SLEep Resistance test - OSLER test) were performed on each subject in random order on 2 separate days. The protocol for both tests was the same with 4 X 40 min sleep resistance challenges throughout the day while sound isolated in a darkened room. During the OSLER test subjects were asked to press a switch in response to a light emitting diode (LED), which was lit for 1 s in every three. Both the switch and the light were connected to a computer that stored both the number of times the light was illuminated and whether a correct response was made. The OSLER test discriminated the normal subjects from the sleep apnoea group (mean sleep latency (min) normal group 39.8, OSA group 10.5) as well as the traditional MWT (normal group 38.1 OSA group 7.3) and was much simpler to administer. This test has the advantage that sleep onset is defined objectively and automatically as a failure to respond to the light, rather than from EEG interpretation, which is inevitable partly subjective. This technique may provide a simple and robust method of objectively quantifying daytime sleepiness for large studies.


CD3ε+ Cells in Pigs With Severe Combined Immunodeficiency Due to Defects in ARTEMIS.
Severe combined immunodeficiency (SCID) is described as the lack of functional T and B cells. In some cases, mutant genes encoding proteins involved in the process of VDJ recombination retain partial activity and are classified as hypomorphs. Hypomorphic activity in the products from these genes can function in the development of T and B cells and is referred to as a leaky phenotype in patients and animals diagnosed with SCID. We previously described two natural, single nucleotide variants in ARTEMIS (DCLR1EC) in a line of Yorkshire pigs that resulted in SCID. One allele contains a splice site mutation within intron 8 of the ARTEMIS gene (ART16), while the other mutation is within exon 10 that results in a premature stop codon (ART12). While initially characterized as SCID and lacking normal levels of circulating lymphoid cells, low levels of CD3ε+ cells can be detected in most SCID animals. Upon further assessment, we found that ART16/16, and ART12/12 SCID pigs had abnormally small populations of CD3ε+ cells, but not CD79α+ cells, in circulation and lymph nodes. Newborn pigs (0 days of age) had CD3ε+ cells within lymph nodes prior to any environmental exposure. CD3ε+ cells in SCID pigs appeared to have a skewed CD4α+CD8α+CD8β- T helper memory phenotype. Additionally, in some pigs, rearranged VDJ joints were detected in lymph node cells as probed by PCR amplification of TCRδ V5 and J1 genomic loci, as well as TCRβ V20 and J1.1, providing molecular evidence of residual Artemis activity. We additionally confirmed that TCRα and TCRδ constant region transcripts were expressed in the thymic and lymph node tissues of SCID pigs; although the expression pattern was abnormal compared to carrier animals. The leaky phenotype is important to characterize, as SCID pigs are an important tool for biomedical research and this additional phenotype may need to be considered. The pig model also provides a relevant model for hypomorphic human SCID patients.


Mutations affecting the different transport systems for isoleucine, leucine, and valine in Escherichia coli K-12.
Uptake of isoleucine, leucine, and valine in Escherichia coli K-12 is due to several transport processes for which kinetic evidence has been reported elsewhere. A very-high-affinity transport process, a high-affinity transport process, and three different low-affinity transport processes were described. In this paper the existence of these transport processes is confirmed by the isolation and preliminary characterization of mutants altered in one or more of them. The very-high-affinity transport process is missing either in strains carrying the brnR6(am) mutation or in strains carrying the brn-8 mutation. This appears to be a pleiotropic effect since other transport systems are also missing. Mutant analysis shows that more than one transport system with high affinity is present. One of them, high-affinity 1, which needs the activity of a protein produced by the brnQ gene, transports isoleucine, leucine, and valine and is unaffected by threonine. The other, high-affinity 2, which needs the activity of a protein produced by the brnS gene, transports isoleucine, leucine, and valine; this uptake is inhibited by threonine which probably is a substrate. Another protein, produced by the brnR gene, is required for uptake through both high-affinity 1 and high-affinity 2 transport systems. The two systems therefore appear to work in parallel, brnR being a branching point. The brnQ gene is located close to phoA at 9.5 min on the chromosome of E. coli, the brnR gene is located close to lac at 9.0 min, and the brnS gene is close to pdxA at 1 min. A mutant lacking the low-affinity transport system for isoleucine was isolated from a strain in which the high-affinity system was missing because of a brnR mutation. This strain also required isoleucine for growth because of an ilvA mutation. The mutant lacking the low-affinity transport system was unable to grow on isoleucine but could grow on glycylisoleucine. This mutant had lost the low-affinity transport for isoleucine, whereas those for leucine and valine were unaffected. A pleiotropic consequence of this mutation (brn-8) was a complete absence of the very-high-affinity transport system due either to the alteration of a common gene product or to any kind of secondary interference which inhibits it. Mutants altered in isoleucine-leucine-valine transport were isolated by taking advantage of the inhibition that valine exerts on the K-12 strain of E. coli. Mutants resistant both to valine inhibition (Val(r)) and to glycylvaline inhibition are regulatory mutants. Val(r) mutants that are sensitive to glycylvaline inhibition are transport mutants. When the very-high-affinity transport process is repressed (for example by methionine) the frequency of transport mutants among Val(r) mutants is higher, and it is even higher if the high-affinity transport process is partially inhibited by leucine.


