Synthesis and muscarinic activity of quinuclidinyl- and (1-azanorbornyl)pyrazine derivatives.
The synthesis and cortical muscarinic activity of a novel series of pyrazine-based agonists is described. Quinuclidine and azanorbornane derivatives were prepared either by reaction of lithiated pyrazines with azabicyclic ketones, followed by chlorination and reduction, or by reaction of the lithium enolate of the azabicyclic ester with 2-chloropyrazines followed by ester hydrolysis and decarboxylation. Substitution at all three positions of the heteroaromatic ring has been explored. Optimal muscarinic agonist activity was observed for unsubstituted pyrazines in the azanorbornane series. The exo-1-azanorbornane 18a is one of the most efficacious and potent centrally active muscarinic agonists known. Studies on the 3-substituted derivatives have provided evidence of the preferred conformation of these ligands for optimal muscarinic activity. Substitution at C6 gave ligands with increased affinity and reduced efficacy. Moving the position of the diazine ring nitrogens to give pyrimidine and pyridazine derivatives resulted in a significant loss of muscarinic activity.


Synthesis and characterization of CdIn(2)S(4) nanorods by converting CdS nanorods via the hydrothermal route.
The ternary semiconductor CdIn(2)S(4) nanorods were synthesized by a method based on CdS nanorods via the hydrothermal route, in which CdS nanorods were converted by reaction with InCl(3) and thiourea in aqueous solution. Transmission electron microscopy (TEM) images revealed that the typical sizes of the CdIn(2)S(4) nanorods were 10-30 nm in diameter and 200-1000 nm in length. X-ray photoelectron spectra (XPS) analysis of the surface stoichiometry (CdIn(2.03)S(4.15)) and room-temperature Raman spectrum (RS) were recorded. The influences of reaction temperature, time, and sulfur sources on the formation for CdIn(2)S(4) nanorods were investigated. A possible formation mechanism of the CdIn(2)S(4) nanorods was also proposed.


[Arthroscopy of the ankle].
Technical advances have facilitated the use of arthroscopic surgery, converting it into a useful technique for the treatment and diagnosis of diverse ankle pathologies. Ankle arthroscopia represents a greater challenge than other arthroscopic operations due to the anatomical limitations involved. This article reviews the equipment and techniques used for this procedure.


Composition of the microbiota in forestomach fluids and feces of Japanese Black calves with white scours.
The objective of this study was to characterize the composition of the forestomach and fecal microbiota in Japanese Black calves with white scours. Forestomach fluid, feces, and peripheral blood were collected from healthy calves ( = 5; age 10 ± 2 d) and scouring calves ( = 5; age 10 ± 1 d) on the day on which white scours occurred. The pH and concentrations of VFA, lactic acid, and ammonia nitrogen (NH-N) of the forestomach fluids were determined. Microbiota composition and gene copy numbers in the forestomach fluid and feces were analyzed by 454 pyrosequencing and quantitative real-time PCR (qPCR), respectively. The cytokine mRNA level in peripheral leukocytes was evaluated by qPCR. The pH of the forestomach fluid of the scouring calves tended to be higher than that of the healthy calves ( = 0.056). No significant difference was detected in the total VFA, lactic acid, or NH-N concentrations in the forestomach fluids of the 2 groups. Firmicutes, Bacteroidetes, and Proteobacteria were the predominant phyla in the forestomach fluid and feces. At the genus level, the relative abundance of in the forestomach fluid was significantly higher in the scouring calves ( < 0.05) and the relative abundance of in the feces was significantly higher than that in the forestomach in the healthy calves ( < 0.05). Furthermore, the bacterial diversity indices of feces were lower in the scouring calves. Quantitative PCR amplification using some of the primer pairs failed in the forestomach fluid and feces in both groups. These results suggested that fermentation in the forestomach may affect the occurrence of white scours, resulting in changes in the composition and diversity of the forestomach fluid and fecal microbiota in Japanese Black calves.


Language XX: What shall it be called and why does it matter?
Terms suggested for unexpected language learning difficulty include specific language impairment, primary language disorder and language learning disability; however, none of them represents the critical element of literacy. Some experts have suggested that debating what to call language disorders is parallel to debating what to call reading disorders and dyslexia. In contrast, it is argued here that reading disorders are language disorders and not separate or parallel. Evidence is presented for quadrant models that explain language disorders and dyslexia along two dimensions-sound/word level (phonological) knowledge and sentence/discourse level (non-phonological) knowledge. Support for these two dimensions comes from factor analysis of a new assessment tool called the Test of Integrated Language and Literacy Skills (TILLS). Two case studies illustrate how a quadrant model can be used to explain patterns of abilities that vary along these two dimensions to parents and teachers. The article concludes with a recommendation to adopt a label that reflects language/literacy commonalities rather than differences, such as language/literacy disorder or specific language/literacy impairment.


Successful treatment of severe extremity pain in myelofibrosis with low-dose single-fraction radiation therapy.
Myelofibrosis (MF) is characterized by cytopenias/cytoses, leukoerythroblastic blood picture, bone marrow fibrosis, and extramedullary hematopoiesis. Extremity bone pain can be a feature of MF. There has been one case report of a patient with MF and bone pain treated with radiation. We treated five patients with MF and extremity pain with radiation at our institution between 2004 and 2010. All patients had severe pain unresponsive to narcotic medication. Radiation was one fraction of 100 to 600 cGy. Most patients saw improvement in the pain within days and achieved a complete response within days to weeks.The response lasted between 1 month and 2 years. Retreatment was performed in four patients and achieved a durable response in three patients. No patients reported any acute or late side effects from radiation.Bone involvement in MF can cause disabling pain, but single-fraction low-dose radiation is a safe and effective treatment, often leading to a durable response. Retreatment is also safe and effective inpatients who experience recurrent pain.


High throughput screening against the peroxidase cascade of African trypanosomes identifies antiparasitic compounds that inactivate tryparedoxin.
In African trypanosomes, the detoxification of broad spectrum hydroperoxides relies on a unique cascade composed of trypanothione (T(SH)(2)), trypanothione reductase, tryparedoxin (Tpx), and nonselenium glutathione peroxidase-type enzymes. All three proteins are essential for Trypanosoma brucei. Here, we subjected the complete system to a high throughput screening approach with nearly 80,000 chemicals. Twelve compounds inhibited the peroxidase system. All but one carried chloroalkyl substituents. The detailed kinetic analysis showed that two compounds weakly inhibited trypanothione reductase, but none of them specifically interacted with the peroxidase. They proved to be time-dependent inhibitors of Tpx-modifying Cys-40, the first cysteine of its active site WCPPC motif. Importantly, gel shift assays verified Tpx as a target in the intact parasites. T(SH)(2), present in the in vitro assays and in the cells in high molar excess, did not interfere with Tpx inactivation. The compounds inhibited the proliferation of bloodstream T. brucei with EC(50) values down to <1 μM and exerted up to 83-fold lower toxicity toward HeLa cells. Irreversible inhibitors are traditionally regarded as unfavorable. However, a large number of antimicrobials and anticancer therapeutics acts covalently with their target protein. The compounds identified here also interacted with recombinant human thioredoxin, a distant relative of Tpx. This finding might even be exploited for thioredoxin-based anticancer drug development approaches reported recently. The fact that the T(SH)(2)/Tpx couple occupies a central position within the trypanosomal thiol metabolism and delivers electrons also for the synthesis of DNA precursors renders the parasite-specific oxidoreductase an attractive drug target molecule.


Readministration of high-dose methotrexate in a patient with suspected immediate hypersensitivity and T-cell acute lymphoblastic lymphoma.
There is a paucity of literature addressing the management of methotrexate (MTX) hypersensitivity. We developed a high-dose MTX readministration protocol based on a modified, prolonged carboplatin desensitization protocol. Over 1.5 hours, 1/1000 of the total intravenous dose was administered followed by 1/100 over 1.5 hours, 1/10 over 6 hours, and the rest of the full dose over 24 hours. MTX readministration was successfully tolerated on three occasions in a 17-year-old male patient with T-cell acute lymphoblastic lymphoma and a history of urticarial reactions to MTX. This high-dose MTX readministration protocol may be valuable for treating patients with T-cell acute lymphoblastic lymphoma and suspected immediate MTX hypersensitivity.


Endoscopic harvest of four muscle flaps: safe and effective techniques.
The recent explosion of endoscopic techniques in plastic surgery has led to the successful harvest of a number of useful muscle flaps. The gracilis, rectus femoris, external oblique, and gastrocnemius muscles can all be harvested safely and reproducibly using endoscopic techniques. The aim of this study was to identify a safe and effective technique for endoscopic muscle flap harvest. Harvesting the gracilis muscle as a free flap and the gastrocnemius as a pedicle flap lends themselves best to the use of endoscopic techniques.


A comparison of knee kinetics between male and female recreational athletes in stop-jump tasks.
We compared the knee kinetics of 10 male and 10 female recreational athletes (aged 19 to 25 years) performing forward, vertical, and backward stop-jump tasks. Three-dimensional videography and force plate data were used to record the subjects' performance of the three stop-jump tasks, and an inverse dynamic procedure was used to estimate the knee joint resultant forces and moments. Women exhibited greater proximal anterior shear force than did men during the landing phase. All subjects exhibited greater proximal tibia anterior shear force during the landing phase of the backward stop-jump task than during the other two stop-jump tasks. Women also exhibited greater knee extension and valgus moments than did men during the landing phase of each stop-jump task. Men exhibited greater proximal tibia anterior shear force than did women during the takeoff phase of vertical and backward stop-jump tasks. These results indicate that female recreational athletes may have altered motor control strategies that result in knee positions in which anterior cruciate ligament injuries may occur. The landing phase was more stressful for the anterior cruciate ligament of both women and men than the takeoff phase in all stop-jump tasks. Technical training for female athletes may need to be focused on reducing the peak proximal tibia anterior shear force in stop-jump tasks. Further studies are needed to determine the factors associated with the increased peak proximal tibia anterior shear force in female recreational athletes.


