Surgical Resection and Adjuvant Radiation Therapy in the Treatment of Skull Base Chordomas.
Chordomas are rare tumors of notochordal origin that are known to be locally aggressive and are often treated with surgical resection followed by adjuvant radiation therapy (RT). The accepted standard of treatment for chordomas of the mobile spine, which includes en-bloc resection with wide margins, cannot be easily applied to the chordomas of the skull base because of their proximity to critical neurovascular structures. We describe our experience with the role of surgery and adjuvant RT in the treatment of chordomas over 16 years. We performed a retrospective chart review on patients with diagnoses of clival chordoma between the years 2000 and 2015 at Northwestern Memorial Hospital. We reviewed presenting symptoms, tumor location and size, extent of resection, complications, recurrence, adjuvant treatment, and follow-up duration. A total of 20 patients underwent 32 surgeries. Of the 20 initial surgeries, 80% underwent gross total resection, and 20% had subtotal resection. The mean follow-up time was 60.75 months. Mean tumor volume was 23.07 cm3. Most common presenting signs and symptoms were headaches (70%), cranial nerve palsies (45%), and diplopia (55%). Diplopia was defined as complaints of double vision without any objective evidence of a cranial nerve palsy. Median time to progression was 57 months, and median overall survival was 136 months. Initial tumor volume and the need for a second dose of RT either as sole or as adjuvant treatment of a recurrence had a statistically significant effect on progression-free survival (P = 0.009, 0.009). None of the factors studied had a statistically significant effect on overall survival. The treatment of chordomas remain challenging and requires multimodal treatment strategies spanning different specialties. Initial tumor size and need for second dose of RT for recurrence appear to play a significant role in progression-free survival. Adjuvant RT after gross total resection may play a role in improved progression-free and overall survival in patients with clival chordomas.


Polymer Modeling of 3D Epigenome Folding: Application to Drosophila.
Mechanistic modeling in biology allows to investigate, based on first principles, if putative hypotheses are compatible with observations and to drive further experimental works. Along this line, polymer modeling has been instrumental in 3D genomics to better understand the impact of key mechanisms on the spatial genome organization. Here, I describe how polymer-based models can be practically used to study the role of epigenome in chromosome folding. I illustrate this methodology in the context of Drosophila epigenome folding.


Identification of Bioactive Compounds against Aedes aegypti (Diptera: Culicidae) by Bioassays and in Silico Assays.
Most of the hematophagous insects act as disease vectors, including Aedes aegypti, responsible for transmitting some of the most critical arboviruses globally, such as Dengue. The use of repellents based on natural products is a promising alternative for personal protection compared to industrial chemical repellents. In this study, the repellent effect of essential oils extracted from Lippia thymoides, Lippia alba, Cymbopogon winterianus, and Eucalyptus globulus leaves was evaluated. Essential oils used showed repellent activity against Ae. aegypti in laboratory bioassays, obtaining protection rates above 70 % from 3.75 mg/mL and higher concentration for all analyzed oils. GC/MS identified 57 constituents, which were used in the ligand-based pharmacophore model to expose compounds with requirements for repellents that modulate mosquitoes behavior through odorant-binding protein 1 Ae. aegypti. Ligand-based pharmacophore model approach results suggested that repellent activity from C. winterianus, L. alba, and L. thymoides essential oils' metabolites is related to Citronelal (QFIT=26.77), Citronelol (QFIT=11.29), Citronelol acetate (QFIT=52.22) and Geranil acetate (QFIT=10.28) with synergistic or individual activity. E. globulus essential oil's repellent activity is associated with Ledol (0.94 %; QFIT=41.95). Molecular docking was applied to understand the binding mode and affinity of the essential oils' data set at the protein binding site. According to molecular docking, Citronelol (ChemPLP=60.98) and geranyl acetate (ChemPLP=60.55) were the best-classified compounds compared to the others and they can be explored to develop new repellents.


The beta bulge: a common small unit of nonrepetitive protein structure.
A beta bulge is a region between two consecutive beta-type hydrogen bonds which includes two residues (positions 1 and 2) on one strand opposite a single residue (position x) on the other strand. Compared to regular beta structure, a beta bulge puts the usual alternation of side-chain direction out of register on one of the strands, introduces a slight bend in the beta sheet, and locally accentuates the usual right-handed strand twist. Almost all beta bulges are between antiparallel strands, usually between a narrow rather than a wide pair of hydrogen bonds. Ninety-one examples are listed. The two commonest types are the "classic" beta bulge, with position 1 in approximately alpha-helical conformation, and the "G1" beta bulge, with a required glycine at position 1 in approximately left-handed alpha-helical conformation, G1 bulges almost always occur in combination with a type II tight turn. The functional roles of beta bulges probably include compensating for the effects of a single-residue insertion or deletion within beta structure and providing the strong local twist required for form closed beta barrel structures.


Killing of Fusobacterium nucleatum, Porphyromonas gingivalis and Prevotella intermedia by protegrins.
Protegrins are broad spectrum antibiotic peptides isolated from porcine leukocytes. In this study, we (i) examine the sensitivity of Gram-negative, anaerobic periodontal pathogens to synthetic protegrins; (ii) determine the relative potencies of protegrin congeners against these bacteria; and (iii) compare the potency of protegrins with other antibiotic peptides, including magainin MSI-78, tachyplesin I, cecropin P1, human defensins HNP-1-3, and clavanin A. Synthetic L- and D-enantiomers of protegrin 1 (PG-1 and D-PG-1, respectively), and L-enantiomers of protegrins 2, 3 and 5 (PG-2, PG-3 and PG-5) were tested against Fusobacterium nucleatum, and black-pigmented organisms including Porphyromonas gingivalis and Prevotella intermedia. Strains of both F. nucleatum and the black-pigmented organisms were sensitive to PG-1, and exhibited mean ED99 of 2.2-2.3 micrograms/ml and 3.4-9.9 micrograms/ml, respectively. The D-form was statistically more potent than the L-form against these oral anaerobes, and although this difference in potency is unlikely to be of decisive therapeutic significance, the D-form may be of value given ability to resist microbial and host-derived proteases. PG-1 was more potent than magainin, tachyplesin, cecropin, defensins and clavanin under test conditions. Hypertonic salt concentrations and heat-inactivated serum were found to be inhibitory to the bactericidal activity of PG-1. PG-1 was found to induce morphologic alterations in the ultrastructural appearance of F. nucleatum consistent with damage to the bacterial membranes. We conclude that protegrins may be useful antimicrobial agents in therapy against Gram-negative anaerobic bacteria believed to be involved in chronic, adult forms of periodontal infections.


Estradiol treatment increases M2-like visceral adipose tissue macrophages in obese ovariectomized mice regardless of its anorectic action.
Estradiol (E2) treatment has been known to induce changes in food intake, energy expenditure, and weight gain. However, its direct effects on adipose tissue macrophages (ATM) in vivo are not fully understood. Thus, we aimed to explore this aspect at cellular and molecular levels in ovariectomized obese mice. We examined the changes in ATMs after eight weeks of a high-fat diet (HFD) in male, female, and ovariectomized (OVX) mice. After eight weeks, osmotic pumps were inserted into OVX mice to provide two weeks of E2 treatment. We additionally set up a vehicle Pair-Fed (PF) control group that supplied the same amount of HFD consumed by the E2-treated group. We then investigated the in vivo phenotypic changes of visceral adipose tissue (VAT) macrophages. The percentage of M1-like ATMs decreased by the anorectic effect of E2, while M2-like ATMs increased regardless of the anorexia. E2 treatment increased the expression of anti-inflammatory genes but decreased pro-inflammatory genes in VAT. Monocyte recruitment and local proliferation contributed to M2-like ATMs. Furthermore, M2-like phenotypes were induced by E2 treatment in human macrophages. E2 treatment increases M2-like macrophages and improves the tissue milieu of VAT regardless of the anorectic reaction of E2.


Analysis of metabolomic profile of fermented Orostachys japonicus A. Berger by capillary electrophoresis time of flight mass spectrometry.
Microbial cell performance in food biotechnological processes has become an important concern for improving human health worldwide. Lactobacillus plantarum, which is widely distributed in nature, is a lactic acid bacterium with many industrial applications for fermented foods or functional foods (e.g., probiotics). In the present study, using capillary electrophoresis time of flight mass spectrometry, the metabolomic profile of dried Orostachys japonicus A. Berger, a perennial medicinal herb with L. plantarum was compared with that of O. japonicus fermented with L. plantarum to elucidate the metabolomic changes induced by the fermentation process. The levels of several metabolites were changed by the fermentation process, indicating their involvement in microbial performance. For example, glycolysis, the pentose phosphate pathway, the TCA cycle, the urea cycle-related metabolism, nucleotide metabolism, and lipid and amino acid metabolism were altered significantly by the fermentation process. Although the fermented metabolites were not tested using in vivo studies to increase human health benefits, our findings provide an insight into the alteration of metabolites induced by fermentation, and indicated that the metabolomic analysis for the process should be accompanied by fermenting strains and conditions.


