Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41).
Antibiotic therapy of pulmonary Mycobacterium abscessus infection is based on a combination treatment including clarithromycin. Recent data demonstrated that M. abscessus may carry a chromosomal, inducible erm gene coding for the ribosomal methylase Erm(41). The purpose of this study was to investigate whether in patients with chronic M. abscessus infection undergoing clarithromycin therapy, M. abscessus acquires clarithromycin resistance mutations in the rrl gene in addition to the presence of an inducible Erm(41) methylase. We determined clarithromycin MICs, erm(41) and rrl sequences for 29 clinical M. abscessus subsp. abscessus isolates of five different patients. The isolates were obtained between 2007 and 2011 covering a longitudinal observation period of 2-4 years for the individual patients. In three out of five patients with an initial rrl wild-type isolate, follow-up isolates demonstrated acquisition of resistance mutations in the rrl gene in addition to the presence of an inducible Erm methylase. Our results show that in M. abscessus, clarithromycin resistance mutations in the 23S rRNA peptidyltransferase region provide an additional selective advantage independent of a functional erm(41) gene.


Vortioxetine: A multimodal antidepressant or another selective serotonin reuptake inhibitor?
The treatment of depressive disorders remains unsatisfactory for many patients with regard to efficacy and tolerability. Vortioxetine has been registered by regulatory authorities for the treatment of major depressive disorder. This paper aims to provide clinicians with a brief overview of vortioxetine and its place in treatment. Vortioxetine is a serotonin reuptake inhibitor with additional serotonergic receptor effects of uncertain significance; hence, its classification as 'multimodal'. The half-life is about 2.75 days and steady state requires about 14 days. Metabolism is hepatic and involves cytochromes 2D6 and 3A4/5. Antidepressant efficacy in major depressive disorder has been established in registration studies, but the effectiveness of vortioxetine in 'real world' patients and in comparison to other antidepressants needs further investigation. The recommended dose range is 5-20 mg. Nausea, constipation and vomiting are the most common side effects. Sexual dysfunction may occur at higher doses but there appears to be low risk of weight gain and sedation. There is still much to learn about this drug, particularly whether it has unique characteristics in comparison to existing antidepressants. At present, vortioxetine can be considered as an antidepressant option in patients with established major depressive disorder who have not responded adequately to other antidepressants.


Stereotactic body radiation therapy: evaluation of setup accuracy and targeting methods for a new couch integrated immobilization system.
A new stereotactic frame system was designed at Indiana University to utilize the precision motion control of newer accelerator couches and treat obese patients previously untreatable in other frame systems during stereotactic body radiation therapy (SBRT). The repositioning accuracy and target reproducibility of this frame was evaluated in the treatment of both lung and liver tumors. The external coordinate system on the new frame was validated using a phantom system. Translational motions were carried out using couch motors. Five patients were treated with SBRT and twenty-three verification CT scans were acquired. The displacement of the gross tumor volume (GTV) and adjacent vertebral body between the original CT scan and the verification CT scans was determined. The mean setup accuracy for the patient study was less than 5 mm. Mean displacement of the GTV was 3.0 mm (0.0-6.0 mm) in the lateral (x) direction, 4.1 mm (0.0-8.9 mm) in the superior-inferior (y) direction, and 2.6 mm (0.0-10.0 mm) in the cranio-caudal (z) direction. Comparison of vertebral body position showed mean displacement of 2.4 mm (0.0 to 8.0 mm), 1.9 mm (0.0 mm to 2.0 mm), and 0.9 mm (0.0 to 5.0 mm) for the same shift directions. Repositioning could be accurately carried out from an initial reference position using the treatment couch controllers. Adequate set-up accuracy using a frame system capable of accommodating wide girth patients was achieved and was comparable to other published studies for narrower frames. With these results, a 5 mm expansion for PTV margins remains the standard for our institution.