14-3-3 binding to the IGF-1 receptor is mediated by serine autophosphorylation.
The phosphoserine-binding 14-3-3 proteins have been implicated in playing a role in mitogenic and apoptotic signaling pathways. Binding of 14-3-3 proteins to phosphoserine residues in the C-terminus of the insulin-like growth factor-1 receptor (IGF-1R) has been described to occur in a variety of cell systems, but the kinase responsible for this serine phosphorylation has not been identified yet. Here we present evidence that the isolated dimeric insulin-like growth factor-1 receptor kinase domain (IGFKD) contains a dual specific (i.e. tyrosine/serine) kinase activity that mediates autophosphorylation of C-terminal serine residues in the enzyme. From the total phosphate incorporation of approximately 4 mol per mol kinase subunit, 1 mol accounts for serine phosphate. However, tyrosine autophosphorylation proceeds more rapidly than autophosphorylation of serine residues (t(1/2) approximately 1 min vs. t(1/2) approximately 5 min). Moreover, dot-blot and far-Western analyses reveal that serine autophosphorylation of IGFKD is sufficient to promote binding of 14-3-3 proteins in vitro. The proof that dual kinase activity of IGFKD is necessary and sufficient for 14-3-3 binding was obtained with an inactive kinase mutant that was phosphorylated on serine residues in a stoichiometric reaction with the catalytically active enzyme. Thus, the IGF-1R itself might be responsible for the serine autophosphorylation which leads to recognition of 14-3-3 proteins in vivo.


Cancer cachexia as a determinant of efficacy of first-line pembrolizumab in patients with advanced non-small cell lung cancer.
Pembrolizumab, either as a type of monotherapy or in combination with cytotoxic anticancer agents, is effective in the treatment of advanced non-small cell lung cancer (NSCLC). However, the development of cancer cachexia may adversely affect anticancer drug therapy. The present study investigated the effect of cancer cachexia on clinical outcomes in patients with advanced NSCLC who received first-line pembrolizumab. The data of patients with advanced NSCLC receiving first-line monotherapy or combination therapy with pembrolizumab were retrospectively analyzed. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and incidence of adverse events (AEs). Clinical outcome was compared between patients with and without cancer cachexia. A total of 53 patients were analyzed. Among all patients, median TTF and OS were significantly shorter in patients with cancer cachexia than in those without [TTF: 5.8 vs. 10 months; hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.07-4.24; P=0.016; OS: 12.1 months vs. not reached; HR: 5.85; 95% CI: 2.0-17.1; P=0.001]. In addition, TTF in the pembrolizumab monotherapy group was significantly shorter in patients with cancer cachexia than in those without, but no significant difference was detected in patients receiving pembrolizumab combination therapy. The incidence of AEs did not significantly differ between patients with and without cancer cachexia, except with regard to hypothyroidism. In conclusion, although cancer cachexia is prognostic of a poor outcome in patients with advanced NSCLC who receive first-line pembrolizumab, cancer cachexia might not affect therapeutic efficacy in combination therapy with pembrolizumab and cytotoxic anticancer agents.


Polar localizing class V myosin chitin synthases are essential during early plant infection in the plant pathogenic fungus Ustilago maydis.
Fungal chitin synthases (CHSs) form fibers of the cell wall and are crucial for substrate invasion and pathogenicity. Filamentous fungi contain up to 10 CHSs, which might reflect redundant functions or the complex biology of these fungi. Here, we investigate the complete repertoire of eight CHSs in the dimorphic plant pathogen Ustilago maydis. We demonstrate that all CHSs are expressed in yeast cells and hyphae. Green fluorescent protein (GFP) fusions to all CHSs localize to septa, whereas Chs5-GFP, Chs6-GFP, Chs7-yellow fluorescent protein (YFP), and Myosin chitin synthase1 (Mcs1)-YFP were found at growth regions of yeast-like cells and hyphae, indicating that they participate in tip growth. However, only the class IV CHS genes chs7 and chs5 are crucial for shaping yeast cells and hyphae ex planta. Although most CHS mutants were attenuated in plant pathogenicity, Deltachs6, Deltachs7, and Deltamcs1 mutants were drastically reduced in virulence. Deltamcs1 showed no morphological defects in hyphae, but Mcs1 became essential during invasion of the plant epidermis. Deltamcs1 hyphae entered the plant but immediately lost growth polarity and formed large aggregates of spherical cells. Our data show that the polar class IV CHSs are essential for morphogenesis ex planta, whereas the class V myosin-CHS is essential during plant infection.


Retrospective evaluation of the effects and outcome of bromethalin ingestion: 192 Dogs (2010-2016).
To evaluate the frequency of clinical signs, dose ingested, and outcome in a large group of dogs with bromethalin ingestion. Retrospective cohort study of dogs from 2010 to 2016. Three university teaching hospitals and 1 private practice. A total of 192 dogs with bromethalin ingestion. Total 192 cases were identified, of which 25 dogs developed clinical signs. Five cases initially had severe neurological signs and were euthanized. A sum of 187 dogs survived to discharge. The total ingested dose was recorded in 59 dogs with a median (interquartile range) 0.2 mg/kg (0.28 mg/kg). The remaining 133 dogs had confirmed ingestion reported by owners (witnessed ingestion or colored feces) but the total dose could not be calculated. The median (interquartile range) time to presentation for all dogs was 2 hours (4.8 h). A majority of patients were treated on an outpatient basis (121/192) and 71 of 192 were treated as inpatients with 58 of 71 receiving fluid diuresis. Decontamination was performed in 179 dogs including emesis induction (14), activated charcoal administration (42), and both (123). Emesis was successful in 128 dogs and apomorphine was the most common emetic agent (121). Mild to severe clinical signs at admission were reported in 19 cases including vomiting (6), tremors (5), lethargy (4), ataxia (3), weakness (2), diarrhea (2), collapse (2), and and anorexia (2). One case developed ataxia and tremors within 72 hours of admission. Symptoms of bromethalin toxicosis are uncommon, and most ingested doses are well below the reported dose expected to cause clinical signs. In this patient population, prognosis was excellent unless severe clinical signs were noted, which carried a high euthanasia rate. Effects of treatment on outcome could not be evaluated due to the low number of patients that developed clinical signs.


Clinical and microbiological features of bacteraemia with Aerococcus urinae.
Aerococcus urinae is a Gram-positive bacterium that can cause invasive infection, including infectious endocarditis (IE), mainly in older men. A. urinae is often misclassified in routine diagnostic laboratories. Through searches in the laboratory databases we identify 16 isolates of A. urinae causing bacteraemia during a 6-year period in southern Sweden, indicating that bacteraemia with A. urinae occurs in at least three cases per million inhabitants per year. The identity of isolates was confirmed by sequencing of the 16S rRNA genes and antibiotic susceptibility testing identified two ciprofloxacin-resistant isolates. A. urinae was the only significant pathogen isolated in all cases. Fifteen of the 16 patients were male, 15/16 were more than 70 years old, and 12/16 had underlying urological conditions. Though a urinary tract focus was suspected in the majority of cases, the bacterium was rarely found in urinary samples. Nine patients fulfilled the criteria for severe sepsis and an additional four fulfilled the criteria for sepsis. Only one fatality was recorded. Patients were treated mainly with beta-lactam antibiotics but fluoroquinolones and clindamycin were also used. Three cases of IE were diagnosed and these were complicated by spondylodiscitis in one case and by septic embolization to the brain in one case. An increased awareness of A. urinae is crucial to establishing its role as an important pathogen in older men with urinary tract disease.


Application of circularly polarized light for non-invasive diagnosis of cancerous tissues and turbid tissue-like scattering media.
Polarization-based optical techniques have become increasingly popular in the field of biomedical diagnosis. In the current report we exploit the directional awareness of circularly and/or elliptically polarized light backscattered from turbid tissue-like scattering media. We apply circularly and elliptically polarized laser light which illuminates the samples of interest, and a standard optical polarimeter is used to observe the polarization state of light backscattered a few millimeters away from the point of incidence. We demonstrate that the Stokes vector of backscattered light depicted on a Poincaré sphere can be used to assess a turbid tissue-like scattering medium. By tracking the Stokes vector of the detected light on the Poincaré sphere, we investigate the utility of this approach for characterization of cancerous and non-cancerous tissue samples in vitro. The obtained results are discussed in the framework of a phenomenological model and the results of a polarization tracking Monte Carlo model, developed in house. Schematic illustration of the experimental approach utilizing circularly and elliptically polarized light for probing turbid tissue-like scattering media.


Role of scavenger receptor MARCO in macrophage responses to CpG oligodeoxynucleotides.
The macrophage Class A scavenger receptor MARCO (macrophage receptor with a collagenous structure) functions as a pattern-recognition receptor for bacterial components, but its role in responses to CpG oligonucleotide sequences (CpG-ODN) in microbial DNA has not been characterized. Phosphorothioate (PS)-linked CpG-ODN stimulated IL-12 and NO production in wild-type but not in MARCO-deficient, thioglycollate-elicited peritoneal macrophages. MARCO and the related class A receptor SR-A belong to a redundant system of receptors for PS ODNs. The ability of MARCO to bind CpG-ODNs and conversely, to costimulate IL-12 and NO production upon specific ligation with immobilized mAb is consistent with MARCO being a signaling receptor for CpG-ODNs, costimulating TLR9-mediated NO and IL-12 production in macrophages. In contrast to MARCO, SR-A is likely to mediate negative regulation of macrophage responses to CpG-ODNs. In particular, increased affinity toward SR-A may contribute to decreased potency of oligo G-modified CpG-ODNs in stimulating IL-12 production. The results suggest that differential involvement of activating and inhibitory membrane receptors, such as SR-A and MARCO, may underlie profound differences observed in biological activities of different ODN sequences.


Combined microwave ablation and antiangiogenic therapy to increase local efficacy.
Purpose: We aim to evaluate the efficacy, safety and survival time of microwave ablation (MWA) with adjuvant antiangiogenic therapy-endostatin in animal models.Material and methods: A total of 40 rabbits successfully implanted with VX2 tumors were randomly assigned to four experimental groups: Group A underwent only microwave ablation of the tumors; Group B received only antiangiogenic drugs endostatin; Group C received endostatin immediately after MWA; Group D followed up without treatment.Results: Two months post-treatment, tumor sizes of Group A and Group C were reduced to 1.936 ± 0.373 cm3 and 1.592 ± 0.382 cm3, respectively. However, tumors grew to 15.091 ± 1.735 cm3 and 47.825 ± 7.664 cm3 in Group B and the control group. Three months post-treatment, tumor sizes in Group A and Group C maintained as 1.395 ± 0.394 cm3 and 1.482 ± 0.305 cm3, significantly smaller than Group B (35.277 ± 6.019 cm3). All animals in the control group died, while four (40%) survived in Group B (Endo Group). The numbers of survivals in Groups A and C were seven (70%) and eight (80%), respectively. The lowest metastasis rate (2/10, 20%) was observed in Group C (combination therapy).Conclusion: The combination of MWA and antiangiogenic therapy triggered a significant reduction in the growth rate and metastases of tumors and may potentially improve survivals.