Effect of high concentrations of dietary vitamin D3 on pullet and laying hen performance, skeleton health, eggshell quality, and yolk vitamin D3 content when fed to W36 laying hens from day of hatch until 68 wk of age.
The objective of this experiment was to investigate the effects of various dietary concentrations of vitamin D3 (D3) on pullet and laying hen performance, eggshell quality, bone health, and yolk D3 content from day of hatch until 68 wk of age. Initially, 440 Hy-line W36-day-old chicks were randomly assigned to 5 dietary treatments: 1,681 (control); 8,348; 18,348; 35,014; 68,348 IU D3/kg. At 17 wk of age, pullets were assigned to experimental diets with 12 replicate groups of 6 birds. At 17 wk of age, pullets fed diets containing 8,348 and 35,014 IU D3/kg had an increased bone mineral density in comparison to the control fed birds (P ≤ 0.01). Body weights of pullets fed the diet with 68,348 IU D3/kg were lower than other treatments (P ≤ 0.01). Hen-housed egg production (HHEP) of hens fed the 35,014 IU D3/kg diet was increased in comparison to control-fed hens (P ≤ 0.01), whereas HHEP of those fed 68,348 IU D3/kg diet was reduced in comparison to all other treatments (P ≤ 0.01). Shell breaking strength of eggs from hens fed 8,348, 35,014 and 68,348 IU D3/kg was increased in comparison to eggs from control-fed birds (P ≤ 0.01). Fat-free tibia ash content of hens fed any of the diets supplemented with D3 (8,348 to 68,348 IU D3/kg) was increased in comparison to control-fed hens (P ≤ 0.05). Yolk D3 content increased linearly with dietary D3 and the D3 transfer efficiency for the control, 8,348 IU, 18,348 IU, 35,014 IU, and 68,348 IU D3 treatments were 8.24, 10.29, 11.27, 12.42, and 12.06%, respectively. These data suggest that supplementation of dietary D3 up to 35,014 IU D3/kg feed maintained if not increased laying hen performance and enhanced pullet and laying hen skeletal quality as well as yolk D3 content and eggshell quality. Feeding pullets at a higher level 68,348 IU of D3 resulted in reduced growth and ultimately decreased performance of laying hens.


Severe subcutaneous hematoma in a patient with psoriatic arthritis: Changes of platelet count in psoriatic patients with biologic agents.
The effectiveness of biologics has changed therapeutic strategies for psoriasis dramatically, but biologics are known to have various adverse effects. We report a 63-year-old woman with psoriatic arthritis who suddenly developed a subcutaneous hematoma after being successfully treated with adalimumab. As she had also suffered from alcoholic cirrhosis, we speculated that she had developed thrombocytopenia severe enough to cause a subcutaneous hematoma. Furthermore, we investigated the changes of platelet counts in 65 psoriatic patients treated with biologics at a single institute from 2010 to 2016. Platelet counts were found to have decreased by 17.4 ± 2.8% during adalimumab therapy (n = 16), 18.5 ± 3.8% during infliximab therapy (n = 17), 14.8 ± 2.1% during ustekinumab therapy (n = 20) and 18.5 ± 5.1% during secukinumab therapy (n = 12). Platelet counts decrease after the administration of biologics in accordance with disease activity, and there is the potential risk of subcutaneous hematoma and other adverse effects. When administrating biologics to psoriatic patients, especially to those with chronic liver disease, dermatologists should carefully monitor for thrombocytopenia.


ProteinVista: a fast molecular visualization system using Microsoft Direct3D.
Many tools have been developed to visualize protein and molecular structures. Most high quality protein visualization tools use the OpenGL graphics library as a 3D graphics system. Currently, the performance of recent 3D graphics hardware has rapidly improved. Recent high-performance 3D graphics hardware support Microsoft Direct3D graphics library more than OpenGL and have become very popular in personal computers (PCs). In this paper, a molecular visualization system termed ProteinVista is proposed. ProteinVista is well-designed visualization system using the Microsoft Direct3D graphics library. It provides various visualization styles such as the wireframe, stick, ball and stick, space fill, ribbon, and surface model styles, in addition to display options for 3D visualization. As ProteinVista is optimized for recent 3D graphics hardware platforms and because it uses a geometry instancing technique, its rendering speed is 2.7 times faster compared to other visualization tools.


Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms.
Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance.


Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation.
The kinetics of lithium diisopropylamide (LDA) in tetrahydrofuran under nonequilibrium conditions are reviewed. These conditions correspond to a class of substrates in which the rates of LDA aggregation and solvation events are comparable to the rates at which various fleeting intermediates react with substrate. Substrates displaying these reactivities, by coincidence, happen to be those that react at tractable rates on laboratory time scales at -78 °C. In this strange region of nonlimiting behavior, rate-limiting steps are often poorly defined, sometimes involve deaggregation, and at other times include reaction with substrate. Changes in conditions routinely cause shifts in the rate-limiting steps, and autocatalysis is prevalent and can be acute. The studies are described in three distinct portions: (1) methods and strategies used to deconvolute complex reaction pathways, (2) the resulting conclusions about organolithium reaction mechanisms, and (3) perspectives on the concept of rate limitation reinforced by studies of LDA in tetrahydrofuran at -78 °C under nonequilibrium conditions.


[Experience with operation for synchronous multiple primary lung cancer].
We presented a 66-year-old man with synchronous double cancers developing in the right upper lobe, which were diagnosed preoperatively. He underwent right upper lobectomy with hilar and mediastinal lymphadenectomy. Post-operative patho-histological study showed two different histologic types of cancer; one was undifferentiated carcinoma of the small cell type, and the other was moderately differentiated adenocarcinoma.


Conformation of desmopressin, an analogue of the peptide hormone vasopressin, in aqueous solution as determined by NMR spectroscopy.
Desmopressin (1-desamino-[DArg8]vasopressin, is a synthetic analogue of the neurohypophyseal peptide hormone vasopressin which has high antidiuretic and antibleeding potency. The structure of desmopressin has been determined in aqueous solution by two-dimensional NMR techniques and molecular dynamics simulations. Both standard and time-averaged distance restraints were used in structure calculations because of the inherent flexibility in small peptides. 21 models calculated with standard restraints were compared with structures refined with time-averaged distance restraints and were found to be good representatives of the conformational ensemble of desmopressin. The macrocyclic ring forms an inverse gamma-turn centered around Gln4. Residues 1 and 2, the disulphide bridge and the three-residue acyclic tail were found to be flexible in solution. Residues 4-6 in the ensemble of calculated structures contain essentially the same backbone conformation as in the crystal structure of pressinoic acid, the cyclic moiety of vasopressin, whereas residues 2-6 superimpose on the NMR-derived conformation of oxytocin bound to neurophysin. The results presented in this work suggest that, in addition to the differences in sequence between desmopressin and vasopressin, differences in conformational and dynamic properties between the two compounds explain their pharmacological differences.


Modified Hill operation vs. Nissen fundoplication in the surgical treatment of gastro-esophageal reflux disease.
The authors compared the results of the Nissen fundoplication technique with the results of the Hill procedure, by using a 10-year history of patients with gastro-esophageal reflux disease. Seventy two consecutive patients entered the study, 32 of whom underwent a 360 degrees fundoplication according to Nissen and 40 with a modified Hill operation. In the Nissen Group, intraoperative manometry (IOM) was carried out in all patients; in the Hill Group, the patients were randomized in two sub-groups (A and B), before operation; in 20 of them (group A), the procedure was randomly associated to IOM. The overall complications were low in both groups (15.6% in the Nissen Group and 5% in the Hill Group, p = 0.1), and there was no mortality rate. The clinical results were excellent or good in 28 patients (87.6%) of the Nissen Group and in 36 patients (90%) of the Hill Group (p = 0.5); in particular, an excellent outcome was observed in 16 patients (80%) with IOM (sub-group A), while 12 patients (60%) without it (sub-group B) showed similar results. The manometric studies carried out six months after surgical treatment showed a decrease of the lower esophageal sphincter pressures in all patients if compared to the pressure recorded intra-operatively. In comparison to the pre-operative values, both the lower esophageal sphincter length and its intra-abdominal portion were markedly increased in the Nissen Group and in the sub-group A of the Hill patients. These results support the conclusions that modified posterior gastropexy and 360 degrees fundoplication are effective, well tolerated, and can be properly used in the treatment of Gastro-esophageal reflux disease (GERD), since both techniques showed good clinical results. A favorable clinical outcome depends mostly on adequate lower esophageal sphincter length (LESL) and LESIA extension, which could be more efficiently achieved by the use of intraoperative manometry (IOM).


Curare--a curative poison: a scientometric analysis.
Curare is one of the best-examined neurotoxins of the world, which has empirically been used for centuries by American Indigenes. Research on curare has been performed much later, a global scientometric analysis on curare research or its derivates does not yet exist. This bibliometric analysis is part of the global NewQis-project and should illuminate both toxic and historic issues of research on curare. The ISI Web of Science was searched for data covering 1900 to 2013 using a term which included as many original articles on curare as possible. 3,867 articles were found and analyzed for common bibliometric items such as the number of citations, language of the articles or the (modified) Hirsch-Index (h-index). Results are illustrated utilizing modern density equalizing map projections (DEMP) or beam diagrams. Most publications were located in North America and Europe. The USA has the highest number of publications as well as the highest h-index. The number of publications overall rose until the late 1990s and later decreased. Furthermore, sudden increases of research activity are ascribable to historic events, like the first use of curare as muscle relaxant during surgery. This scientometric analysis of curare research reflects several tendencies as previously seen in other bibliometric investigations, i.e. the scientific quality standard of North America and Europe. Research on curare decreased however, due to the declining attention towards this muscle relaxant. This work exemplifies also how scientometric methods can be used to illuminate historic circumstances immediately stimulating scientific research.


A density functional study of the various forms of UN4O12 containing uranyl nitrate.
In this paper we report the computational results of a density functional study of 73 UN4O12 isomers containing uranyl nitrate, UO2(NO3)2, as a component. The isomers are grouped into three categories and 19 types. Forty-four isomers of 14 types are dinitrogen tetroxide adducts of uranyl nitrate, UO2(NO3)2.N2O4, 22 are nitrosonium salt adducts of uranyl nitrate, NO+UO2(NO3)3-, NO+UO2(NO3)2O(NO2)-, NO+UO2(NO3)2(ONOO)-, or (NO+)2UO2(NO3)2O22-, and 7 are bis(nitrogen dioxide) adducts of uranyl nitrate, UO2(NO3)2.2NO2. The 22 most stable isomers in solution, representing the 20 most stable gas-phase isomers, were selected for analysis. Of these selected structures only two categories and six types were represented. Structures, frequencies, gas-phase and solution energetics, atomic charges, dipole moments, and the bonding within the N2O4 unit and between NO+ and UO2(NO3)3- components have been analyzed in detail. On the basis of relative Gibbs free energy calculations five isomers (the N2O4 adducts a1, a2, and a3 and the nitrosonium salts b1 and b2) were identified as strong candidates to exist and possibly predominate in the gas phase, with a1 and a2 being the strongest candidates. Similarly, four isomers (a6, a5, a8, and a1, all of them N2O4 adducts) were identified as strong candidates to exist and possibly predominate in a nonaqueous solution of nitromethane/dinitrogen tetroxide. Of these, a6 was determined to be the most likely candidate to predominate in solution. The possibility of dissociation in solution has been addressed briefly. In addition, computational evidence for the existence of four new N2O4 isomers 20, 22, 27, and 28 in both the gas and the solution phases is presented for the first time.