Managing Interface Defects via Mixed-Salt Passivation toward Efficient and Stable Perovskite Solar Cells.
Iodine vacancies and uncoordinated Pb0 defects existing at the perovskite surface have been widely demonstrated to induce deep-level defects, which can greatly limit improvement of the efficiency and stability of perovskite solar cells (PSCs). In this work, a novel strategy is proposed for functionalizing perovskite surface by using trimethylsulfoxonium iodide (TMSI), which can enhance the defect formation energy and inhibit Pb0 defects. Meanwhile, TMSI modification also can fill the iodine vacancies of perovskite surface-terminating ends. Consequently, the optimized device shows the improved charge dynamics and the reduced energy losses, achieving a champion efficiency of up to 24.03% along with excellent air-storage and thermal stabilities. This work offers guidelines for more efficient and stable PSCs based on the management of interface defects.


Synthesis and Properties of Benzo-Fused Indeno[2,1-c]fluorenes.
A set of fully-conjugated indenofluorenes has been synthesized and confirmed by solid-state structure analysis. The indeno[2,1-c]fluorenes and their benzo-fused analogues all contain the antiaromatic as-indacene core. The molecules possess high electron affinities and show a broad absorption that reaches into the near-IR region of the electromagnetic spectrum. All of the featured compounds reversibly accept up to two electrons as revealed by cyclic voltammetry. Analysis of molecule tropicity using NICS-XY scan calculations shows that, while the as-indacene core is less paratropic than s-indacene, benz[a]-annulation further reduces the antiaromaticity of the core. Antiaromatic strength of the as-indacene core can also be tuned by the position of fusion of additional arenes on the outer rings.


Botulinum toxin assessment, intervention and aftercare for paediatric and adult drooling: international consensus statement.
Many individuals with neurological problems or anatomical abnormalities of the jaw, lips or oral cavity may drool, which can impact on health and quality of life. A thorough evaluation of the patient's history, examination of the oral region by a speech pathologist and, in individuals over 3 years, a dental examination is warranted. Questionnaires with established validity such as the Drooling Impact Scale are useful assessment tools. A hierarchical approach to treatment is taken from least invasive therapies, such as speech pathology, to more invasive, such as injection of botulinum neurotoxin type-A (BoNT-A) into the salivary glands (parotid and submandibular). The wishes of the individual and their carer are crucial considerations in determining the suitability of the intervention for the patient. In the presence of dysphagia and cerebral palsy (CP), careful assessment is required prior to the injection of BoNT-A. Favourable responses to intervention include a reduction in the secretion of saliva and in drooling, as well as psychosocial improvements. BoNT-A is usually well tolerated, although potential side effects should be discussed with the patient and carer.


[Chronic back pain: more than pain in the back. Findings of a regional survey among insurees of a workers pension insurance fund].
Surveys with a main focus on back pain tend to isolate the complaint from possibly concomitant pains, other symptoms and disorders. Severe chronic back pain is assumed here to imply more than pain in the back. We report results from a two stage survey conducted in 1998 - 2000. The initial postal questionnaire addressed all 10,000 actively employed blue collar workers from a regional pension fund (Landesversicherungsanstalt Schleswig-Holstein) aged 40 - 54 and residing in or around Luebeck/Germany (68 % males). Subjects reporting severe and disabling back pain were invited to a socio-medical examination. The response and participation rates were 58 % and 65 % respectively. Non-response and non-participation seem to result in minor though opposite, effects. The prevalence of current back pain (back pain of any severity within the past 7 days) is high (68 %; including 16 % with severe, disabling back pain) despite the preponderance of males and a probable healthy worker effect. 82 % of subjects participating in the second round reported recurrent or persisting back pain on the day of examination, in the majority with a chronic fluctuating and overall deteriorating course pattern. 18 % reported no current back pain and hence gave prospective (and additionally retrospective) evidence of an episodic-intermittent course of the disorder. The former group showed significantly more pains, bodily complaints, dysfunctional cognitions, emotional distress and concomitant disorders. 35 % of them indicated back pain as their dominant health problem; 49 % identified back pain and another disorder as dominant, and 16 % reported other prominent health problems. More than 70 % of "other" disorders originated from the musculoskeletal system often involving the extremities. Back pain is very common among blue collar workers. Severe disabling back pain is usually associated with numerous other pains, bodily complaints, disorders, and indicators of psychological distress ("amplified back pain"). However, even amplified back pain is not always the sole or dominant health problem. Assessing the degree of "amplification" seems helpful in splitting a previously homogeneous group of severely affected back pain sufferers-with possible prognostic and therapeutic consequences.