[Quality assurance for the measured values and quality control].
It is essential for us to build a liable quality control system in order to report excellent results assured of quality. For the purpose, not only the execution of quality control on laboratory side but also the recognition of quality control on clinical side are important. And more important matter is to record the error of measured values.


[Comparison of the mean deviation of retinal sensitivity in the static perimetry threshold test with biomorphometric parameters of the optic disc in eyes with glaucoma].
The aim of the study is to evaluate results of mean deviation of retinal sensitivity obtained in static perimetry threshold test in glaucoma simplex eyes and to compare them with some biomorphometric parameters of the optic disc measured with scanning laser ophthalmoscope. The analysis was performed with the results obtained in 50 glaucomatous eyes with the disease lasting 4 to 15 years. The mean values of mean deviation, cup to disc ratio, mean cup depth and neuroretinal rim area were 6.71, 0.459, 0.031 and 1.464, respectively. The best correlation coefficient value (0.847) was found between mean deviation and neuroretinal rim area. The results confirm the importance of neuroretinal rim area value in evaluation of optic disc in glaucoma cases.


Cyclooxygenase-2 and atherosclerosis.
Cyclooxygenase regulates the production of eicosanoids, which modulate physiologic processes in the vessel wall contributing to atherosclerosis and thrombosis, including platelet aggregation, control of vascular tone, and the local inflammatory response. Cyclooxygenase-1 mediates production of platelet thromboxane A(2), a potent vasoconstrictor and platelet agonist, whereas both cyclooxygenase 1 and 2 contribute to production of endothelial prostacyclin, a vasodilator that inhibits platelet activation. Concerns have been raised that cyclooxygenase-2 inhibitors may increase thrombotic cardiovascular events by disturbing the balance between platelet thromboxane A(2) and endothelial prostacyclin, but this controversial issue will only be resolved by prospective clinical trials. Because cyclooxygenase-2 is upregulated in activated monocyte/macrophages, which play a key role in the pathogenesis of atherosclerosis, we have recently tested the hypothesis that pharmacological inhibition of cyclooxygenase-2 in LDL-receptor deficient mice would reduce early atherosclerosis. After 6 weeks on a Western-type diet, male LDL-receptor deficient mice treated with either rofecoxib (a selective cyclooxygenase-2 inhibitor) or indomethacin (a non-selective cyclooxygenase inhibitor) had significant reductions in atherosclerosis when compared with control mice. Also, LDL-receptor deficient mice null for macrophage cyclooxygenase-2 were generated by fetal liver cell transplantation and developed significantly less atherosclerosis than control LDL-receptor deficient mice transplanted with fetal liver cells wildtype for cyclooxygenase-2, providing genetic evidence in support of a proatherogenic role for macrophage cyclooxygenase-2 expression. These results support the potential of antiinflammatory approaches for the prevention of atherosclerosis and identify cyclooxygenase-2 as a target for intervention.


Children's reading of words, pseudohomophones, and other nonwords.
In Experiment 1 children aged 8-9 and 9-10 years were tested for neighbourhood and pseudohomophone effects in nonword reading. Neighbourhood effects (N effects) were robust irrespective of group or type of nonword. Pseudohomophones were read more accurately than other nonwords but this finding was robust only for the younger 8-9-year-olds. High-frequency words were read more accurately than low-frequency words, but the reverse applied to pseudohomophones based on high- and low-frequency words, although this was not robust. Error rates for the 9-10-year-olds in Experiment 1 were low, and so it was difficult to interpret the lack of a pseudohomophone advantage for reading nonwords in this age group. Experiment 2 was therefore carried out, which consisted of a replication of the first study with a further group of 9-10-year-olds, but pronunciation latencies were measured, as well as accuracy. All the effects obtained in Experiment 1 were replicated but, in addition, an advantage for pseudohomophones in terms of pronunciation latencies was observed. The implications for accounts of reading development are discussed.


[Role of Iphosphamide in the treatment of breast cancer]
Breast cancer is the most frequent solid tumor in women. Predictive and prognostic factors play an important role in the treatment of this cancer. We focused on high risk and heavily pre-treated metastatic breast cancer patients, trying to find the best combination of cytotoxic drugs with high efficacy and low toxicity. Ifosfamide is chemically related to nitrogen mustard and is a synthetic analogue of cyclophosphamide. Ifosfamide has a wide range of antitumor activity. Since ifosfamide as monotherapy has introduced significant tumor reduction in 1(st) line chemotherapy for advanced breast cancer, some studies started with high-dose continuous infusion of ifosfamide,or combined with paclitaxel or vinorelbine. Patients with poor prognosis primary breast cancer treated with high-dose chemotherapy supported by peripheral blood progenitor cell (PBSC) transplantation have lower risk for local relapse and longer disease-free-survival. Ifosfamide working in the mobilization regimen has effective anti-tumor activity while mobilizing sufficient PBPCs in the majority of patients. In combination with other cytotoxics showed to be effective in high-dose protocols.


Salvage chemotherapy for ovarian carcinoma recurring during or after consolidation chemotherapy with paclitaxel.
The aim of the study was to analyze the effectiveness of salvage chemotherapy for recurring ovarian carcinoma during or after consolidation chemotherapy. During the study period, 12 patients received salvage chemotherapy for recurrence during or after consolidation chemotherapy. These cases were retrospectively reviewed. The response rate for salvage chemotherapy was 67% and was significantly associated with treatment-free interval (TFI) after consolidation (p=0.038). Progression-free survival was also significantly related to TFI (p=0.032). Combination chemotherapy of cisplatin plus irinotecan was effective in all five cases with TFI≥6 months and in three out of seven cases with TFI<6 months. Our study provides, for the first time, evidence that effectiveness of salvage chemotherapy for recurrent ovarian carcinoma occurring during or after consolidation chemotherapy can be predicted by TFI, and that combination chemotherapy of cisplatin plus irinotecan is potentially useful for these cases.


Stiffness of out-of-plane-motion stages with large-motion folded fractal flexible hinges.
This paper introduces a new planar flexible hinge of fractal configuration to be incorporated in out-of-plane-motion compliant stages that cover a wide stiffness range. The large-displacement fractal hinge consists of a series of scaled-down, concentric, circular-axis flexible segments that are connected in a folded manner by radial rigid links. In-plane and out-of-plane compliance matrices are derived for fractal hinges with variable planar geometry features. The flexible hinges are assembled in a radial architecture to form compliant stages that can be utilized for piston-type, out-of-plane sensing or actuation. The analytical model calculates the stage active, out-of-plane stiffness, as well as its parasitic, in-plane stiffness. The stage analytical stiffness is confirmed by the experimental testing of a prototype and by finite element simulation. Furthermore, analytical-model simulation is performed to evaluate the variations in the active and parasitic stiffnesses with key geometric parameters, which also enables optimization.


Prechilling of Xanthium strumarium L. Reduces Net Photosynthesis and, Independently, Stomatal Conductance, While Sensitizing the Stomata to CO(2).
Greenhouse-grown plants of Xanthium strumarium L. were exposed in a growth cabinet to 10 C during days and 5 C during nights for periods of up to 120 hours. Subsequently, CO(2) exchange, transpiration, and leaf temperature were measured on attached leaves and in leaf sections at 25 or 30 C, 19 C dew point of the air, 61 milliwatts per square centimeter irradiance, and CO(2) concentrations between 0 and 1000 microliters per liter ambient air. Net photosynthesis and stomatal conductance decreased and dark respiration increased with increasing duration of prechilling. The reduction in net photosynthesis was not a consequence of decreased stomatal conductance because the intercellular CO(2) concentration in prechilled leaves was equal to or greater than that in greenhouse-grown controls. The intercellular CO(2) concentration at which one-half maximum net photosynthesis occurred remained the same in prechilled leaves and controls (175 to 190 microliters per liter). Stomata of the control plants responded to changes in the CO(2) concentration of the air only slightly. Prechilling for 24 hours or more sensitized stomata to CO(2); they responded to changes in CO(2) concentration in the range from 100 to 1000 microliters per liter.


Behcet's Disease and Endocrine System.
Behcet's disease (BD) is a chronic disease which is characterized by recurrent oral apthous ulcerations, recurrent genital ulcerations, skin eruptions, ocular involvements and other various systemic manifestations as well as systemic vasculitis. Endocrine involvement in BD regarding various systems can be seen. Hypophysis is one of the best and dense vascularized organs of the body, thus it is likely that it can be affected by BD. Not only anterior hypophysis functions, but posterior hypophysis functions as well can be affected. As BD is a disease of autoimmune process, it may be possible that adrenal insufficiency or alterations in the cortisol levels could be expected. Another concern is whether or not there is insulin resistance in patients with BD. The avaliable data suggests that there is an increased susceptibility to insulin resistance in patients with BD.


Lobeline-induced hyperpnea in equids. Comparison with rebreathing bag and exercise.
In order to facilitate lung auscultation, a transitory hyperpnea may be obtained by lobeline administration, use of a rebreathing bag or exercise. The effect of these three methods on the pulmonary function were studied and compared in 5 healthy ponies. Respiratory airflow and tidal volume were measured with a pneumotachograph Nr. 5 and pleural pressure with the esophageal balloon catheter technique. Pulmonary function values were measured before, during and after the hyperpnea induced by (i) lobeline, (ii) rebreathing and (iii) exercise. Lobeline administration induced an hyperpnea due to both an increase in tidal volume and respiratory rate; this increase in ventilation lasted for about 90 s and was accompanied by a sharp rise in the respiratory peak airflows, especially the expiratory ones. The rebreathing method induced a less hyperpnea which lasted only 30 s. Lastly the hyperpnea after a light treadmill exercise was the longer in duration and intermediate between the preceding methods in intensity.


Genome Reviews: standardizing content and representation of information about complete genomes.
The Genome Reviews database provides up-to-date, standardized, and comprehensively annotated views of the genomic sequence of organisms with completely deciphered genomes. Currently, Genome Reviews contains information about the genomes of archaea, bacteria, and selected lower eukaryotes. Expansion to viral genomes and additional eukaryotes is planned. Genome Reviews is available for download in relational and flat file formats. In this paper, the rationale behind the creation of Genome Reviews, the approach taken in standardizing the data and its representation, and particular issues encountered in doing so are described.