Neutron diffraction studies of a four-coordinated hydride in near square-planar geometry.
The structure of a nanospheric polyhydrido copper cluster, [Cu20(H)11{S2P(O(i)Pr)2}9], was determined by single-crystal neutron diffraction. The Cu20 cluster consists of an elongated triangular orthobicupola constructed from 18 Cu atoms that encapsulate a [Cu2H5](3-) ion with an exceptionally short Cu-Cu distance. The 11 hydrides in the cluster display three different coordination modes to the Cu atoms: six μ3-hydrides in a pyramidal geometry, two μ4-hydrides in a tetrahedral cavity, and three μ4-hydrides in an unprecedented near square-planar geometry. The neutron data set was collected for 7 days on a small crystal with dimensions of 0.20 mm × 0.50 mm × 0.65 mm using the Spallation Neutron Source TOPAZ single-crystal time-of-flight Laue diffractometer at Oak Ridge National Laboratory. The final R-factor was 8.63% for 16,014 reflections.


The Thiamin-Requiring 3 Mutation of Arabidopsis 5-Deoxyxylulose-Phosphate Synthase 1 Highlights How the Thiamin Economy Impacts the Methylerythritol 4-Phosphate Pathway.
The thiamin-requiring mutants of Arabidopsis have a storied history as a foundational model for biochemical genetics in plants and have illuminated the central role of thiamin in metabolism. Recent integrative genetic and biochemical analyses of thiamin biosynthesis and utilization imply that leaf metabolism normally operates close to thiamin-limiting conditions. Thus, the mechanisms that allocate thiamin-diphosphate (ThDP) cofactor among the diverse thiamin-dependent enzymes localized in plastids, mitochondria, peroxisomes, and the cytosol comprise an intricate thiamin economy. Here, we show that the classical thiamin-requiring 3 (th3) mutant is a point mutation in plastid localized 5-deoxyxylulose synthase 1 (DXS1), a key regulated enzyme in the methylerythritol 4-phosphate (MEP) isoprene biosynthesis pathway. Substitution of a lysine for a highly conserved glutamate residue (E323) located at the subunit interface of the homodimeric enzyme conditions a hypomorphic phenotype that can be rescued by supplying low concentrations of thiamin in the medium. Analysis of leaf thiamin vitamers showed that supplementing the medium with thiamin increased total ThDP content in both wild type and th3 mutant plants, supporting a hypothesis that the mutant DXS1 enzyme has a reduced affinity for the ThDP cofactor. An unexpected upregulation of a suite of biotic-stress-response genes associated with accumulation of downstream MEP intermediate MEcPP suggests that th3 causes mis-regulation of DXS1 activity in thiamin-supplemented plants. Overall, these results highlight that the central role of ThDP availability in regulation of DXS1 activity and flux through the MEP pathway.


Lack of bone lesions at diagnosis is associated with inferior outcome in multisystem langerhans cell histiocytosis of childhood.
Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis (LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty-eight children with multisystem (MS) LCH, both high (386 RO+) and low (RO-) risk, were evaluated for bone lesions at diagnosis. Risk organ (RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4·0 × 10(9) /l and/or platelet count <100 × 10(9) /l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+RO+ LCH the probability of survival with bone involvement 74 ± 3% (n = 230, 56 events) was reduced to 62 ± 4% (n = 156, 55 events) if this was absent (P = 0·007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 ± 5% survival (n = 105; 52 events) if patients had bony lesions, versus 47 ± 5% (n = 111; 39 events) if they did not (P = 0·014). This difference was retained in multivariate analysis (P = 0·048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+RO+ LCH.


Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine.
The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [125I]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain.


Extracts and components of Ficus carica leaves suppress survival, cell cycle, and migration of triple-negative breast cancer MDA-MB-231 cells.
Products from Ficus carica have been used in traditional medicine to treat many diseases. This study aimed to analyze anticancer effects of extracts of F. carica leaves on the triple-negative breast cancer cell line MDA-MB-231. The human breast cancer cell line MDA-MB-231 was used to evaluate effects of F. carica extracts. Effects of F. carica on cell viability were evaluated using MTT assays. Cell-cycle distribution was examined using cell-cycle analysis. Wound-healing assays were used to evaluate migration of MDA-MB-231. Quantitative reverse-transcription polymerase chain reaction was used to detect levels of Bax, p53, p21, GATA3, ELF5, cyclin-dependent kinases, MMP2, and tissue inhibitors of metalloproteinase. We investigated the mechanism of anti-growth effects, and found that the expressions of genes that promote apoptosis were increased. In addition, the treated cells illustrated increased portion at S phase and changed expression of cyclin-dependent kinases, demonstrating cell-cycle arrest at the S phase. Furthermore, treated cells showed decreased cell mobility, which is essential for metastasis. Two of the active components of F. carica leaves, bergapten and psoralen, had similar anticancer effects as F. carica leaf extracts, indicating that these two components might play important roles in anticancer effects of F. carica leaves. Our findings suggest that F. carica leaves might be a good source to develop drugs for suppressing cancer-cell growth and migration to treat triple-negative breast cancers.


Fludarabine phosphate therapy in other lymphoid malignancies.
The promising results obtained with Fludara I.V. (fludarabine phosphate) treatment in the common indolent B-cell neoplasms have led to their further evaluation in other unusual B-cell malignancies, in Hodgkin's disease, and in T-cell diseases. A significant response rate has been found among patients with macroglobulinemic lymphoma, those with prolymphocytic leukemia or prolymphocytoid variant of chronic lymphocytic leukemia, and those with mycosis fungoides. The limited therapeutic data in hairy-cell leukemia and in Hodgkin's disease are also interesting.


Fine needle aspiration biopsy of complex renal cystic tumors in the era of modern imaging modalities: where shall we go?
To report on a series of fine needle aspiration (FNA) biopsies for preoperative diagnosis of complex cystic renal mass. From August 2002 to February 2009, 32 patients with a complex cystic renal mass were studied. Tumor size ranged from 1.5-7.7 cm, with a median of 3.0 cm. Bosniak classification was 15 IIF, 12 III, and 5 IV. FNA biopsy was performed under CT guidance to obtain the fluid. Malignant and suspect cytological reports were considered as a positive diagnosis, and absence of epithelial cells as a negative diagnosis. Sufficient fluid was obtained in all cases. A positive preoperative diagnosis was found in 11 patients, and 21 cysts presented as absence of epithelial cells. Of the 26 patients who underwent surgery, pathology proved that there were 21 malignant and 5 benign cysts. Among the operated patients with a malignant cystic tumor, 11/21 (52.3%) presented a negative preoperative diagnosis. One preoperative positive diagnosis was proved to be a benign cyst. The accuracy of preoperative positive cytology was 10/11 (90.9%). No difficulty was noticed in obtaining the fluid by FNA of a cystic small renal mass. A false negative diagnosis was due mainly to the absence of malignant cells in the fluid of cysts. Biomarkers in fluid shall be studied to solve the diagnostic problem.


The role of nucleocapsid and U5 stem/A-rich loop sequences in tRNA(3Lys) genomic placement and initiation of reverse transcription in human immunodeficiency virus type 1.
We have studied the effect of mutations in the human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) sequence on tRNA(3Lys) genomic placement, i.e., the in vivo placement of primer tRNA(3Lys) on the HIV-1 primer binding site (PBS). HIV-1 produced from COS cells transfected with wild-type or mutant proviral DNA was used in this study. We have found that mutations in the amino acid sequences flanking the first Cys-His box in the NC sequence produce the maximum inhibition of genomic placement. A similar finding was obtained when the NC-facilitated annealing of primer tRNA(3Lys) to the HIV PBS in vitro was studied. However, since the genomic placement of tRNA(3Lys) occurs independently of precursor protein processing, the NC mutations studied here have probably exerted their effect through one or both of the precursor proteins, Pr55gag and/or Pr160(gag-pol). One mutation in the linker region between the two Cys-His boxes, P31L, prevented packaging of both Pr160(gag-pol) and tRNA(3Lys) and prevented the genomic placement of tRNA(3Lys). Both packaging and genomic placement were rescued by cotransfection with a plasmid coding for wild-type Pr160(gag-pol). For other linker mutations [R7R10K11 S, R32G, and S3(32-34)], packaging of Pr160(gag-pol) and tRNA(3Lys) was not affected, but genomic placement was, and placement could not be rescued by cotransfection with plasmids coding for either Pr55gag or Pr160(gag-pol). After placement, the initiation of reverse transcription within extracellular virions is characterized by a 2-base DNA extension of the placed tRNA(3Lys). This process requires precursor processing, and those NC mutations which showed the most inhibition of initiation were in either of the two NC Cys-His boxes. Destabilization of a U5 stem-A-rich loop immediately upstream of the PBS (through deletion of four consecutive A's in the loop) did not affect the in vivo genomic placement of tRNA(3Lys) but resulted in the presence in the extracellular virus of longer cDNA extensions of tRNA(3Lys), with a corresponding decrease in the presence of unextended and 2-base-extended tRNA(3Lys).


Processed bovine cartilage: an improved biosynthetic implant for contour defects.
Irradiated human cartilage has been found to be a superior implant material for correction of contour defects; however, availability problems have prevented this material from gaining wide acceptance. Implantation of processed irradiated bovine cartilage in primates and rabbits, as described here, provides strong evidence that this material performs like irradiated allograft cartilage antigenically and has certain cosmetic advantages over allograft cartilage. Our studies in primates have shown that there is no systemically measurable antibody-antigen reaction, either cellular or noncellular, to irradiated processed bovine cartilage. Neither primary nor second-set provocative implantations produced any measurable rejection. In rabbits, composite grafts of two pieces of irradiated bovine cartilage adjacent to each other were also well tolerated, with no measurable absorption and with capsule formation typical of a foreign body reaction to an inert object.