Selective COX-2 inhibitors, NSAIDs and cardiovascular events - is celecoxib the safest choice?
Inhibitors of cyclo-oxogenase (COX) are widely used anti-inflammatory drugs. In recent years concerns have arisen about the cardiovascular safety of these drugs, initially because of reported associations between therapy with the COX-2 selective inhibitor rofecoxib and myocardial infarction. However, subsequent data have suggested an association between therapy with non-selective COX inhibitors (NSAIDs) and serious cardiovascular events. This article reviews the clinical trial and population data linking COX inhibition to cardiovascular events. The data currently available suggests that both specific and non-specific COX inhibitors may increase the risk of serious cardiovascular events, but that the effect varies between the individual drugs. The strongest evidence for an increased risk of serious cardiovascular events is with rofecoxib therapy. Celecoxib therapy may be associated with an increased risk of cardiovascular events, but only when used at doses substantially higher than those recommended for the treatment of arthritis. There is a greater body of evidence supporting the relative cardiovascular safety of celecoxib when used at the doses recommended for the treatment of arthritis than for any of the other selective COX-2 inhibitors or NSAIDs.


Endoscopic management of sphenoclival neoplasms: anatomical correlates and patient outcomes.
To characterize the endoscopic anatomy of the sphenoid sinus and the adjacent clivus and cavernous sinus, and to review patient outcomes for neoplasms in this region. Cadaver dissection and chart review. Cadaver laboratory and tertiary care center. Fresh-frozen cadaver heads were dissected to study the endoscopic anatomy of the sphenoclival region. Retrospective chart review of patients undergoing endoscopic resection of sphenoclival neoplasms between 2000 and 2008 was performed. Transnasal endoscopic access to the sphenoid sinus was obtained in 10 cadaver heads. A clival window with mean dimensions of 1.4 cm x 1.7 cm was created. Through the clival window, identification and dissection of the basilar and vertebral arteries, mamillary bodies, third ventricle, cranial nerves III through VI, and cervical rootlets were possible. Nineteen patients with mean age of 56.2 years were treated. The most common pathologies were inverted papilloma (5), chordoma (4), squamous cell carcinoma (2), and adenoid cystic carcinoma (2). None of the patients required adjunct craniotomies. Nine patients received adjuvant therapies. Thirteen (68.4%) patients had no evidence of disease, five (26.3%) patients were alive with disease, and one (5.3%) patient died of disease at mean follow-up of 32.6 months. The sphenoclival region poses a significant surgical challenge given its central location at the skull base and proximity to critical structures. This study demonstrates that transnasal endoscopic access to the sphenoclival region is technically feasible and allows successful surgical extirpation of tumors with a low complication rate and acceptable patient outcomes.