Autophagy in Cancer Cell Transformation: A Potential Novel Therapeutic Strategy.
Basal autophagy plays a crucial role in maintaining intracellular homeostasis and prevents the cell from escaping the cell cycle regulation mechanisms and being cancerous. Mitophagy and nucleophagy are essential for cell health. Autophagy plays a pivotal role in cancer cell transformation, where upregulated precancerous autophagy induces apoptosis. Impaired autophagy has been shown to upregulate cancer cell transformation. However, tumor cells upregulate autophagy to escape elimination and survive the unfavorable conditions and resistance to chemotherapy. Cancer cells promote autophagy through modulation of autophagy regulation mechanisms and increase expression of the autophagyrelated genes. Whereas, autophagy regulation mechanisms involved microRNAs, transcription factors, and the internalized signaling pathways such as AMPK, mTOR, III PI3K, and ULK-1. Disrupted regulatory mechanisms are various as the cancer cell polymorphism. Targeting a higher level of autophagy regulation is more effective, such as gene expression, transcription factors, or epigenetic modification that are responsible for the up-regulation of autophagy in cancer cells. Currently, the CRISPR-CAS9 technique is available and can be applied to demonstrate the potential effects of autophagy in cancerous cells.


A case of orbital hemangiopericytoma in a dog.
A 7-and-a-half-year-old-dog was presented with progressive unilateral exophthalmos. Computed tomography imaging revealed an orbital mass that was surgically excised by lateral orbitotomy to preserve vision. The tumor was diagnosed histologically as a hemangiopericytoma. Twelve months postoperatively there were no signs of a local recurrence. This is the first case report of a hemangiopericytoma involving the orbit of a dog.


Gastrin suppresses the interdependent expression of p16 and anion exchanger 1 favoring growth inhibition of gastric cancer cells.
Our previous studies demonstrated that expression and interaction of p16 with anion exchanger 1 (AE1) in gastric cancer cells is correlated with progression and shorter survival of the cancer. In this article, the effects of gastrin on p16 and AE1 and its implication in prevention and treatment of gastric cancer were studied by molecular biology techniques, animal experiment and clinical analysis. The results showed that expression of p16 in human gastric body carcinoma was downregulated along with the progression of the cancer, suggesting the reverse correlations between gastrin and p16 in vivo. Further experiments indicated that gastrin suppressed the expression of p16 via the p16 promoter and thereafter resulted in the degradation of AE1 in gastric cancer cells. Silencing of AE1 or p16 significantly inhibited the proliferation of the cancer cells. Using a xenograft tumor model in nude mice, we showed that experimental systemic hypergastrinemia induced by the administration of omeprazole led to decreased expression of AE1 and p16 as well as to a marked growth inhibition of SGC7901 tumors. It is concluded that a moderate plasma gastrin level is beneficial to the growth inhibition of gastric cancer by suppressing the expression of AE1 and p16. This finding may have an important implication for the prevention and treatment of cancers arise in the gastric antrum.


Enhanced Expression of ABCB1 and Nrf2 in CD133-Positive Cancer Stem Cells Associates with Doxorubicin Resistance.
The precise mechanism about drug resistance of cancer stem cells (CSCs) has not yet been completely understood. Based on the expression of CD44 and CD133, two well-recognized cell surface markers for CSC identification, we tried to separate HCT8 colorectal cancer cells into different subpopulations and then investigated how the expression of CD44 and CD133 associated with doxorubicin (DXR) resistance. Interestingly, DXR resistance was observed in CD44+CD133+ (P < 0.01vs. all other subpopulations), but not in CD44+CD133- cells. CD44+CD133+ cells also showed an enhanced expression of ABCB1 and drug efflux ability (P < 0.001vs. all other subpopulations), but verapamil, an inhibitor of ABCB1, only partially mitigated the DXR resistance. Independent on the accumulation of DXR, lower level of reactive oxygen species and higher expression of Nrf2 were detected in CD44+CD133+ than CD44+CD133- cells (P < 0.05). Unexpectedly, silencing CD133 by siRNA only partially enhanced the cytotoxicity of DXR, but did not obviously change the expression of ABCB1 and the accumulation of DXR in CD44+CD133+ cells. Complex mechanisms, including drug excretion and redox regulation, are likely involved in the DXR resistance of CD133-positive cells, suggesting the difficulty of drug resistance problem in cancer chemotherapy.


Selection of key recommendations for the management of women with endometriosis by an international panel of patients and professionals.
Can the differences in patients' and professionals' perspective regarding essential endometriosis care be accommodated in one set of key recommendations? Consensus between patients and professions on a key set of recommendations for essential endometriosis care was achieved. Guideline development alone will not lead to healthcare improvement. Quality indicators are needed to monitor actual care and guideline adherence. These can help with better implementation of the ESHRE guidelines in European hospitals and thereby improve the quality of endometriosis care. The first step in the development of quality indicators is to select a compact set of key recommendations. Using a RAND modified Delphi method, this study reports the systematic selection of key recommendations based on the ESHRE guideline 'Management of Women with Endometriosis' by an international expert panel of both patients and professionals during the study period of September 2015 and December 2015. An international panel of patients (n = 10) and medical professionals (n = 11) rated and prioritized the 83 recommendations extracted from the ESHRE guideline for relevance in three rounds. A strict consensus methodology was used to select key recommendations. The main outcome measure was one set of key recommendations for endometriosis care. A representative set of 17 key recommendations was selected from the preliminary set of 83 recommendations. This selection covers all dimensions of endometriosis care, including diagnosis, treatment of endometriosis-associated pain, treatment of endometriosis-associated infertility and miscellaneous topics such as prevention, menopause and relationship with cancer. Of the 21 experts, 17 participated in at least one round while 16 (76.2%) participated in all 3 rounds. The feasibility of the selected key recommendations was not assessed in this study. As not all panel members took part in all three rounds, some response bias may have occurred. This set of key recommendations is the first step in the development of quality indicators for monitoring and improving endometriosis care. The set is generic and can be used in hospitals internationally. A practice test should be conducted to assess the feasibility of our key recommendations in clinical practice. No funding was received for the conduct of this study. Members of the EndoKey study group did not receive payment. The authors and members of the EndoKey study group have no conflict of interest.


Membrane microdomains, rafts, and detergent-resistant membranes in plants and fungi.
The existence of specialized microdomains in plasma membranes, postulated for almost 25 years, has been popularized by the concept of lipid or membrane rafts. The idea that detergent-resistant membranes are equivalent to lipid rafts, which was generally abandoned after a decade of vigorous data accumulation, contributed to intense discussions about the validity of the raft concept. The existence of membrane microdomains, meanwhile, has been verified by unequivocal independent evidence. This review summarizes the current state of research in plants and fungi with respect to common aspects of both kingdoms. In these organisms, principally immobile microdomains large enough for microscopic detection have been visualized. These microdomains are found in the context of cell-cell interactions (plant symbionts and pathogens), membrane transport, stress, and polarized growth, and the data corroborate at least three mechanisms of formation. As documented in this review, modern methods of visualization of lateral membrane compartments are also able to uncover the functional relevance of membrane microdomains.


Carbon nanotube field-effect transistors functionalized with self-assembly gold nanocrystals.
Self-assembly gold nanocrystals (Au-NCs) are formed on the surface of single-walled carbon nanotubes (SWNTs) on a platform of field-effect transistors by electron-beam evaporation and post-rapid thermal annealing processes. Strong oscillations in the SWNT channel (approximately 2000 nm long) current occur below 150 K. The Raman scattering from the SWNTs suggests that the electronic structure of the SWNTs has been significantly altered by the strong Coulombic interaction with the attached Au-NCs. Two possible mechanisms are presented to explain the observations: (1) the charging process of Au-NCs is dominated by the Coulomb blockade effect. Thus the electrostatic potential of the charged Au-NCs modifies the Schottky barrier at the SWNT/Au electrode contacts, and subsequently affects the SWNT channel current (or the Schottky barrier modulation) and (2) the charged Au-NCs serve as scattering centers, which modify the local potential along the SWNT channel and then induce the oscillations in the current (i.e. energy band modulation).


Plasma YKL-40 and total and disease-specific mortality in the general population.
Increased plasma YKL-40 is associated with short-term survival in patients with cardiovascular disease and cancer. We tested the hypothesis that increased plasma YKL-40 is associated with total and disease-specific mortality in the general population. We measured plasma YKL-40 in 8899 study participants, aged 20-95 years, in the Copenhagen City Heart Study from the Danish general population who were followed for 16 years: 3059 died, 2158 had ischemic cardiovascular disease, 2271 had cancer, and 2820 had other diseases associated with increased YKL-40. Hazard ratios for early death and absolute 10-year mortality rates were calculated according to plasma YKL-40 percentile groupings computed within sex and age decade: 0%-33%, 34%-66%, 67%-90%, 91%-95%, and 96%-100%. Median survival age decreased from 83 years for participants with plasma YKL-40 in category 0%-33% to 69 years in category 96%-100% (trend, P < 0.0001). Risk of early death was increased (multifactorially adjusted hazard ratios) by 10% for YKL-40 category 34%-66%, by 30% for 67%-90%, by 70% for 91%-95%, and by 90% for 96%-100% vs YKL-40 category 0%-33% (trend, P < 0.0001). Corresponding increases in participants with ischemic cardiovascular disease were 10%, 20%, 80%, and 60% (P < 0.0001); in those with cancer were 10%, 20%, 50%, and 70% (P < 0.0001); and in those with other diseases were 10%, 20%, 40%, and 60% (P < 0.0001). Highest absolute 10-year mortality rates were 78% and 90% in women and men, respectively, who were >70 years old, smoked, and were in YKL-40 category 96%-100%. Increased plasma YKL-40 is associated with risk of early death from cardiovascular disease, cancer, and other diseases in the general population.