Periodic nonlinear sliding modes for two uniformly magnetized spheres.
A uniformly magnetized sphere slides without friction along the surface of a second, identical sphere that is held fixed in space, subject to the magnetic force and torque of the fixed sphere and the normal force. The free sphere has two stable equilibrium positions and two unstable equilibrium positions. Two small-amplitude oscillatory modes describe the sliding motion of the free sphere near each stable equilibrium, and an unstable oscillatory mode describes the motion near each unstable equilibrium. The three oscillatory modes remain periodic at finite amplitudes, one bifurcating into mixed modes and circumnavigating the free sphere at large energies. For small energies, the free sphere is confined to one of the two discontiguous domains, each surrounding a stable equilibrium position. At large energies, these domains merge and the free sphere may visit both positions. The critical energy at which these domains merge coincides with the cumulation point of an infinite cascade of mixed-mode bifurcations. These findings exploit the equivalence of the force and torque between two uniformly magnetized spheres and the force and torque between two equivalent point dipoles, and offer clues to the rich nonlinear dynamics of this system. Online MagPhyx visualizations illustrate the dynamics.


Pioneering medical advances through nanofluidic implantable technologies.
Nanofluidic implantables represent a recent advance in a broad effort for developing personalized, point-of-care medical technologies. Such systems have unprecedented potential when matched with the newest developments in robotics, microprocessing, and tissue engineering. In this review, we present their emergence in medicine within the fields of diagnostics, biosensing, therapeutics, and theranostics. Discussion includes current limitations and future directions for these systems, as commensurate advances in power density and electronic processing are continually redefining the possible. As the research and funding attention coincide with complementary technological breakthroughs, the field is expected to grow into an advanced toolset for preserving human health. WIREs Nanomed Nanobiotechnol 2017, 9:e1455. doi: 10.1002/wnan.1455.


A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases.
Neutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in-depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment. This review explores the multifaceted processes and characteristics of neutrophil death, with a focus on tailored investigations within various autoimmune diseases. It also highlights the potential interplay between neutrophil death and the landscape of autoimmune disorders. The review encapsulates the pertinent pathways implicated in various neutrophil death mechanisms across diverse autoimmune diseases while also charts possible avenues for future research.


In vitro screening for antitumour activity of Clinopodium vulgare L. (Lamiaceae) extracts.
Aqueous extract of Clinopodium vulgare L. showed strong antitumour activity when tested in vitro on A2058 (human metastatic melanoma), HEp-2 (epidermoid carcinoma, larynx, human) and L5178Y (mouse lymphoma) cell lines-6 h after treatment disintegration of the nuclei and cell lysis started. Applied at a concentration of 80 microg/ml it reduced the cell survival to 1.0, 5.6 and 6.6%, respectively. The concentrations of aqueous extract inhibiting the growth of A2058, HEp-2 and L5178Y cells by 50% (IC50 values) were calculated to be 20, 10 and 17.8 microg/ml respectively. Two groups of active substances were detected: the first one, probably combining glycosides, influenced adhesion, while the second one caused massive cell vacuolisation. The chloroform extract, which contained ursolic acid and gentriacontan had also cytotoxic, however a little bit weaker effect. All changes observed were irreversible.


Extrication, immobilization and radiologic investigation of patients with cervical spine injuries.
Most cervical spine injuries are due to motor vehicle accidents. Proper extrication of the victims is vital; the ideal device should be easily assembled and applied, should facilitate removal of victims from automobile seats without changing the body's position, must not hinder airway access or the performance of cardiopulmonary resuscitation, must accommodate all types of patients, including children and obese or pregnant patients, and must completely immobilize the patient, especially if hyperextension is suspected. Current methods of immobilization, such as the use of a soft collar and sandbags, allow neck extension; the short board protects against extension but interferes with airway access. Newer devices are discussed in this article. Injuries of the upper cervical spine are less common but more serious than those of the lower portion and usually involve the vertebral arch. Radiologic examination of the first and second cervical vertebrae and the seventh cervical and first thoracic vertebrae should be emphasized. If lateral and anteroposterior views do not reveal abnormal findings and injury is still suspected, oblique views and computed or conventional tomography should be used. Cervical spinal cord injuries can be minimized or prevented if proper early management is applied.


EZH2 suppresses the nucleotide excision repair in nasopharyngeal carcinoma by silencing XPA gene.
The enhancer of zeste homolog 2 (EZH2) is involved in a number of fundamental pathological processes of cancer. However, its role in DNA repair pathway is still unclear. Here, we have identified XPA as a novel target gene of EZH2 via a DNA repair pathway PCR array. XPA plays a pivot role in nucleotide excision repair (NER). The expression of XPA was significantly increased by EZH2 specific inhibitor GSK126 or lentiviral shEZH2 in nasopharyngeal carcinoma (NPC) CNE and 8F cell lines. Chromatin immunoprecipitation assay demonstrated that EZH2 catalyzes H3K27 trimethylation at the XPA promoters. Furthermore, we validated the negative correlation of EZH2 and XPA in a NPC tissue microarray by immunohistochemistry staining. We also found that high expression of EZH2 was positively correlated with advanced T, N, and AJCC stage of NPC; and low expression of XPA was positively correlated with advanced T and N stage. In NPC cell lines, increased XPA expression by EZH2 inhibition resulted in a more rapid removal of UVC induced 6-4PP- and CPD-DNA adducts, as well as enhanced efficiency of DNA repair after UVC irradiation as detected by the Comet assay and immunofluorescence staining of γH2Ax. Consistently, increased cell clonogenic survival, decreased apoptosis, and necrosis after UVC irradiation, and increased resistance to DNA damaging agent cisplatin was also observed in EZH2 inhibited cells. These results illustrate that EZH2 may promote carcinogenesis and cancer development of NPC by transcriptional repression of XPA gene and inactivation of NER pathway. © 2016 Wiley Periodicals, Inc.


Correlations between the biochemistry and mechanical states of a sea-urchin ligament: a mutable collagenous structure.
Mutable collagenous tissues (MCTs) of echinoderms can be regarded as intelligent and dynamic biomaterials, due to their ability to reversibly change their mechanical properties in a short physiological time span. This mutability phenomenon is nervously mediated and involves secreted factors of the specialized 'juxtaligamental' cells, which, when released into the extracellular matrix (ECM), change the cohesive forces between collagen fibrils. MCTs exist in nature in several forms, including some associated with echinoderm autotomy mechanisms. Since the molecular mechanism of mutability is still incompletely understood, the aim of this work was to provide a detailed biochemical analysis of a typical mutable collagenous structure and to identify possible correlations between its biochemistry and mechanical states. A better understanding of the mutability phenomena is likely to provide a unique opportunity to develop new concepts that can be applied in the design of dynamic biomaterial for tissue regeneration, leading to new strategies in regenerative medicine. The MCT model used was the compass depressor ligament (CDL) of a sea urchin (Paracentrotus lividus), which was analyzed in different mechanical states, mimicking the mutability phenomenon. Spectroscopic techniques, namely Fourier transform infrared (FT-IR) and confocal Raman microscopy, were used to identify the specific molecular components that contribute to the CDL biochemical microenvironment and to investigate the possibility that remodelling/synthesis of new ECM components occurs during the mutability phenomenon by analogy with events during pregnancy in the uterine cervix of mammals (which also consists mainly of mechanically adaptable connective tissues). The results demonstrate that CDL ECM includes collagen with biochemical similarities to mammalian type I collagen, as well as sulphated glycosaminoglycans (GAGs). CDL mutability seems to involve a molecular rearrangement of the ECM, without synthesis of new ECM components. Although there were no significant biochemical differences between CDLs in the various mechanical states were observed. However, subtle adjustments in tissue hydration seemed to occur, particularly during stiffening.


Cervical Spinal Cord Compression: A Rare Presentation of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver. Distant metastasis to various organs is well known. Skeletal metastasis is also reported to various locations. Vertebral metastasis has been reported mostly to thoracic spine. However, cervical spinal cord involvement leading to cord compression has been reported very rarely in literature. We present a case of 58-year-old male with liver cirrhosis presenting as neck pain. Further work-up revealed metastatic HCC to cervical spinal cord resulting in acute cord compression. Patient has been treated with neurosurgical intervention.


Cells from Rana pipiens gastrulae and arrested hybrid gastrulae show differences in adhesion to fibronectin-sepharose beads.
Experiments were performed to examine adhesion of Rana pipiens gastrula cells and arrested hybrid gastrula cells to fibronectin-Sepharose beads (FN-beads). Blastula cells from both normal and hybrid embryos show poor adhesion to FN-beads. Beginning at the early gastrula stage, however, normal cells show a progressively increasing tendency to adhere to beads. In two different arrested hybrid embryos, cells from all developmental stages lack the ability to adhere to beads. A third hybrid shows an increase and then a decrease in cell-bead adhesion. A fourth hybrid shows a late increase in cell-bead adhesion in animal-half cells and no increase at all in vegetal-half cells. Blastula-stage cells have the ability to adhere to con A-beads and two kinds of Cytodex beads but will not adhere to FN-beads. Similarly, some cells from arrested hybrid embryos lack the ability to adhere to FN-beads but will adhere to con A-beads and cytodex beads. Observations in the light and scanning electron microscope show that normal cells form lamellipodia on FN-beads and move about actively on them, much like they do in vivo on surfaces coated by fibrils containing fibronectin. For adherent hybrid cells attached to beads, one kind does so by small pseudopodia but does not move on them and another kind forms active lamellipodia at the tips of fusiform cells and moves on beads.