D-dimer in patients with clinically suspected pulmonary embolism.
To determine whether measurement of D-dimer, using an enzyme-linked immunosorbent assay (ELISA) with a cutoff of 300 ng/ml, and a latex agglutination assay with a cutoff of 500 ng/ml, is clinically useful in patients with suspected pulmonary embolism (PE). Prospective cohort. Tertiary care referral center, university-affiliated hospital. Two hundred twenty-one consecutive patients with clinically suspected PE. All patients had blood drawn to measure levels of D-dimer and underwent ventilation/perfusion (V/Q) lung scanning and bilateral impedance plethysmography (IPG); pulmonary angiography was performed in nine patients. Patients were classified as follows: (1) PE-positive; positive pulmonary angiography or high probability V/Q scan or non-high-probability V/Q scan and either abnormal IPG (either at presentation or on serial testing and confirmed by contrast venography) or symptomatic thromboembolic event within 3 months of presentation; or (2) PE-negative; normal V/Q scan or normal pulmonary angiography or non-high-probability V/Q scan and either normal serial IPG or abnormal IPG with normal venography and absence of symptomatic venous thromboembolism within 3 months of followup. Forty-three patients were classified as PE positive and 178 patients were classified as PE negative. The sensitivities, specificities, positive predictive values, and negative predictive values of the ELISA and latex agglutination assay were calculated for all patients and for the subgroup of patients with non-high-probability V/Q scans. The ELISA D-dimer, using a cutoff of 300 ng/ml, showed a sensitivity and negative predictive value of 100 percent in all patients and patients with non-high-probability V/Q scans, but the corresponding specificities were only 26 percent and 13 percent, respectively. The latex agglutination assay for D-dimer using a cutoff of 500 ng/ml showed the following: sensitivities of 84 percent in all patients and 90 percent in patients with non-high-probability scans, negative predictive values of 93 percent in all patients, and 98 percent in patients with non-high-probability scans and specificities of 56 percent in all patients and 55 percent in patients with non-high-probability scans. This study demonstrates that an ELISA D-dimer result of less than 300 ng/ml excludes PE but occurs in a small proportion of patients with clinically suspected PE. The latex agglutination assay, using a cutoff of 500 ng/ml, has potential clinical utility in excluding PE in the subgroup of patients with clinically suspected PE and non-high-probability V/Q scans. However, the 95 percent confidence interval on the observed sensitivity of the latex agglutination assay in patients with non-high-probability V/Q scans is wide. Therefore, these promising results should be confirmed in a large clinical trial before the latex agglutination assay is used to make management decisions.


Oxidative Stability of Vacuum-Packed Chicken Wings Marinated with Fruit Juices during Frozen Storage.
Antioxidants present in fruits and vegetables have a potential to reduce disease risk, and increase the shelf life of food products by reducing lipid oxidation. The effect of marination with antioxidants-rich fruit juices on quality characteristics of vacuum-packed chicken wings were examined during frozen storage. Chicken wings were mixed separately with marinades containing pineapple juice, June plum juice, and mango juice and kept for 12 h and 24 h. Three best marination conditions were selected based on a sensory evaluation. Antioxidant activity and total phenolic content of fruit juices, and marinade uptake, and marinade loss of marinated chicken wings were determined. In addition, vacuum packed marinated chicken wings were tested for pH, water holding capacity (WHC), 2-thiobarbituric acid reactive substances (TBARS) value and antioxidant activity over a 4-wk frozen storage. The best sensory properties were reported from chicken wings marinated with pineapple juice for 24 h, mango juice for 24 h, and June plum juice for 12 h (p<0.05) compared to other marinade-time combinations. Mango juice showed the highest antioxidant activity (92.2%) and total phenolic content (38.45 μg/mL; p<0.05) compared to other fruit juices. The pH and WHC of vacuum-packed chicken wings were slightly decreased over the frozen storage (p<0.05). Moreover, chicken wings marinated with mango juice had the lowest TBARS values and the highest 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical scavenging activity. In conclusion, mango juice was selected among tested as the most effective marinade for enhancing the oxidative stability of lipid while maintaining the other meat quality traits of vacuum-packed chicken wings.


An age difference of two billion years between a metal-rich and a metal-poor globular cluster.
Globular clusters trace the formation history of the spheroidal components of our Galaxy and other galaxies, which represent the bulk of star formation over the history of the Universe. The clusters exhibit a range of metallicities (abundances of elements heavier than helium), with metal-poor clusters dominating the stellar halo of the Galaxy, and higher-metallicity clusters found within the inner Galaxy, associated with the stellar bulge, or the thick disk. Age differences between these clusters can indicate the sequence in which the components of the Galaxy formed, and in particular which clusters were formed outside the Galaxy and were later engulfed along with their original host galaxies, and which were formed within it. Here we report an absolute age of 9.9 ± 0.7 billion years (at 95 per cent confidence) for the metal-rich globular cluster 47 Tucanae, determined by modelling the properties of the cluster's white-dwarf cooling sequence. This is about two billion years younger than has been inferred for the metal-poor cluster NGC 6397 from the same models, and provides quantitative evidence that metal-rich clusters like 47 Tucanae formed later than metal-poor halo clusters like NGC 6397.