Apical transportation and canal straightening with different continuously tapered rotary file systems in severely curved root canals: F6 SkyTaper and OneShape versus Mtwo.
To compare apical transportation and canal straightening when using three continuous tapered rotary NiTi systems [F6 SkyTaper (Komet/Brasseler, Lemgo, Germany), Mtwo (VDW, Munich, Germany) and OneShape (Micro Méga, Besançon, France)] in severely curved root canals. A total of 60 root canals in extracted human teeth with angles of curvatures ranging between 25° and 35° and radii ranging between 4 and 9 mm were divided into three groups (n = 20). Based on radiographs taken prior to instrumentation, the groups were balanced with respect to the angle and the radius of canal curvature (P = 1.0 and P = 0.994, respectively). All canals were prepared to an apical size 30 according to the manufacturer's instructions. Pre- and post-instrumentation radiographs were superimposed and apical transportation and canal straightening were analysed using a computer imaging program. Preparation time and instrument failure were also recorded. Data were analysed statistically using anova and Student-Newman-Keuls test. During preparation, no file fractured. All instruments maintained the original canal curvature well with no significant differences between the instruments (P = 0.542). Concerning apical transportation, no significant differences were obtained (P = 0.414). Regarding preparation time, no significant differences were obtained between F6 SkyTaper and OneShape (P > 0.05), but both were significantly faster than Mtwo (P < 0.05). Under the conditions of this study, all instruments respected the original canal curvature well and apical transportation was negligible. Instruments were safe to use. Preparation with F6 SkyTaper and OneShape was faster than with Mtwo.


Injection and removal of Teflon for unilateral vocal cord paralysis.
For over 70 years, reinnervation attempts have been unsuccessful in restoring motion to paralyzed vocal cords, in spite of occasional claims to the contrary. Fortunately, the major defect of unilateral vocal cord paralysis, a soft and breathy voice, can be eliminated if the edge of the paralyzed vocal cord is moved to the midline. This permits the mobile vocal cord to adduct and therefore to vibrate firmly against the edge of the paralyzed vocal cord during phonation, eliminating the air leak between the vocal cords. Teflon injection of the paralyzed vocal cord does this effectively. It is accomplished most easily and reliably via indirect laryngoscopy under local anesthesia, so the effect on the voice can be monitored during the injection. Teflon can be easily removed from the vocal cord via direct laryngoscopy. The disadvantages of trying to medialize the edge of a paralyzed vocal cord via a window in the thyroid cartilage (laryngeal framework surgery) will be discussed.


Indirect pulp treatment: in vivo outcomes of an adhesive resin system vs calcium hydroxide for protection of the dentin-pulp complex.
The purpose of this prospective and randomized in vivo study was to compare the clinical and radiographic outcomes of an adhesive resin system vs a calcium hydroxide liner for protection of the dentin-pulp complex of primary molars treated with indirect pulp treatment. Forty-eight primary molars with deep occlusal caries, but without preoperative signs and symptoms of irreversible pulpitis, received indirect pulp treatment and were restored with a composite resin (Z100). The teeth were randomly divided into 2 groups according to the material used for protection of the dentin-pulp complex: (1) adhesive resin system (Scotchbond MultiPurpose); and (2) calcium hydroxide liner (Dycal). These teeth were evaluated clinically and radiographicaly for 2 years. After 2 years, 83% (19/23) of the teeth treated with calcium hydroxide and 96% (24/25) of teeth treated with only the adhesive resin system presented a successful outcome, as determined by clinical and radiographic examination. Interradicular and/or periapical lesions were the most predominant signs of treatment failure, since 3 out of 23 teeth treated with calcium hydroxide and 1 out of 25 teeth treated with only adhesive resin presented this outcome. One tooth treated with the calcium hydroxide liner was diagnosed with internal root resorption at the 18-month examination. Of the 5 teeth diagnosed from radiographs as a failure of the indirect pulp treatment, none presented clinical signs/symptoms of pulpitis or necrosis such as the presence of fistula, enhanced tooth mobility, or pain. This study demonstrates that protection of the dentin-pulp complex of primary molars with an adhesive resin system results in similar clinical and radiographic 2-year outcomes as compared to calcium hydroxide when indirect pulp treatment is performed in Class I composite restorations.


Siren call of metaphor: subverting the proper task of neuroscience.
Under the assumption that nervous systems form a distinct category among the objects in Nature, applying metaphors of psychological and behavioral science disciplines is flawed and invites confusion. Moreover, such practices obscure and detract from the primary task of Neurophysiology: to investigate the intrinsic properties of nervous systems, uncontaminated with concepts borrowed from other disciplines.


A single-center analysis of chronic graft-versus-host disease-free, relapse-free survival after alternative donor stem cell transplantation in children with hematological malignancies.
We assessed the clinical outcomes of allogeneic hematopoietic stem cell transplantation (SCT) from alternative donors for pediatric patients with hematological malignancies, defining graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) as a composite endpoint. We also defined chronic GVHD-free, relapse-free survival (cGRFS) as survival without severe chronic GVHD, relapse, or death. The probabilities of 2-year disease-free survival from a human leukocyte antigen (HLA) matched unrelated donor (n = 57), related donor with HLA-1 antigen mismatch in the graft-versus-host direction (1Ag-GvH-MMRD, n = 28), and unrelated umbilical cord blood (n = 35) were 52.2, 38.5, and 40.4%, respectively (P = 0.14), and for 2-year GRFS were 26.2, 13.4, and 30.4%, respectively (P = 0.089), and for 2-year cGRFS were 36.2, 16.7, and 40.4%, respectively (P = 0.015). Of the three groups, the 1Ag-GvH-MMRD group showed a significantly higher cumulative incidence of severe cGVHD, and was identified as a significant risk factor for worse cGRFS. These results suggest that intensification of GVHD prophylaxis may be needed for SCT from 1Ag-GvH-MMRD. As with GRFS, cGRFS should be used as an endpoint of the clinical study to predict long-term morbidity and mortality for patients who need longer follow-up such as pediatric SCT recipients.


Evaluation of Acridine Orange Staining for a Semi-Automated Urinalysis Microscopic Examination at the Point-of-Care.
A urinary tract infection (UTI) can be diagnosed via urinalysis, consisting of a dipstick test and manual microscopic examination. Point-of-care (POC) image-based systems have been designed to automate the microscopic examination for low-volume laboratories or low-resource clinics. In this pilot study, acridine orange (AO) was evaluated as a fluorescence-based contrast agent to aid in detecting and enumerating urine sediment specific for diagnosing a UTI. Acridine orange staining of epithelial cells, leukocytes, and bacteria provided sufficient contrast to successfully implement image segmentation techniques, which enabled the extraction of classifiable morphologic features. Surface area bounded by each cell border was used to differentiate the sediment; epithelial cells were larger than 500μm2, bacteria were less than 30μm2, and leukocytes in between. This image-based semi-automated technique using AO resulted in similar cell counts to the clinical results, which demonstrates the feasibility of AO as an aid for POC urinalysis systems.


Hybridized Graphene for Supercapacitors: Beyond the Limitation of Pure Graphene.
Graphene-based supercapacitors have been attracting growing attention due to the predicted intrinsic high surface area, high electron mobility, and many other excellent properties of pristine graphene. However, experimentally, the state-of-the-art graphene electrodes face limitations such as low surface area, low electrical conductivity, and low capacitance, which greatly limit their electrochemical performances for supercapacitor applications. To tackle these issues, hybridizing graphene with other species (e.g., atom, cluster, nanostructure, etc.) to enlarge the surface area, enhance the electrical conductivity, and improve capacitance behaviors are strongly desired. In this review, different hybridization principles (spacers hybridization, conductors hybridization, heteroatoms doping, and pseudocapacitance hybridization) are discussed to provide fundamental guidance for hybridization approaches to solve these challenges. Recent progress in hybridized graphene for supercapacitors guided by the above principles are thereafter summarized, pushing the performance of hybridized graphene electrodes beyond the limitation of pure graphene materials. In addition, the current challenges of energy storage using hybridized graphene and their future directions are discussed.


Bone mineralization.
This review attempts to summarize the findings made available by the literature on the mineralization of bone. The types of bone, their structures and compositions, the nature and organization of organic and inorganic matter, the organic-inorganic relationships, and the mineralization mechanism itself, are the main topics of the present review. As in other hard tissues, bone mineralization occurs in, and is conditioned by, the components of the organic matrix. Collagen fibrils have long been considered the factor that is able to induce the deposition of apatite crystallites through a process of heterogeneous nucleation. Interfibrillar non-collagenous proteins are now considered to be co-factors that permit crystallite deposition. The main components of these proteins are reviewed. It is hypothesized that two independent types of mineral are present in bone, one contained in the collagen fibrils and corresponding to the granular, electron-dense bands, and the other contained in the interfibrillar spaces and corresponding to needle- and filament-like crystals. The deposition mechanism of these mineral structures remains elusive. The formation of the crystallites through an epitaxial mechanism is discussed.


Constructing a European healthcare market: the private healthcare company Capio and the strategic aspect of the drive for transparency.
This article analyses the private healthcare company Capio and its participation in the drive for transparency in the European healthcare field. An important point of departure for the paper is that technologies for transparency, such as accounting and auditing, are not neutral devices for increased openness, but carry with them programmatic dimensions that affect our norms and rules of how healthcare is to be organized and controlled. The drive for transparency engages different actors with various motives. To investigate this we carried out semi-structured interviews with 11 persons, mainly management members of Capio. We show that transparency in healthcare has been put forward by a private actor for strategic reasons. We argue that Capio's involvement in the drive for transparency should be seen as a 'second-order strategy' with the aim to create advantageous opportunities in a future European healthcare market. We show that Capio, through its propagation of various transparency technologies, has put forward programmatic ideals of industrialisation, marketisation and Europeanisation in healthcare. The main conclusion is that although Capio has engaged in the drive for transparency for business reasons, the company has also furthered certain political ideals in the field. This study contributes to the literature which problematizes the division between private and public, and between business and politics in healthcare, and is of interest to a broad health policy audience.


The effectiveness of a clinical reasoning teaching workshop on clinical teaching ability in nurse preceptors.
To explore the effectiveness of a clinical reasoning teaching workshop (CRTW) in preceptors' teaching ability, self-efficacy of clinical reasoning teaching. Preceptors' teaching skills are crucial for training novice nurses. How to enhance preceptors' teaching ability is a pertinent concern in clinical practice. This study comprised two stages. At stage I, we administered a pre- to post-test single group with 33 participants to investigate the changes in preceptors' knowledge and self-efficacy in clinical reasoning teaching after clinical reasoning teaching workshop. At stage II, a quasi-experimental design was adopted to assess the effectiveness of the clinical reasoning teaching workshop by comparing the preceptors' teaching ability by novice nurses. There were 22 nurses' preceptors who underwent the clinical reasoning teaching workshop and 70 nurses with preceptors who did not undergo clinical reasoning teaching workshop and matched with preceptors' age and working experience. After clinical reasoning teaching workshop, preceptors' knowledge and self-efficacy of clinical reasoning teaching ware increased significantly. Novice nurses (study group) scored their preceptors' teaching ability significantly higher than nurses' (control group). The clinical reasoning teaching workshop can enhance preceptors' teaching ability and confidence, thereby improving their teaching ability. A well-designed workshop with appropriated teaching method can allow preceptors to learn effectiveness. Clinical reasoning teaching workshop can be used in the training of preceptors.