Immunohistochemistry and molecular analyses in myeloid sarcoma of the breast in a patient with relapse of NPM1-mutated and FLT3-mutated AML after allogeneic stem cell transplantation.
Myeloid sarcoma of the breast is a rare manifestation of acute myeloid leukaemia (AML). This report describes a patient who was diagnosed with AML FAB M2. Molecular analysis showed evidence of an NPM1 mutation (subtype A) and internal tandem duplications of the FLT3 gene (FLT3-ITD). Eight months after allogeneic stem cell transplantation, the patient developed a palpable mass in the left breast initially suspected as breast carcinoma. Core needle biopsy of the lesion resulted in diagnosis of myeloid sarcoma. Molecular analysis of formalin-fixed specimens of the breast tumour confirmed the known FLT3 and NPM1 gene mutations. Immunohistochemically, an aberrant cytoplasmic staining pattern for NPM1 and overexpression of FLT3 were demonstrated. The myeloid sarcoma showed complete transient resolution following treatment with the kinase inhibitor sorafenib. However, the patient developed bone marrow relapse and died in fatal cerebral haemorrhage 1 year after initial diagnosis of AML. In summary, combined molecular and immunohistochemical examination of NPM1 and FLT3 is helpful in the diagnosis of extramedullary manifestations of AML in core needle biopsies.


A Bushmaster bite during a birding expedition in lowland southeastern Peru.
Birders and other ecotourists are traveling to increasingly remote areas of the world where sophisticated medical care may be difficult to obtain. This report presents a case of a Bushmaster (Lachesis muta muta) bite in Peru and details the difficulties encountered from initial care to evacuation and definitive medical care.


Pediatric emergency: assessing gut pain.
"Tummyache" is probably the most common complaint among children. It can be the result of too much candy, a virus, or a life-threatening gastrointestinal disorder. Symptoms of different conditions can mimic each other. Here's how to tell the difference.


Emergence and Persistence of High-Risk Clones Among MDR and XDR A. baumannii at a Brazilian Teaching Hospital.
Dissemination of carbapenem-resistant Acinetobacter baumannii is currently one of the priority themes discussed around the world, including in Brazil, where this pathogen is considered endemic. A total of 107 carbapenem-resistant A. baumannii (CRAB) isolates were collected from patients with bacteraemia attended at a teaching hospital in Brazil from 2008 to 2014. From these samples, 104 (97.2%) carried bla OXA-23-like, all of them associated with ISAba1 The bla OXA-231 (1.9%) and bla OXA-72 (0.9%) genes were also detected in low frequencies. All isolates were susceptible to minocycline, and 38.3% of isolates presented intermediate susceptibility to tigecycline (MIC = 4 μg/ml). Molecular typing assessed by multi-locus sequence typing demonstrated that the strains were mainly associated with clonal complexes CC79 (47.4%), followed by CC1 (16.9%), and CC317 (18.6%), belonging to different pulsotypes and in different prevalences over the years. Changes in the clones' prevalence reinforce the need of identifying and controlling CRAB in hospital settings to preserve the already scarce therapeutic options available.


Evaluation of the safety and tolerability of tamoxifen for ischemia-incited renal injury in mice.
Tamoxifen is used to activate tamoxifen-dependent Cre recombinase (CreER) to generate time- and tissue-specific genetically mutant mice. However, tamoxifen is also an active estrogen analogue that binds with higher affinity to estrogen receptors and exhibits anti-apoptosis, anti-inflammation, and antifibrotic properties. Renal ischemia reperfusion (I/R) injury is characterized by increased apoptosis and inflammation, so optimal utility of tamoxifen-inducible CreER genetic systems in I/R model is important. The purpose of this study was to optimize the tamoxifen dose and evaluate its safety and tolerability in the development of mouse I/R injury. Seven-week-old C57/B6 mice were subjected to moderate reversible unilateral I/R and then injected intraperitoneally daily for 5 days with tamoxifen at doses of 50, 100, or 200 mg/kg/day. Regardless of the time of sacrifice, at 5 day or 28 day after I/R injury, there were no differences in pathological damage, apoptosis, inflammation, or the extent of fibrosis between untreated and treated mice from the time point of acute kidney injury (AKI) to subsequently chronic kidney disease. Data above indicated that tamoxifen with a dose among 0 to 200 mg/kg/day was safe and tolerable for mice, without influencing I/R induced kidney injury in mice. The results suggest that tamoxifen-inducible CreER genetic systems can be safely used in the mouse I/R model.


Subpopulations of T alpha cells in patients with IgA nephropathy: correlation between T alpha 4 cells and in vitro IgA production.
T cells play important roles in the regulation of the immune system and are divided into subpopulations by various kinds of markers on the membrane surface. T cells with Fc-receptors for IgA are termed T alpha cells, and the properties of this cell population have been revealed in recent years. T alpha cells are increased in patients with IgA nephropathy and possess IgA specific helper activity. T alpha cells consist of two subpopulations, T alpha cells with OKT4 antigen (T alpha 4 cells) and with OKT8 antigen (T alpha 8 cells). To investigate the immunological aberrations in patients with IgA nephropathy, we detected immunoglobulin produced by peripheral blood lymphocytes and enumerated the numbers of T alpha cells (including both T alpha 4 and T alpha 8 cells). The numbers of T alpha 4 cells (but not T alpha 8 cells) and in vitro IgA production were increased in patients with IgA nephropathy (IgA nephropathy, mean 1.9%. Control, mean 0.8%. P = 0.0075). In addition, the numbers of T alpha 4 cells and the amount of IgA in the supernatant of lymphocyte cultures were positively correlated in these patients (P = 0.025. r = 0.3836). From the results in the present study, it was suggested that T alpha 4 cells might be related to immunological aberrations, such as an increase in IgA seen in patients with IgA nephropathy.


Challenges in Aortic Stenosis: Review of Antiplatelet/Anticoagulant Therapy Management with Transcatheter Aortic Valve Replacement (TAVR): TAVR with Recent PCI, TAVR in the Patient with Atrial Fibrillation, and TAVR Thrombosis Management.
This review aims to describe the current evidence and consensus recommendations around antiplatelet and anticoagulant management in three common clinical scenarios in transcatheter aortic valve replacement (TAVR): (1) recent percutaneous coronary intervention (PCI) preceding TAVR, (2) atrial fibrillation (AF) management in patients undergoing TAVR, and (3) bioprosthetic valve thrombosis management in TAVR. Several small clinical trials have evaluated the use of single vs. dual antiplatelet therapy in patients undergoing TAVR, with most recent data favoring single antiplatelet therapy. There are several trials currently enrolling and in follow-up that evaluate the use of anticoagulants in combination with single and dual antiplatelet therapy for patients with AF undergoing TAVR, but as yet, there is no data to support a clear strategy. The use of DAPT after PCI continues to potentially shorten in patients undergoing elective PCI, thus prolonged DAPT may not be necessary post TAVR for the sake of PCI. Bioprosthetic valve thrombosis occurs more commonly than previously thought, but has uncertain clinical significance. In observational studies, antiplatelet therapy has little effect on bioprosthetic valve thrombosis, whereas anticoagulation is effective in both prevention and treatment of thrombosis. DAPT is currently recommended for 1-6 months for all patients without an indication for oral anticoagulation who undergo TAVR; however, there is a growing amount of evidence for single antiplatelet therapy. In the special situation of patients who have recently undergone PCI, the length of DAPT will depend on stent selection (BMS vs. DES), but may not be significantly prolonged unless the patient experienced an acute coronary syndrome prior to TAVR. There is no clear, optimal antithrombotic strategy for patients with AF who undergo TAVR, but avoidance of triple therapy by using OAC and low-dose ASA seems to be reasonable. OAC, not DAPT, is now known to prevent bioprosthetic valve thrombosis in TAVR and SAVR patients; however, the optimal therapy remains unknown. For patients who develop bioprosthetic valve thrombosis, OAC for 3-6 months, and repeat imaging is recommended to document resolution.


A retrograde y-stenting of the trachea for treatment of mediastinal fistula in an unusual situation.
Stents have been used for quite some time for the treatment of benign and malignant airway stenosis. Silicon stents are preferred for benign situations, whereas metallic self-expanding stents are preferred for malignant comorbidities. In general, stents can be placed in different approach directions, although in pulmonary medicine it is logical to apply only antegrade techniques - until now. A 63-year-old patient, 168 cm height and 53 kg weight on referral, suffered chronical diseases. The patient was diagnosed with a papillary thyroid carcinoma in 1989, which was treated by resection and radiotherapy. In the following years, she developed a stenosis of the esophagus. The decision to try endobronchial stenting was made upon the plan to close that fistula with a pedicled omentum majus replacement through the diaphragmal opening of the esophagus. This surgical plastic needed an abutment and a secured continuous airway replacement above the tracheostoma level. A Freitag stent (FS), 11 cm in length (110-25-40) and an inner diameter of 13 mm, was placed successfully retrograde into the trachea and completely bridged the big fistula. Unfortunately the patient passed away due to pulmonary infections after several weeks. In this case report, a successful but unusual case of retrograde stent placement of a modified FS is presented.


Olive fruit fly (Diptera: Tephritidae) populations in relation to region, trap type, season, and availability of fruit.
Olive fruit fly, Bactrocera oleae (Gmelin), was monitored with adult captures by season and trap type, and was related to fruit volume and nonharvested fruit to elucidate the occurrence of the newly introduced pest in California. The highest numbers of adults captured in ChamP traps in olive trees, Olea europaea, were in October in an inland valley location, and in September in a coastal location. Comparisons of trap types showed that the number of olive fruit fly adults captured in Pherocon AM traps in a commercial orchard was significantly greater than in ChamP traps. A significantly greater number of females were captured in Pherocon AM traps with bait packets and pheromone lures than traps with pheromone lures alone, while a significantly greater number of adults and males were captured in traps with pheromone lures alone. Significantly more adults were captured in ChamP traps with bait packets and pheromone lures versus traps with bait packets alone. Fruit volume increased by four times from mid-June to mid-November. Olive fruit fly was found to oviposit on small olive fruit <1 cm3 shortly after fruit set, the maximum number of ovipositional sites per fruit occurred in October, and the greatest number of pupae and adults were reared from fruit collected in September and October. The highest numbers of pupae were collected from nonharvested fruit in March when high numbers of adults were captured in the same orchard.


Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias.
In isolated superfused left atria of the rabbit, inhomogeneity in conduction was quantified using the activation times measured with a high-density mapping system. At each recording site, the maximal difference with neighboring activation times (i.e., phase difference) was calculated. Local phase differences were plotted in a phase map, revealing the spatial distribution of inhomogeneities in conduction, and from each map a total index of inhomogeneity was calculated. During slow pacing (2 Hz) local differences in conduction velocity, depending on the direction of propagation, were found already. Inhomogeneity in conduction increased significantly during single early premature beats (inhomogeneity index increased from 2.3 to 3.1; P less than 0.001). The application of multiple premature beats further increased inhomogeneity in conduction, whereas rapid pacing induced the highest level of inhomogeneity (inhomogeneity index 5.3; P less than 0.001). An analysis of the spatial distribution of maximal phase differences revealed that during premature beats inhomogeneities in conduction were limited to an area of 6 mm around the point of origin of the premature impulse, whereas during rapid pacing inhomogeneities in conduction were found throughout the whole preparation. Phase maps constructed during the initiation of reentrant tachyarrhythmias showed that reentry occurred at sites with the highest phase differences. Quantification of spatial inhomogeneities in conduction is a useful tool to evaluate the vulnerability of the myocardial substrate for reentrant arrhythmias.


Environmental effects on a prion's helix II domain: copper(II) and membrane interactions with PrP180-193 and its analogues.
An abnormal interaction between copper and the prion protein is believed to play a pivotal role in the pathogenesis of prion diseases. Copper binding has been mainly attributed to the N-terminal domain of the prion protein, but this hypothesis has recently been challenged in some papers which suggest that the C-terminal domain might also compete for metal anchoring. In particular, the segment corresponding to the helix II region of the prion protein, namely PrP180-193, has been shown both to bind copper and to exhibit a copper-enhanced cytotoxicity, as well as to interact with artificial membranes. The present work is aimed at extending these results by choosing the most representative model of this domain and by determining its copper affinity. With this aim, the different role played by the electrostatic properties of the C- and N-termini of PrP180-193 (VNITIKQHTVTTTT) in determining its conformational behaviour, copper coordination and ability to perturb model membranes was investigated. Owing to the low solubility of PrP180-193, its copper affinity was evaluated by using the shorter PrPAc184-188NH2 (IKQHT) analogue as a model. ESI-MS, ESR, UV/Vis, and CD measurements were carried out on the copper(II)/PrPAc184-188NH2 and copper(II)/PrP180-193NH2 systems, and showed that PrPAc184-188NH2 is a reliable model for the metal interaction with the helix II domain. The affinity of copper(II) for the helix II fragment is higher than that for the octarepeat and PrP106-126 peptides. Finally, the different ability of PrP180-193 analogues to perturb the DPPC model membrane was assessed by DSC measurements. The possible biological consequences of these findings are also discussed briefly.


Lobular Breast Carcinoma Mimicking a Primary Gastric Malignancy.
Invasive lobular carcinoma (ILC) is the second most common subclass of breast cancer and adds to the breast malignancy burden in women. Studies focused on metastatic patterns of ILC have reported bone, gynecologic organs, the peritoneum, and the gastrointestinal tract as potential sites of metastasis. Metastatic spread to the stomach has been reported, but generally remains an infrequent finding. Due to vague symptomatology and the visual limitations of endoscopic examination, metastatic lesions can often mimic a primary gastric malignancy. Metastasis in the stomach can be challenging to diagnose and requires a multimodal, thorough endoscopic and immunohistochemical evaluation. It is important to distinguish the primary origin of malignant lesions as treatment can range from systemic chemotherapy to surgical resection based on the diagnosis. We present a case of an underlying ILC metastatic lesion mimicking a primary gastric adenocarcinoma.


Review: typically-developing students' views and experiences of inclusive education.
The present review aimed to summarize and critique existing qualitative studies that have examined typically-developing students' views of inclusive education (i.e. the policy of teaching students with special educational needs in mainstream settings). Guidelines from the Centre for Reviews and Dissemination were followed, outlining the criteria by which journal articles were identified and critically appraised. Narrative Synthesis was used to summarize findings across studies. Fourteen studies met the review's inclusion criteria and were subjected to quality assessment. Analysis revealed that studies were of variable quality: three were of "good" methodological quality, seven of "medium" quality, and four of "poor" quality. With respect to findings, three overarching themes emerged: students expressed mostly negative attitudes towards peers with disabilities; were confused by the principles and practices of inclusive education; and made a number of recommendations for improving its future provision. A vital determinant of the success of inclusive education is the extent to which it is embraced by typically-developing students. Of concern, this review highlights that students tend not to understand inclusive education, and that this can breed hostility towards it. More qualitative research of high methodological quality is needed in this area. Implications for Rehabilitation Typically-developing students are key to the successful implementation of inclusive education. This review shows that most tend not to understand it, and can react by engaging in avoidance and/or targeted bullying of peers who receive additional support. Schools urgently need to provide teaching about inclusive education, and increase opportunities for contact between students who do and do not receive support (e.g. cooperative learning).


Efficacy of combination therapy for the management regime of Alopecia areata.
Alopecia areata is a world wide cosmetic problem. Cases are seen in Bangladesh. Due to financial constraint and lack of modern facilities the patients of this country needs cheap, easily available and conveniently usable treatment modality. The present study revealed that the oral administration of prednisolone for 06 weeks followed by topical application of 02% minoxidil for another period of 14 weeks is noninvasive and could act as better remedy for alopecia areata. It is claimed that steroid could induce hair growth through immunosuppression rather than a direct effect on hair growth promotion. When applied together steroid it induced regrowing hair gave more encouraging result. The combination therapy indicated that the gradual loss of hair could be minimized and regrowth of hair could be made possible. To fulfill the demand for the best compliance of treatment modality further study should be directed and dictated amongst a large group of population.


Structure of outer membrane protein G by solution NMR spectroscopy.
The bacterial outer membrane protein G (OmpG), a monomeric pH-gated porin, was overexpressed in Escherichia coli and refolded in beta-octyl glucoside micelles. After transfer into dodecylphosphocholine micelles, the solution structure of OmpG was determined by solution NMR spectroscopy at pH 6.3. Complete backbone assignments were obtained for 234 of 280 residues based on CA, CB, and CO connection pathways determined from a series of TROSY-based 3D experiments at 800 MHz. The global fold of the 14-stranded beta-barrel was determined based on 133 long-range NOEs observed between neighboring strands and local chemical shift and NOE information. The structure of the barrel is very similar to previous crystal structures, but the loops of the solution structure are quite flexible.


Esophageal pressure monitoring: a practical adjuvant to hemodynamic monitoring with positive end-expiratory pressure.
With positive end-expiratory pressure (PEEP)-induced reduction in cardiac output, measurement of ventricular filling pressure assists in proper therapeutic decision-making. Because PEEP may increase pleural and juxtacardiac pressure, central venous pressure (CVP) and left atrial pressure (LAP) measurements during PEEP may not simply reflect ventricular filling, but rather reflect the sum of intracardiac and extracardiac forces. Monitoring devices placed within the central circulation use saline solution-filled lumens and transducer systems for pressure monitoring. Therefore, any device designed to estimate the extracardiac influence of PEEP on intraluminal monitoring devices would be expected to reflect such changes best when the device is also filled with saline solution. In the present study, esophageal pressure (Pes) was measured with a saline solution-filled balloon-equipped nasogastric tube to estimate the extracardiac influence of PEEP on CVP and LAP. Pes, CVP, LAP, and cardiac index (CI) were measured in 17 patients subjected to 0, 5, 10, 15, 20 cm H2O PEEP. Comparing 0 with 20 cm H2O PEEP, CVP (7 +/- 1.0 mm Hg to 13.4 +/- 1.3 mm Hg), LAP (6.3 +/- 1.1 mm Hg to 11.7 +/- 1.4 mm Hg), and Pes (6.1 +/- 1.4 mm Hg to 12.1 +/- 1.5 mm Hg) all increased significantly as CI fell (2.72 +/- 0.14 L/min/m2 to 2.20 +/- 0.15 L/min/m2).(ABSTRACT TRUNCATED AT 250 WORDS)


Lost bioscapes: Floristic and arthropod diversity coincident with 12th century Polynesian settlement, Nuku Hiva, Marquesas Islands.
Knowledge of biodiversity in the past, and the timing, nature, and drivers of human-induced ecological change, is important for gaining deep time perspectives and for modern conservation efforts. The Marquesas Islands (Polynesia) are one of the world's most remote archipelagos and illustrate the vulnerability of indigenous bioscapes to anthropogenic activities. Characterised by high levels of endemism across many biotic groups, the full spectrum of the group's flora and fauna is nonetheless incompletely known. Several centuries of Polynesian settlement reshaped biotic communities in ways that are not yet fully understood, and historically-introduced mammalian herbivores have devastated the indigenous lowland flora. We report here on archaeological recovery of a diverse assemblage of plant and arthropod subfossils from a waterlogged deposit on the largest Marquesan island: Nuku Hiva. These materials offer new perspectives on the composition of lowland plant and arthropod communities pene-contemporaneous with human arrival. Bayesian analysis of multiple 14C results from short-lived materials date the assemblages to the mid-12th century AD (1129-1212 cal. AD, 95.4% HPD). Evidence for human activities in the catchment coincident with deposit formation includes Polynesian associated arthropods, microcharcoal, and an adzed timber. Plant macrofossils (seeds, fruits, vegetative structures) and microfossils (pollen, phytoliths) reveal coastal and lowland wet-moist forest communities unlike those observed today. Several apparently extinct taxa are identified, along with extant taxa currently constrained to high altitude and/or interior areas. A diverse inventory of subfossil arthropods-the first pre-18th century records for the islands-includes more than 100 distinct taxa, with several new archipelago records and one previously unreported for eastern Polynesia. The assemblages provide new insights into lowland Marquesan forest communities coincident with human arrival, and portend the considerable anthropogenic transformations that followed. These records also have implications for human colonisation of the Marquesas Islands and East Polynesia at large.


Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study.
Studies in hypertensive patients suggest that ambulatory blood pressure (BP) is prognostically superior to office BP. Much less information is available in the general population, however. Obtaining this information was the purpose of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Office, home, and 24-hour ambulatory BP values were obtained in 2051 subjects between 25 and 74 years of age who were representative of the general population of Monza (Milan, Italy). Subjects were followed up for an average of 131 months, during which time cardiovascular and noncardiovascular fatal events were recorded (n=186). Office, home, and ambulatory BP values showed a significant exponential direct relationship with risk of cardiovascular or all-cause death. The goodness of fit of the relationship was greater for systolic than for diastolic BP and for night than for day BP, but its overall value was not better for home or ambulatory than for office BP. The slope of the relationship, however, was progressively greater from office to home and ambulatory BP. Home and night BP modestly improved the goodness of fit of the risk model when added to office BP. In the PAMELA population, risk of death increased more with a given increase in home or ambulatory than in office BP. The overall ability to predict death, however, was not greater for home and ambulatory than for office BP, although it was somewhat increased by the combination of office and outside-of-office values. Systolic BP was almost invariably superior to diastolic BP, and night BP was superior to day BP.


GENETIC DIVERGENCE IN PERIPHERALLY ISOLATED POPULATIONS OF CHAFFINCHES IN THE ATLANTIC ISLANDS.
Peripherally isolated populations of common chaffinches (Fringilla coelebs) in the Canaries, Madeira, and Azores were compared genetically with their putative ancestral stock in Iberia and Morocco, and with a population of blue chaffinches (F. teydea) from Tenerife, using protein electrophoresis of 42 loci. The continental populations are only weakly differentiated genetically (FST = 0.092), despite distinctive subspecific differences in plumage and morphometrics between Iberia and Morocco populations. Estimated levels of gene flow among continental populations are high enough to account for their relative genetic homogeneity, and it is unlikely that homogenizing selection is operating to mimic the effects of gene flow. In contrast, the Atlantic island populations are well differentiated genetically (FST = 0.321), and have diverged considerably from their continental conspecifics. The development of significant genetic differentiation within the Canaries but not the Azores likely results from smaller population sizes, very restricted gene flow, and enhanced random drift in the former populations. There is no convincing evidence in support of stronger directional selection acting on genotypes or phenotypes to reduce within-population variability in Canaries populations as proposed by Grant (1979), although other tenets of his model of island evolution are supported by our analysis. Although genetic variability is reduced in four of the Canaries populations, only the Hierro population appears to have encountered a severe bottleneck. Yet it has not differentiated markedly from the La Palma population to which it is subspecifically allied. We conclude that gradual divergence in isolated populations of small to moderate size is the most plausible explanation for the evolution of intraspecific and interspecific diversity in Atlantic island chaffinches.


Influence of food intake on the absorption of diftalone in man.
An average 2.2-fold increase in the peak plasma concentrations of the non-steroidal anti-inflammatory agent diftalone in the presence of food was observed in three studies carried out with healthy volunteers who received an oral dose of 0.75 g (6 subjects, study 1), 0.25 g (10 subjects, study II) and 0.5 g (6 subjects, study V) of the compound at 9:00 a.m. both in fasting conditions and after a meal. The effect does not depend on the unusual time (8:00 a.m., selected for experimental needs) at which the subjects were given the meal. In fact, a 2.5-fold increase in plasma concentrations was observed when an oral dose of 0.75 g of diftalone was administered to 2 subjects (study II) both at 8:00 a.m. in fasting conditions and at 1:00 p.m. after a meal. A similar enhancement in the absorption of diftalone was observed when 5 healthy volunteers (study VI) received an oral dose of 0.5 g of the compound both as plain capsules and as capsules containing dry ox bile. However, the absorption of diftalone was not modified when the compound was administered orally as an aqueous suspension or in tensioactive vehicles, or after 20 mg of metoclopramide (study II). Also, the results of a study (IV) on 2 subjects partly deprived of bile after surgery, showed that diftalone does not undergo enterohepatic circulation. The hypothesis that the increase in diftalone absorption is mainly due to bile flow following food intake is supported by all the above experimental results.


Management of Complex Duodenal Injuries After Penetrating Trauma.
Penetrating injuries to the duodenum can present a complex case for trauma or acute care surgeons. The associated injuries and complications can have devastating results. This report presents the case of a 41-year-old male who presented with a gunshot wound to his abdomen and suffered a gastric injury, transverse colon injury, duodenal injury, renal injury, and pancreatic tail injury. In this case, the patient underwent a complex Roux-en-Y reconstruction. The patient had a good outcome and continues to recover at home.


Covalent capture of oriented calix[6]arene rotaxanes by a metal-free active template approach.
We describe the active template effect of a calix[6]arene host towards the alkylation of a complexed pyridylpyridinium guest. The acceleration of the reaction within the cavity is significant and rim-selective, enabling the efficient preparation of rotaxanes with full control of the mutual orientation of their nonsymmetric components.


Apoptosis of autoreactive CD8 lymphocytes as a potential mechanism for the abrogation of type 1 diabetes by islet-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.
The role of TNF-alpha in type 1 diabetes pathogenesis is controversial. Using double transgenic mice expressing (i) the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) as an islet self-antigen and (ii) TNF-alpha under control of a tetracycline-regulated promotor system (tTA) in the pancreatic beta cells, we could previously demonstrate a differential effect of TNF-alpha on the incidence of type 1 diabetes. Most interestingly, late expression of TNF-alpha resulted in a reversion of mice that were already diabetic to a nondiabetic state. Here we provide a model of how experienced autoaggressive CD8 lymphocytes are dying by apoptosis as a result of beta cell-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.


Does harvesting the medial third of the patellar tendon cause lateral shift of the patella after ACL reconstruction?
Many centers do not use the medial third of the patellar tendon as a graft for ACL reconstruction due to the apprehension that there may be post harvest maltracking of the patella towards the lateral side. We undertook a prospective study to evaluate patellar alignment in 30 patients in whom ACL reconstruction was done using the medial third of the patellar tendon. Q-angle assessment was the rough clinical parameter, and the Merchant view, Laurin views, and CT scans were used for radiological assessment. The assessment was done preoperatively and at six months post surgery, and the contralateral normal knees were used as controls. We observed no significant changes in the congruence angle (pre-op -13.86 degrees, postop -12 degrees) or the lateral patellofemoral angles in the pre-operative and postoperative knees as compared to the controls. CT scans were more sensitive for evaluating the congruence angles, and picked up an insignificant abnormal lateralisation of the patella in four cases. None of these patients however had any postoperative symptoms of misalignment. Although medial third graft harvesting did have a 13% change in patellar alignment, this was not statistically significant. Post harvesting local problems are inherent to the procedure, and are independent of the site of harvesting, as they were also seen in cases with no evidence of misalignment.


Desiccation survival of populations of the entomopathogenic nematodes Steinernema feltiae and Heterorhabditis megidis from Greece and the UK.
The desiccation survival and ability to control water loss during drying of individual infective juveniles (IJs) of populations of Steinernema feltiae and Heterorhabditis megidis from Greece and the UK were examined at different relative humidities. Survival at all relative humidities was for minutes only and there was no evidence of enhanced survival of the populations of either species from Greece compared with those from the UK. The survival of individuals of both populations of H. megidis was superior to that of S. feltiae and the rate of drying of H. megidis was significantly slower. The sheath surrounding the IJs of H. megidis appears to be involved in slowing the rate of water loss of the enclosed nematodes.


Food quality and the risk of light exposure affect patch-choice decisions in the slime mold Physarum polycephalum.
How individuals deal with multiple conflicting demands is an important aspect of foraging ecology, yet work on foraging behavior has typically neglected neurologically simple organisms. Here we examine the impact of an abiotic risk (light) and energetic status on the foraging decisions of a protist, the slime mold Physarum polycephalum. We examined patch choice in a "non-risky" environment by presenting starved and non-starved P. polycephalum amoebas with a choice between two shaded food patches (one high quality, one low quality). We next examined patch choice in the presence of a conflict between foraging risk (light exposure) and food quality by presenting amoebas with a choice between a shaded, low-quality patch, and a light-exposed, high-quality patch. When both patches were shaded, 100% of amoebas selected the higher quality food patch, irrespective of food-quality differences or the individual's energetic status. When light exposure and food quality conflicted, amoebas selected the patch with the higher food quality when the quality difference between the patches was high. When the quality difference between patches was small, amoebas selected the shaded, lower quality patch.


The pattern of gastroesophageal reflux in asthmatic children.
The association between gastroesophageal reflux (GER) and asthma is not fortuitous. The objective of our study was to test a group of children with asthma by, 24 hr gastroesophageal pH monitoring and to relate the results to the patients medical history and clinical data. We studied 77 children aged from 39 to 170 months suffering from particularly recurrent and/or therapy-resistant asthma. Medical history data were collected for each patient and included: severity and characteristics of respiratory symptoms, presence, if any of allergy; presence, if any, of GER-related symptoms; and presence, if any, of esophagitis-related symptoms. Esophageal pH was measured by 24 hr computerized monitoring of the main measures in all patients. Forty-seven children were also examined by gastroesophageal endoscopy. The prevalence of GER was 61% on the basis of the reflux index (cutoff: 4.2%). Gastroesophageal reflux in these asthmatic children was characterized mainly by short-lasting daytime episodes. The patients tended to present GER mainly associated with vomiting but not with signs and symptoms of esophagitis. The short-lasting nature of the reflux episodes demonstrates good esophageal clearance. The time of onset of respiratory symptoms (day/night) was not associated with any particular type of GER, the severity of which tends to be proportional to the seriousness of the asthma. No correlation was found between GER and allergy. No statistically significant differences were found in clinical or medical history findings between patients with pathologic and nonpathologic GER.