Graphene sheet orientation of parent material exhibits dramatic influence on graphene properties.
The production of graphene from various sources has garnered much attention in recent years with the development of methods that range from "bottom-up" to "top-down" approaches. The top-down approach often requires thermal treatment to obtain a few-layered and lowly oxygenated graphene sheets. Herein, we demonstrate the production of graphene through oxidation and thermal-reduction/exfoliation of two sources of differently orientated graphene sheets: multiwalled carbon nanotubes (MWCNTs) and stacked graphene nanofibers (SGNFs). These two carbon-nanofiber-like materials have similar axial (length: 5-9 μm) and lateral dimensions (diameter: about 100 nm). We demonstrate that, whereas SGNFs exfoliate along the lateral plane between adjacent graphene sheets, carbon nanotubes exfoliate along its longitudinal axis and leads to opening of the carbon nanotubes owing to the built-in strain. Subsequent thermal exfoliation leads to graphene materials that have, despite the fact that their parent materials exhibited similar dimensions, dramatically different proportions and, consequently, materials properties. Graphene that was prepared from MWCNTs exhibited dimensions of about 5000×300 nm, whereas graphene that was prepared from SGNFs exhibited sheets with dimensions of about 50×50 nm. The density of defects and oxygen-containing groups on these materials are dramatically different, as are the electrochemical properties. We performed morphological, structural, and electrochemical characterization based on TEM, SEM, high-resolution X-ray photoelectron spectroscopy, Raman spectroscopy, and cyclic voltammetry (CV) analysis on the stepwise conversion of the target source into the exfoliated graphene. Morphological and structural characterization indicated the successful chemical and thermal treatment of the materials. Our findings have shown that the orientation of the graphene sheets in starting materials has a dramatic influence on their chemical, material, and electrochemical properties.


Neutral sphingomyelinase 2 modulates cytotoxic effects of protopanaxadiol on different human cancer cells.
Some of ginsenosides, root extracts from Panax ginseng, exert cytotoxicity against cancer cells through disruption of membrane subdomains called lipid rafts. Protopanaxadiol (PPD) exhibits the highest cytotoxic effect among 8 ginsenosides which we evaluated for anti-cancer activity. We investigated if PPD disrupts lipid rafts in its cytotoxic effects and also the possible mechanisms. Eight ginsenosides were evaluated using different cancer cells and cell viability assays. The potent ginsenoside, PPD was investigated for its roles in lipid raft disruption and downstream pathways to apoptosis of cancer cells. Anti-cancer effects of PPD was also investigated in vivo using mouse xenograft model. PPD consistently exerts its potent cytotoxicity in 2 cell survival assays using 5 different cancer cell lines. PPD disrupts lipid rafts in different ways from methyl-β-cyclodextrin (MβCD) depleting cholesterol out of the subdomains, since lipid raft proteins were differentially modulated by the saponin. During disruption of lipid rafts, PPD activated neutral sphingomyelinase 2 (nSMase 2) hydrolyzing membrane sphingomyelins into pro-apoptotic intracellular ceramides. Furthermore, PPD demonstrated its anti-cancer activities against K562 tumor cells in mouse xenograft model, confirming its potential as an adjunct or chemotherapeutic agent by itself in vivo. This study demonstrates that neutral sphingomyelinase 2 is responsible for the cytotoxicity of PPD through production of apoptotic ceramides from membrane sphingomyelins. Thus neutral sphingomyelinase 2 and its relevant mechanisms may potentially be employed in cancer chemotherapies.


The time course of aggressive behaviour in juvenile matrinxã Brycon amazonicus fed with dietary L-tryptophan supplementation.
This study evaluated the influence of dietary L-tryptophan (TRP) supplementation on the time course of aggressive behaviour and on neuroendocrine and hormonal indicators in juvenile matrinxã Brycon amazonicus. Supplementation with TRP promoted a change in the fight pattern at the beginning of an interaction with an intruder, resulting in decreased aggressive behaviours during the first 20 min. The decrease in aggression did not persist throughout the interaction but increased at 3 and 6 h after the beginning of the fight. Monoamine levels in the hypothalamus were not influenced by TRP before or after the fight; however, the hypothalamic serotonin (5-HT) concentration and the 5-hydroxyindole-3-acetic acid (5HIAA):5-HT ratio were significantly correlated with the reduction in aggressive behaviour at the beginning of the fight. Cortisol was not altered by TRP before the fight. After the fight cortisol increased to higher levels in B. amazonicus fed with supplementary TRP. These results indicate that TRP supplementation alters the aggressive behaviour of B. amazonicus and that this effect is limited to the beginning of the fight, suggesting a transient effect of TRP on aggressive behaviour. This is the first study reporting the effects of TRP supplementation on the time course of aggressive interaction in fishes.