Putative dental pulp-derived stem/stromal cells promote proliferation and differentiation of endogenous neural cells in the hippocampus of mice.
Until now, interest in dental pulp stem/stromal cell (DPSC) research has centered on mineralization and tooth repair. Beginning a new paradigm in DPSC research, we grafted undifferentiated, untreated DPSCs into the hippocampus of immune-suppressed mice. The rhesus DPSC (rDPSC) line used was established from the dental pulp of rhesus macaques and found to be similar to human bone marrow/mesenchymal stem cells, which express Nanog, Rex-1, Oct-4, and various cell surface antigens, and have multipotent differentiation capability. Implantation of rDPSCs into the hippocampus of mice stimulated proliferation of endogenous neural cells and resulted in the recruitment of pre-existing Nestin(+) neural progenitor cells (NPCs) and beta-tubulin-III(+) mature neurons to the site of the graft. Additionally, many cells born during the first 7 days after implantation proliferated, forming NPCs and neurons, and, to a lesser extent, underwent astrogliosis, forming astrocytes and microglia, by 30 days after implantation. Although the DPSC graft itself was short term, it had long-term effects by promoting growth factor signaling. Implantation of DPSCs enhanced the expression of ciliary neurotrophic factor, vascular endothelial growth factor, and fibroblast growth factor for up to 30 days after implantation. In conclusion, grafting rDPSCs promotes proliferation, cell recruitment, and maturation of endogenous stem/progenitor cells by modulating the local microenvironment. Our results suggest that DPSCs have a valuable, unique therapeutic potential, specifically as a stimulator and modulator of the local repair response in the central nervous system. DPSCs would be a preferable cell source for therapy due to the possibility of a "personalized" stem cell, avoiding the problems associated with host immune rejection. Disclosure of potential conflicts of interest is found at the end of this article.


Cardiac resynchronization therapy increases plasma levels of the endogenous inotrope apelin.
Cardiac resynchronization therapy (CRT) has been introduced to treat drug refractory chronic heart failure (CHF). Apelin, the endogenous ligand of the APJ receptor, is under evaluation for its potential role in human CHF pathophysiology. This study aims to assess whether biventricular pacing affects plasma apelin levels in patients with severe CHF. Fourteen patients (9 men, 5 women, mean age 68+/-13 years) undergoing biventricular pace-maker/ICD implantation were studied. Patients underwent baseline clinical and echocardiographic evaluation, and assessment of plasma apelin and NT-proBNP levels. The evaluation was repeated 48 h and 9+/-2 months after device implantation to assess the acute and chronic effects of CRT on apelin and NT-proBNP levels. Eight healthy age- and sex-matched subjects served as controls. In CHF patients, baseline apelin levels were reduced and NT-proBNP increased compared to control subjects (apelin: 0.47+/-0.2 vs. 0.97+/-0.3 ng/mL, p<0.001; NT-proBNP: 2007+/-114 vs. 229+/-72 pmol/L, p<0.001). Short-term evaluation did not reveal any effect of CRT on apelin or NT-proBNP levels. By contrast, at 9+/-2 months follow-up, CRT responders showed left ventricular reverse remodelling and an increase in ejection fraction, together with a significant increase in plasma apelin levels (0.99+/-0.1 vs. 0.47+/-0.2 ng/mL, p<0.001) and decrease in NT-proBNP (938+/-591 vs. 2007+/-114 pmol/L, p<0.05). Long-term CRT increases plasma levels of the endogenous inotrope apelin in patients with CHF.


Perforated tympanic membrane after blast injury.
The rate of spontaneous healing of tympanic membrane perforations in relation to time after blast injury, size, and location of perforations, was evaluated in 147 patients (210 ears). In 46 patients a paper patch was placed over the perforation. Spontaneous healing was seen in 155 ears (74%), 131 (62%) healed within the first 3 months and 145 ears (69%) healed within 10 months. Large and central kidney-shaped perforations had the least tendency to heal and usually required surgical intervention. Tympanoplasty was performed on 33 ears (15%), ossiculoplasty on 5 and mastoidectomy on 10. Intervention is recommended when the tympanic membrane remains unhealed for at least 10 months.


Research on the application of mobile phone location signal data in earthquake emergency work: A case study of Jiuzhaigou earthquake.
After an earthquake, the important task of emergency rescue work is to minimize casualties, but due to the suddenness of earthquake disasters, it is difficult to obtain enough disaster information immediately, especially personnel distribution and movement information. The traditional methods of obtaining disaster data are through reports from the disaster area or field investigations by the emergency rescue team; this work lags, and its efficiency is low. This paper analyzes the feasibility of using mobile phone location signal data in earthquake emergency rescue work in several respects, such as quantity, location, change rate, and epicentral distance. The results show that mobile phone location signal data can quickly obtain the situation of personnel distribution and quantity after an earthquake, and we find the change rate, distance, etc., can determine the approximate range of the earthquake impact field. Through the data distribution in different time periods, the movement of personnel after the earthquake can be obtained. Based on several situations, we can determine the basic situation of the disaster-stricken areas in times after the earthquake, especially the personnel relevant to the situation, and these data can provide a scientific basis for emergency rescue decision making.


Nicotinic excitatory postsynaptic potentials in hippocampal CA1 interneurons are predominantly mediated by nicotinic receptors that contain α4 and β2 subunits.
In the hippocampus, activation of nicotinic receptors that include α4 and β2 subunits (α4β2*) facilitates memory formation. α4β2* receptors may also play a role in nicotine withdrawal, and their loss may contribute to cognitive decline in aging and Alzheimer's disease (AD). However, little is known about their cellular function in the hippocampus. Therefore, using optogenetics, whole cell patch clamping and voltage-sensitive dye (VSD) imaging, we measured nicotinic excitatory postsynaptic potentials (EPSPs) in hippocampal CA1. In a subpopulation of inhibitory interneurons, release of ACh resulted in slow depolarizations (rise time constant 33.2 ± 6.5 ms, decay time constant 138.6 ± 27.2 ms) mediated by the activation of α4β2* nicotinic receptors. These interneurons had somata and dendrites located in the stratum oriens (SO) and stratum lacunosum-moleculare (SLM). Furthermore, α4β2* nicotinic EPSPs were largest in the SLM. Thus, our data suggest that nicotinic EPSPs in hippocampal CA1 interneurons are predominantly mediated by α4β2* nicotinic receptors and their activation may preferentially affect extrahippocampal inputs in SLM of hippocampal CA1.


Invertebrate predation selects for the loss of a morphological antipredator trait.
Antagonistic selection by different predators has been suggested to underlie variation in morphological antipredator traits among and within species. Direct empirical proof is equivocal, however, given the potential interrelationships of morphological and behavioral traits. Here, we tested whether spines in larvae of the dragonfly Leucorrhinia caudalis, which are selected for by fish predators, are selected against by invertebrate aeshnid predators. Using a manipulative approach by cutting spines instead of making comparisons among species or inducing spines, we were able to decouple the presence of spines from other potentially covarying morphological antipredator traits. Results showed survival selection for the loss of spines imposed by invertebrate predation. Moreover, spined and nonspined larval L. caudalis did not differ in the key antipredator behaviors, activity level, and escape burst swimming speed. The observed higher mortality of spined larvae can therefore be directly linked to selection by aeshnid predation against spines.


Hepatitis B virus infection: pathogenesis, reactivation and management in hematopoietic stem cell transplant recipients.
Hepatitis B virus (HBV) is a partially double stranded DNA virus that can integrate into host cell chromosomes as covalently closed circular DNA forms. HBV reactivation following hematopoietic stem cell transplantation in recipients with evidence of past HBV exposure, as well as exacerbation of a current HBV infection in HBV carrier recipients, secondary to chemotherapy and post-transplant immunosuppression that affect both humoral and cell-mediated control of HBV infection, are well documented in the literature. Management options include HBV-DNA screening and antiviral prophylaxis. Nucleos(t)ide analogues have been used at the start of chemotherapy and pretransplantation, with the course continuing for 6 months. However, depending on the serum HBV-DNA level, the antiviral agent might be given until a therapeutic end point is reached.


[Clinical study on relationship between JAK2 V617F mutation and chronic myeloproliferative disorders].
To investigate JAK2V617F mutation and its clinical significance in patients with chronic myeloproliferative disorders (cMPD). A retrospective study was performed on 523 cMPD patients diagnosed according to the current World Health Organization (WHO) criteria. Allele-specific PCR (ASP) was used to identify JAK2V617F mutation, the mutation status was analyzed by PCR-RFLP, and the results were confirmed by sequence analysis. The mutation burden was calculated by the ratio of T/G. The correlation between the allele burden and the clinical and hematologic features was analysed. For those without JAK2 V617F, MPL W515L mutation was analyzed. JAK2 V617F was detected in 66% of all patients (94% in PV, 80% in ET, 78% in CIMF, 75% in CMPD-U and 14% in HES). The majority of patients carried JAK2 V617F mutation were heterozygous , homozygote was found in only 5 cases (4 in PV and 1 in ET). The mutation burden in most patients (71.5%) was low with PV>ET>CIMF (P =0.003). Hemoglobin level was significantly related to high mutation burden in PV (r = 0. 203, P =0.033). Bone marrow megakaryocyte counts were found to be marked increased in ET with high JAK2 V617F loads (P = 0.024), and hepatomegaly in CIMF was significantly associated with high JAK2 V617F mutation burden (r = 0.315, P = 0.001). 1) Most cMPD patients, especially those with PV, carry JAK2 V617F mutation, except for CML. 2) .98% of JAK2 V617F mutation occurs of heterozygous status. 3) The mutation burden is PV>FT>CIMF. High JAK2 V617F loads are significantly associated with higher hemoglobin level in PV and higher bone marrow megakaryocyte counts in ET. 4) The positive correlation between hepatomegaly and JAK2 V617F mutation burden is found in CIMF.