Adenovirus-mediated HSV-TK gene therapy using the human telomerase promoter induced apoptosis of small cell lung cancer cell line.
Telomerase is a ribonucleoprotein complex the function of which is to add telomeric repeats (TTAGGG)n to chromosomal ends, and it is known to play an important role in cellular immortalization. Telomerase is highly active in most tumor cells, but not in normal cells. As such, it may have possible applications in cancer gene therapy. Telomerase consists of two essential components, telomerase RNA template (hTR) and catalytic subunit (hTERT). hTERT is expressed only in cells and tissues positive for telomerase activity, i.e., tumor and fetal cells. We tested the possibility of the utilization of the hTERT promoter in targeted cancer gene therapy. We cloned the hTERT promoter in the place of the CMV promoter and sub-cloned HSV-TK gene to be controlled by hTERT gene promoter in adenovirus shuttle plasmid. Then we constructed recombinant adenovirus Ad-hT-TK, and infected them into a normal and a small cell lung cancer cell line. Through these experiments, we identified the selective tumor specific cell death by Ad-hT-TK. Furthermore, cell death detection ELISA and FACS analysis suggest that the reduced viability is mediated through the induction of apoptosis, indicating that this approach may be a useful method for suppressing cancer growth in targeted cancer gene therapy. These results show that Ad-hT-TK could be used for SCLC gene therapy.


Long-range Regulation of Partially Folded Amyloidogenic Peptides.
Neurodegeneration involves abnormal aggregation of intrinsically disordered amyloidogenic peptides (IDPs), usually mediated by hydrophobic protein-protein interactions. There is mounting evidence that formation of α-helical intermediates is an early event during self-assembly of amyloid-β42 (Aβ42) and α-synuclein (αS) IDPs in Alzheimer's and Parkinson's disease pathogenesis, respectively. However, the driving force behind on-pathway molecular assembly of partially folded helical monomers into helical oligomers assembly remains unknown. Here, we employ extensive molecular dynamics simulations to sample the helical conformational sub-spaces of monomeric peptides of both Aβ42 and αS. Our computed free energies, population shifts, and dynamic cross-correlation network analyses reveal a common feature of long-range intra-peptide modulation of partial helical folds of the amyloidogenic central hydrophobic domains via concerted coupling with their charged terminal tails (N-terminus of Aβ42 and C-terminus of αS). The absence of such inter-domain fluctuations in both fully helical and completely unfolded (disordered) states suggests that long-range coupling regulates the dynamicity of partially folded helices, in both Aβ42 and αS peptides. The inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in partially folded helical monomers. This approach could be applied to study the broad range of amyloidogenic peptides, which could provide a new path to curbing pathogenic aggregation of partially folded conformers into oligomers, by inhibition of sites far from the hydrophobic core.


Musculoskeletal ultrasound: applications in the hip.
This article illustrates how ultrasound (US) can be useful in the evaluation of painful hips. For an experienced examiner using high quality equipment, US is the imaging test of choice for tendon abnormalities, hernias, bursitis, and dynamic abnormalities such as extra-articular snapping hip. Ultrasound is also useful in screening for hip effusions and guiding diagnostic and therapeutic interventions. Ultrasound has a complementary role to magnetic resonance imaging (MRI) for labral pathology, although MRI or MR arthrography is preferable for most intra-articular pathologies. It is better tolerated, less expensive, and more readily available than MRI, and as US technology continues to improve, its role in hip imaging should grow.


Characterization of the effects of charged residues in the intracellular loop on ion permeation in alpha1 glycine receptor channels.
The Cys loop receptor channels mediate fast synaptic transmission in the nervous system. The M2-demarcated transmembrane pore is an important determinant of their ion permeation properties. Portals within the intracellular domain are also part of the permeation pathway in cationic Cys loop receptors, with charged residues in a helical MA stretch partially lining these openings profoundly affecting channel conductance. It is unknown whether analogous portals contribute to the permeation pathway in anionic Cys loop receptors. We therefore investigated the influence of charged residues within the proposed MA stretch on functional properties of the homomeric glycine alpha1 receptor. Up to eight basic residues in the MA stretch were concurrently mutated to a negatively charged glutamate, and wild-type and mutant subunits were expressed in HEK-293 cells. Mutation of all eight residues produced a non-functional receptor. The greatest reduction in conductance at negative membrane potentials (from 92.2+/-2.8 to 60.0+/-2.2 picosiemens) was observed with glutamate present at the 377, 378, 385, and 386 positions (the 4E subunit). Inclusion of additional glutamate residues within this subunit did not decrease conductance further. Neutralizing these residues (the 4A subunit) caused a modest decrease in conductance (80.5+/-2.3 picosiemens). Outward conductance at positive potentials was not markedly affected. Anion to cation selectivity and concentration-response relationships were unaffected by the 4A or 4E mutations. Our results identify basic residues affecting conductance in the glycine receptor, suggesting that portals are part of the extended permeation pathway but that the M2-demarcated channel pore is the dominant determinant of permeation properties in glycine receptors.


[Role of procalcitonin in the diagnosis of ventilator-associated pneumonia].
To evaluate the diagnostic value of procalcitonin (PCT) in ventilator-associated pneumonia (VAP). Prospective study was performed. All adult patients who were admitted into the intensive care unit (ICU) of West China Hospital of Sichuan University between June 1st and October 1st and were clinically suspected of having developed VAP after 48 hours of mechanical ventilation were enrolled. Patients who had active infection or lung cancer at ICU admission or developed extrapulmonary infection during the study period were excluded. PCT and C-reactive protein (CRP) levels were measured and the clinical pulmonary infection score (CPIS) was calculated at study entry and on the day of VAP suspicion. In total, 49 suspected episodes of VAP in 31 cases were microbiologically confirmed in 23 and refuted in 26. Median PCT levels were 0.68 microg/L (interquartile range 0.28, 2.31) and 0.18 microg/L (0.06, 0.28) respectively in patients with and without VAP on the suspicion day (P<0.01). Using 0.31 microg/L as the best cutoff, PCT had 73.9% sensitivity and 80.8% specificity. The CPIS resulted in higher sensitivity (95.7%) but lower specificity (53.8%) when the cutoff of CPIS > or = 5. CRP had the lowest sensitivity and specificity (56.5%, 61.5%) when the cutoff of CRP was 109.5 mg/L. A CPIS > or = 5 combined with serum levels of PCT > or = 0.31 microg/L did not improve the sensitivity (69.6%), but resulted in 88.5% specificity. PCT had better specificity than CRP and CPIS in early diagnosis of VAP. Combined values of PCT and CPIS below the cut-off points could effectively exclude false-positive diagnosis of VAP.


Hydroxamic Acids as Chemoselective (ortho-Amino)arylation Reagents via Sigmatropic Rearrangement.
The use of readily available hydroxamic acids as reagents for the chemoselective (ortho-amino)arylation of amides is described. This reaction proceeds under metal-free, mild conditions, displays a very broad scope, and constitutes a direct approach for the metal-free attachment of aniline residues to carbonyl derivatives.


Pulse versus oral methylprednisolone therapy in pemphigus vulgaris.
Although corticosteroids have dramatically altered the prognosis of patients with pemphigus vulgaris, morbidity and mortality from systemic corticosteroid side-effects remains high. High-dose intravenous methylprednisolone has been used successfully in blistering diseases to avoid the complications of long-term orally-administered glucocorticoids. The objective of this study was to compare the effectiveness and side-effects of oral and pulse steroid therapy in the treatment of pemphigus vulgaris. One hundred and twenty-three patients with pemphigus vulgaris were categorized into two groups of study and control according to the disease severity and patient's preferred method of treatment. The study group included 36 males and 36 females. The control group included 26 males and 25 females. The mean +/- SD age of the two groups was 42.6 +/- 11.9 and 46.9 +/- 12.8 years, respectively. The mean +/- SD duration of the disease was 6.8 +/- 1.1 months in new cases (n = 45) and 25.9 +/- 26.0 months overally in the study group; it was 7.2 +/- 1.8 months in new cases (n = 30) and 28.4 +/- 24.6 months overally in the control group. During the induction phase, we performed pulse therapy with methylprednisolone in three consecutive monthly courses. Each course included 1000 mg intravenous methylprednisolone for 4 days plus 500 mg intravenous cyclophosphamide for 1 day. In this phase, the control group received 1 - 2 mg/kg/day oral prednisolone for 28 days plus 1.5 mg/kg/day azathioprine. All patients were followed for at least 12 months during which period, clinical response, relapse rate, and side-effects were evaluated. Pulse intravenous methylprednisolone with cyclophosphamide was generally safe and well-tolerated. Therapeutic responses of skin and mucosal lesions, rates of complete remission and relapse, and major organ-specific complications were similar in both groups. Significant statistical differences existed in total orally-administered prednisolone in one year, admission duration, and annual weight increments between the two groups (P < 0.05). Considering the side-effects of long-term oral steroids, hazards of obesity, and complications of long-term hospitalization, pulse methylprednisolone could be considered in patients who have problems with long-term admissions or with high-dose oral steroid usage, and also in obese patients.


Innate allorecognition by monocytic cells and its role in graft rejection.
Innate recognition of microbial products and danger molecules by monocytes and macrophages has been well established; this is mediated primarily by pattern-recognition receptors and is central to the activation of innate and adaptive immune cells required for productive immunity. Whether monocytes and macrophages are equipped with an allorecognition system that allows them to respond directly to allogeneic grafts is a topic of much debate. Recent studies provide compelling evidence that these cells can recognize allogeneic entities and that they mediate graft rejection via direct cytotoxicity and priming of alloreactive T cells. In addition, these studies have uncovered a mechanism of innate allorecognition based on detection of the polymorphic molecule signal regulatory protein α (SIRPα) on donor cells. Further understanding of innate allorecognition and its consequences would provide essential insight into allograft rejection and lead to better therapies for transplant patients.


Haven't we met before? Don't call it a merger--a spate of new joint operating agreements may spark '90s deja vu, but it's different now, executives say.
While a legal ruling in 2000 put a damper on joint operating agreements, hospital officials are again testing the waters. Systems or hospitals in Georgia, Maine, New York and Wisconsin are all looking at some kind of cooperation. "There are a lot more conversations occurring again between organizations, between health systems," says William Petasnick, left. "Some of this is a reflection of times changing again."