Orbital energies and negative electron affinities from density functional theory: Insight from the integer discontinuity.
Orbital energies in Kohn-Sham density functional theory (DFT) are investigated, paying attention to the role of the integer discontinuity in the exact exchange-correlation potential. A series of closed-shell molecules are considered, comprising some that vertically bind an excess electron and others that do not. High-level ab initio electron densities are used to calculate accurate orbital energy differences, Deltavarepsilon, between the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), using the same potential for both. They are combined with accurate vertical ionization potentials, I(0), and electron affinities, A(0), to determine accurate "average" orbital energies. These are the orbital energies associated with an exchange-correlation potential that averages over a constant jump in the accurate potential, of magnitude Delta(XC)=(I(0)-A(0))-Deltavarepsilon, as given by the discontinuity analysis. Local functional HOMO energies are shown to be almost an order of magnitude closer to these average values than to -I(0), with typical discrepancies of just 0.02 a.u. For systems that do not bind an excess electron, this level of agreement is only achieved when A(0) is set equal to the negative experimental affinity from electron transmission spectroscopy (ETS); it degrades notably when the zero ground state affinity is instead used. Analogous observations are made for the local functional LUMO energies, although the need to use the ETS affinities is less pronounced for systems where the ETS values are very negative. The application of an asymptotic correction recovers the preference, leading to positive LUMO energies (but bound orbitals) for these systems, consistent with the behavior of the average energies. The asymptotically corrected LUMO energies typically agree with the average values to within 0.02 a.u., comparable to that observed with the HOMOs. The study provides numerical support for the view that local functionals exhibit a near-average behavior based on a constant jump of magnitude Delta(XC). It illustrates why a recently proposed DFT expression involving local functional frontier orbital energies and ionization potential yields reasonable estimates of negative ETS affinities and is consistent with earlier work on the failure of DFT for charge-transfer excited states. The near-average behavior of the exchange-correlation potential is explicitly illustrated for selected systems. The nature of hybrid functional orbital energies is also mentioned, and the results of the study are discussed in terms of the variation in electronic energy as a function of electron number. The nature of DFT orbital energies is of great importance in chemistry; this study contributes to the understanding of these quantities.


Neutron macromolecular crystallography.
Neutron diffraction techniques permit direct determination of the hydrogen (H) and deuterium (D) positions in crystal structures of biological macromolecules at resolutions of ∼1.5 and 2.5 Å, respectively. In addition, neutron diffraction data can be collected from a single crystal at room temperature without radiation damage issues. By locating the positions of H/D-atoms, protonation states and water molecule orientations can be determined, leading to a more complete understanding of many biological processes and drug-binding. In the last ca. 5 years, new beamlines have come online at reactor neutron sources, such as BIODIFF at Heinz Maier-Leibnitz Zentrum and IMAGINE at Oak Ridge National Laboratory (ORNL), and at spallation neutron sources, such as MaNDi at ORNL and iBIX at the Japan Proton Accelerator Research Complex. In addition, significant improvements have been made to existing beamlines, such as LADI-III at the Institut Laue-Langevin. The new and improved instrumentations are allowing sub-mm3 crystals to be regularly used for data collection and permitting the study of larger systems (unit-cell edges >100 Å). Owing to this increase in capacity and capability, many more studies have been performed and for a wider range of macromolecules, including enzymes, signalling proteins, transport proteins, sugar-binding proteins, fluorescent proteins, hormones and oligonucleotides; of the 126 structures deposited in the Protein Data Bank, more than half have been released since 2013 (65/126, 52%). Although the overall number is still relatively small, there are a growing number of examples for which neutron macromolecular crystallography has provided the answers to questions that otherwise remained elusive.


Factors associated with haemoglobin concentration among Timor-Leste children aged 6-59 months.
The study was conducted to assess the prevalence of and factors associated with haemoglobin (Hb) concentrations among children aged 6-59 months in Timor-Leste. The 2003 Demographic and Health Survey was a multi-stage cluster survey of 4,320 households from four different geographic regions in Timor-Leste. In total, 4,514 children aged 6-59 months were included in the analysis. The prevalence of anaemia (Hb concentration <11.0g/dL) was 38.2% (638/1,668) for children aged 6-23 months and 22.6% (644/2,846) for older children (p<0.001). Girls had a higher mean Hb concentration than boys (11.9g/dL vs 11.7g/ dL, p<0.006) and children who had diarrhoea in the previous two weeks had a lower Hb concentration than children without diarrhoea (11.5g/dL vs 11.9g/dL, p<0.001). Children from the richest and middle-class households had a lower average Hb concentration than those from the poorest households (11.8g/ dL, 11.7g/dL vs 12.0g/dL, p<0.001). Children of mothers with some secondary or more education had a lower mean Hb concentration than children of mothers with completed primary, some primary and no education (11.7 g/dL vs 11.9 g/dL, 11.8 g/dL, and 11.9 g/dL, p=0.002). Children from severely-anaemic mothers had a lower mean Hb concentration than children from moderately-, mild and not anaemic mothers (10.5 g/dL vs 11.1 g/dL, 11.6 g/dL, 12.0 g/dL, p<0.001). After backward stepwise hierarchical multiple regression, wasting, male sex, recent diarrhoea, household wealth index (richest and middle-class), maternal educational status (some secondary or more and some primary), and maternal anaemic status were significantly associated with a lower Hb concentration in children and increased age of child and duration of breastfeeding (6 months) with a higher Hb concentration. Anaemia-prevention programmes among children in Timor-Leste should focus on those children aged less than two years, children with recent diarrhoea, wasted children, high socioeconomic status, and anaemic mothers.


A novel nano-structured porous polycaprolactone scaffold improves hyaline cartilage repair in a rabbit model compared to a collagen type I/III scaffold: in vitro and in vivo studies.
To develop a nano-structured porous polycaprolactone (NSP-PCL) scaffold and compare the articular cartilage repair potential with that of a commercially available collagen type I/III (Chondro-Gide) scaffold. By combining rapid prototyping and thermally induced phase separation, the NSP-PCL scaffold was produced for matrix-assisted autologous chondrocyte implantation. Lyophilizing a water-dioxane-PCL solution created micro and nano-pores. In vitro: The scaffolds were seeded with rabbit chondrocytes and cultured in hypoxia for 6 days. qRT-PCR was performed using primers for sox9, aggrecan, collagen type 1 and 2. In vivo: 15 New Zealand White Rabbits received bilateral osteochondral defects in the femoral intercondylar grooves. Autologous chondrocytes were harvested 4 weeks prior to surgery. There were 3 treatment groups: (1) NSP-PCL scaffold without cells. (2) The Chondro-Gide scaffold with autologous chondrocytes and (3) NSP-PCL scaffold with autologous chondrocytes. Observation period was 13 weeks. Histological evaluation was made using the O'Driscoll score. In vitro: The expressions of sox9 and aggrecan were higher in the NSP-PCL scaffold, while expression of collagen 1 was lower compared to the Chondro-Gide scaffold. In vivo: Both NSP-PCL scaffolds with and without cells scored significantly higher than the Chondro-Gide scaffold when looking at the structural integrity and the surface regularity of the repair tissue. No differences were found between the NSP-PCL scaffold with and without cells. The NSP-PCL scaffold demonstrated higher in vitro expression of chondrogenic markers and had higher in vivo histological scores compared to the Chondro-Gide scaffold. The improved chondrocytic differentiation can potentially produce more hyaline cartilage during clinical cartilage repair. It appears to be a suitable cell-free implant for hyaline cartilage repair and could provide a less costly and more effective treatment option than the Chondro-Gide scaffold with cells.


The changing healthcare market and how it has influenced the treatment of cardiovascular disease--Part 1.
The dramatic transformations taking place in the healthcare environment have created a new paradigm for healthcare and pose far-reaching changes for cardiovascular care. This 2-part paper reviews these changes and discusses the major implications for cardiovascular specialists, based on literature reviews and summaries of legislative initiatives. The new healthcare paradigm focuses on a continuum of care, wellness maintenance and promotion, accountability for the healthcare of defined populations, and provider differentiation based on ability to add 'value' to the patient's healthcare outcome. This paradigm will become 'standard operating procedure' in the cardiovascular market. As a result, major areas of change in the cardiovascular environment include: continuing growth of managed care arrangements, expanding physician and other payment reforms, growing influence of state and private payer initiatives, expanding role of 'centers of excellence,' continuing surplus of physicians, growth in pharmaceuticals and new technologies, and extension of evidence-based guidelines. Practice guidelines, in particular, will become an integral part of medical practice and will represent the standards against which medical practice will be measured. Given the prominent position of cardiovascular disease in healthcare, cardiovascular specialists will remain in the forefront of these developments.


[Induction chemotherapy followed by adjuvant surgery (IC-AS) in patients with stage I-II small cell lung cancer (SCLC)].
Ten patients with stage I-II SCLC received IC-AS between 1984 and 1993. As induction chemotherapy, COMP-VAN alternating chemotherapy and CAV-PVP hybrid chemotherapy were administered. The former consisted of a 4-drug combination of cyclophosphamide (CPA), vincristine (VCR), methotrexate (MTX) and procarbazine alternated with a 3-drug combination of etoposide (ETP), adriamycin (ADM) and nimustine every 4 weeks. In the latter, a 3-drug combination of CPA, ADM and VCR given on day 1, and a 2-drug combination of ETP and cisplatin on day 8, were repeated every 4 weeks. All the patients had an objective response, including one complete response by induction chemotherapy. Post-operative pathology revealed SCLC in 4 patients, adenocarcinoma in 2 and no tumor (pathological CR) in 4. Four patients relapsed, and a intrathoracic relapse was experienced in only 2 patients. Six patients have died: 3 from relapsing SCLC, 2 from stomach cancer, and 1 from squamous lung cancer, who was salvaged from relapsing SCLC. The median survival time was 27.5 months, and the 3-year survival rate 37.5%. These results indicate that IC-AS is highly effective for stage I-II SCLC and warrant additional studies comparing IC-AS with chemo-radiotherapy.


Head and Neck Squamous Cell Carcinoma in Western Uganda: Disease of Uncertainty and Poor Prognosis.
Patients with head and neck squamous cell carcinoma (HNSCC) have symptoms that masquerade as benign conditions, resulting in late presentations. The objective is to describe characteristics and stages of patients with HNSCC and document their prognosis from clinical experience in western Uganda. Cross-sectional study with clinical follow-up. Mbarara Regional Referral Hospital. Fifty-one participants were recruited from February to July 2016. A questionnaire was used for patient characteristics, and staging, serologic studies, biopsy for histopathology, and immunohistochemistry were investigated. Staging was subclassified as early (stage I and II) and late (stage III and IV). Analysis was done with Fisher's exact test. Of 51 participants, 44 (86.5%) were male; the group had a mean age of 57.7 years, and 41 (80.1%) presented with late stage. Of 10 participants who presented with early stage, 6 (60%) had laryngeal HNSCC. The pharynx was ranked as the highest subsite (n = 19, 37.3%), followed by the oral cavity (n = 9, 17.6%), the larynx (n = 9, 17.6%), an unknown primary (n = 8, 15.7%), and sinonasal area (n = 6, 11.8%). Tobacco smoking, alcohol consumption, and prior use of traditional remedy were common characteristics among participants. Moderate differentiation was the most common grade (n = 23, 45.1%). Helicobacter pylori, Epstein-Barr virus, human immunodeficiency virus, and human papilloma virus type 16 were identified among 51 participants. However, none could afford referral for radiotherapy; hence, 1-year survival was 4%. The majority of our patients with HNSCC present at late stage, and the prognosis is poor. There is great need for preventative community-based education and early screening services to save our population.


Case-control study of body size and breast cancer risk in Nigerian women.
Previous studies have shown that weight is inversely associated with premenopausal breast cancer and positively associated with postmenopausal disease. Height has been shown to be positively correlated with breast cancer risk, but the association was not conclusive for premenopausal women. These previous studies were conducted primarily in Western countries, where height is not limited by nutritional status during childhood. The authors assessed the association between breast cancer and anthropometric measures in the Nigerian Breast Cancer Study (Ibadan, Nigeria). Between 1998 and 2009, 1,233 invasive breast cancer cases and 1,101 controls were recruited. The multivariate-adjusted odds ratio for the highest quartile group of height relative to the lowest was 2.03 (95% confidence interval (CI): 1.51, 2.72; P-trend < 0.001), with an odds ratio of 1.22 (95% CI: 1.14, 1.32) for each 5-cm increase, with no difference by menopausal status. Comparing women with a body mass index in the lowest quartile group, the adjusted odds ratio for women in the highest quartile category was 0.72 (95% CI: 0.54, 0.94; P-trend = 0.009) for premenopausal and postmenopausal women. Influence of height on breast cancer risk was quite strong in this cohort of indigenous Africans, which suggests that energy intake during childhood may be important in breast cancer development.


FDA drug list: key to generic substitution.
Americans sometimes pay a premium price for brand name drugs when lower - priced products that are "therapeutically equivalent" are available. Two lanmark projects recently unveiled by the Department of Health, Education, and Welfare and the Federal Trade Commission may help consumers save money on the prescription drugs they buy.


Betaxolol inhibits extracellular signal-regulated kinase and P70S6 kinase activities and gene expressions of platelet-derived growth factor A-chain and transforming growth factor-beta1 in Dahl salt-sensitive hypertensive rats.
We evaluated the protective effects of long-term treatment with betaxolol, a specific beta-antagonist, on platelet-derived growth factor (PDGF) A-chain and transforming growth factor (TGF)-beta1 gene expression in the left ventricle of Dahl salt-sensitive hypertensive rats fed a high-salt diet. In addition, we evaluated the relations between these effects and coronary microvascular remodeling, expression of extracellular signal-regulated kinases (ERK) belonging to one subfamily of mitogen-activated protein kinases, and expression of p70S6 kinase belonging to one subfamily of ribosomal S6 kinases. Betaxolol (0.9 mg/kg/day, subdepressor dose) was administered for 5 weeks, from 6 weeks of age to the left ventricular hypertrophy stage at 11 weeks of age. Increased PDGF A-chain and TGF-beta1 mRNA and protein expression were suppressed by betaxolol. Upregulated activities of ERK1/2 and p70S6 kinase phosphorylations were decreased by betaxolol. Betaxolol administration resulted in significant improvements in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis. Thus, we conclude that ERK1/2 and p70S6 kinase activities may play a key role in coronary microvascular remodeling of Dahl salt-sensitive hypertensive rats, and that beneficial effects of betaxolol on cardiovascular remodeling may be at least partially mediated by decreased PDGF A-chain and TGF-beta1 expression in the left ventricle.


Calcium effects on human esophageal smooth and striated muscle.
Because of conflicting results in earlier investigations, our study was carried out to determine the effects of acute hypercalcemia on esophageal muscle function at the lower esophageal sphincter and on the smooth and striated muscle of the esophageal body. Variables measured included lower esophageal sphincter pressure and length and esophageal body contraction pressure, duration, and velocity in the middle, distal, and proximal esophagus. Despite 3 hr of induced acute hypercalcemia, there were no statistically significant changes in any of the variables. Although esophageal muscle contraction requires calcium, our results, in contrast to some earlier studies, suggest that the availability of excess calcium does not effect esophageal function.


Flow cytometric analysis of group B streptococci phagocytosis and oxidative burst in human neutrophils and monocytes.
Group B streptococci (GBS) are a major cause of meningitis and septicemia in neonates and numerous invasive diseases in adults. Host defense against GBS infections relies upon phagocytosis and killing by phagocytic cells. To better understand the importance of this defense mechanism a flow cytometric assay was developed to study phagocytosis and oxidative burst of leukocytes stimulated by bacteria. GBS labeled with fluorescein isothiocyanate were used for phagocytosis experiments and the extracellular fluorescence was quenched by ethidium bromide to differentiate intracellular from extracellular bacteria. The intracellular oxidative burst was determined by using 2',7'-dichlorofluorescein diacetate to measure hydrogen peroxide production and hydroethidine for superoxide anion production. We found that for GBS serotypes Ia, Ib/c, II, and III phagocytosis was greater in neutrophils than monocytes. Hydrogen peroxide production and superoxide anion production were also greater for neutrophils than monocytes in all serotypes tested. A comparison of seven type III strains revealed greater phagocytosis and superoxide anion production by neutrophils than monocytes but no difference in hydrogen peroxide production. Therefore, monocytes react similarly as neutrophils in response to GBS but at a reduced level. This methodology of measuring both phagocytosis of GBS and oxidative burst simultaneously in neutrophils and monocytes should be very useful in further studies on the importance of factors such as complement and IgG receptors for the killing of bacteria.


Introduction of a fifth carboxylate ligand heightens the affinity of the oncomodulin CD and EF sites for Ca2+.
The acid-pair hypothesis, proposed by Reid and Hodges [(1980) J. Theor. Biol. 84, 401-444], suggests that the affinity of an EF-hand motif for Ca2+ will be maximal with four acidic ligands, paired along the +x, -x and +z, -z axes. Addition of a fifth anionic ligand is predicted to reduce Ca(2+)-binding affinity, as a consequence of increased electrostatic repulsion. Interestingly, for oncomodulin, we observe that introduction of a fifth carboxylate residue at the +z position in the CD coordination sphere or at the -x position in the EF coordination sphere significantly increases the affinity of those sites for Ca2+. The variants resulting from replacement of serine-55 by aspartate (S55D), glycine-98 by aspartate (G98D), and the combined mutations (55/98) have been examined in Ca(2+)- and Mg(2+)-binding studies, titration calorimetry, and differential scanning calorimetry. The KCa for the CD site is reduced from 800 to 67 nM by the S55D mutation, while KCa for the EF site is reduced from 45 to 4 nM by the G98D mutation. Both mutations destabilize the apo form of the protein and increase the thermal stability on the Ca(2+)-bound state. Interestingly, the S55D mutation also increases the affinity of the oncomodulin CD site for Mg2+, decreasing the dissociation constant from > 1 mM to approximately 30 microM. This increase in affinity is reflected in a substantially increased thermal stability of the Mg(2+)-bound form of the protein. In 0.15 M NaCl, 0.025 M Hepes (pH 7.4), and 0.01 M Mg2+, the wild-type protein denatures at 68.5 degrees C. By contrast, under identical conditions, the S55D mutations denatures at 79.0 degrees C. The increased metal ion-binding affinity displayed by the variant proteins may result in part from preferential destabilization of the apo-protein by the additional carboxylate.


Management of post-traumatic malunion of fractures of the distal radius.
Distal radius malunions are a common cause of patient morbidity. This review of the literature surrounding distal radius malunion covers the demographics, pathologic anatomy, and indications for surgery, surgical techniques, and salvage options. Particular emphasis is placed on subject areas that have not been reviewed as extensively in previous articles, including: intra-articular malunion, computer-assisted techniques, bone graft alternatives, and volar fixed-angle plate osteosynthesis.


Design and evaluation of a porous burner for the mitigation of anthropogenic methane emissions.
Methane constitutes 15% of total global anthropogenic greenhouse gas emissions. The mitigation of these emissions could have a significant near-term effect on slowing global warming, and recovering and burning the methane would allow a wasted energy resource to be exploited. The typically low and fluctuating energy content of the emission streams makes combustion difficult; however porous burners-an advanced combustion technology capable of burning low-calorific value fuels below the conventional flammability limit-are one possible mitigation solution. Here we discuss a pilot-scale porous burner designed for this purpose. The burner comprises a cylindrical combustion chamber filled with a porous bed of alumina saddles, combined with an arrangement of heat exchanger tubes for preheating the incoming emission stream. A computational fluid dynamics model was developed to aid in the design process. Results illustrating the burner's stable operating range and behavior are presented: stable ultralean combustion is demonstrated at natural gas concentrations as low as 2.3 vol%, with transient combustion at concentrations down to 1.1 vol%; the system is comparatively stable to perturbations in the operating conditions, and emissions of both carbon monoxide and unburned hydrocarbons are negligible. Based on this pilot-scale demonstration, porous burners show potential as a methane mitigation technology.


Modulation by Acanthospermum australe extracts of the tumor induced hematopoietic changes in mice.
Previous studies on the Ehrlich ascites tumor (EAT) model indicate that tumor progression is associated with reduced myelopoiesis and increased extramedullar hematopoiesis. In order to investigate the in vivo antitumor activity of Acanthospermum australe, its hydroalcoholic extract was partitioned with different solvents and the resulting extracts were monitored by their effects on bone marrow and spleen hematopoietic progenitor cell proliferation and differentiation in EAT-bearing mice. Oral treatment of tumor-bearing mice with 3 doses of 100, 500 and 1000 mg/kg of the crude hydroalcoholic extract and its chloroformic, butanolic and aqueous fractions significantly stimulated myelepoiesis and brought extramedullar hematopoiesis back to near control values. In normal mice, stimulation of myelopoiesis was only observed with the crude and the butanolic extracts. All the extracts at 500 mg/kg significantly increased survival of tumor-bearing mice, however a clear survival advantage in the group treated with the butanolic extract was observed. These results suggest that A. australe may exert effects on myelopoiesis that may be implicated in antitumor immune responses.