Preparation and characterization of zinc oxide nanoparticles and their sensor applications for electrochemical monitoring of nucleic acid hybridization.
In this study, ZnO nanoparticles (ZNP) of approximately 30 nm in size were synthesized by the hydrothermal method and characterized by X-ray diffraction (XRD), Braun-Emmet-Teller (BET) N2 adsorption analysis and transmission electron microscopy (TEM). ZnO nanoparticles enriched with poly(vinylferrocenium) (PVF+) modified single-use graphite electrodes were then developed for the electrochemical monitoring of nucleic acid hybridization related to the Hepatitis B Virus (HBV). Firstly, the surfaces of polymer modified and polymer-ZnO nanoparticle modified single-use pencil graphite electrodes (PGEs) were characterized using scanning electron microscopy (SEM). The electrochemical behavior of these electrodes was also investigated using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Subsequently, the polymer-ZnO nanoparticle modified PGEs were evaluated for the electrochemical detection of DNA based on the changes at the guanine oxidation signals. Various modifications in DNA oligonucleotides and probe concentrations were examined in order to optimize the electrochemical signals that were generated by means of nucleic acid hybridization. After the optimization studies, the sequence-selective DNA hybridization was investigated in the case of a complementary amino linked probe (target), or noncomplementary (NC) sequences, or target and mismatch (MM) mixture in the ratio of (1:1).


Patterns of reflux in the great saphenous vein system.
To report the patterns of reflux in the great saphenous vein as well as to investigate the correlations between patterns of reflux, the demographics and the clinical findings in the population studied. A total of 1882 limbs were assessed by duplex ultrasound examination in 1449 patients (348 men and 1101 women). Ages ranged from 21 to 94 years (mean 51.8). The presence of symptoms of venous disease (aching, heaviness, night cramps, swelling, itching, burning, tingling and throbbing) and clinical signs were recorded. Varicose veins without saphenous reflux occurred at a younger age (43 versus 55.6 years P < 0.05). The presence of incompetence at the saphenofemoral junction occurred in older patients (58.5 versus 54.1 years P < 0.05). Venous reflux to the ankle also occurred in older patients (mean 64.0 years P < 0.05). Saphenous vein reflux without clinical varices was associated with more advanced signs (C4-C6: 20.3% P < 0.05). A younger age was associated with less advanced signs (C0-C2:49.4 versus C4-C6: 60.1 years P < 0.05). Presence of symptoms was associated with advancing patient age (51.1 versus 49.1 years P < 0.05). A significant correlation between the extent of great saphenous vein reflux and the patient age and the clinical stage of SVI has been observed in this study. The authors hypothesize that these findings support the concept of early treatment of venous insufficiency before symptomatic and physiological deterioration occurs.


Refractory Lactic Acidosis and an Approach to its Management - A Case Report.
Lactic acidosis (LA) is a complication of diseases commonly seen in intensive care patients which carries an increased risk of mortality. It is classified by its pathophysiology; Type A results from tissue hypo-perfusion and hypoxia, and Type B results from abnormal metabolic activity in the absence of hypoxia. Reports of the co-occurrence of both types have been rarely reported in the literature relating to intensive care patients. This case report describes the challenging management of a patient diagnosed with both Type A and Type B LA. A 55-year-old female with newly diagnosed diffuse large B-cell lymphoma (DLBCL) developed hospital-acquired pneumonia, respiratory failure, shock and intra-abdominal septicaemia from a bowel perforation. Blood gases revealed a mixed picture lactic acidosis. Correction of septic shock, respiratory failure and surgical repair caused initial improvement to the lactic acidosis, but this gradually worsened in the intensive care unit. Only upon starting chemotherapy and renal replacement therapy was full resolution of the lactic acidosis achieved. The patient was discharged but succumbed to her DLBCL several months later. Type A and Type B LA can co-occur, making management difficult. A systematic approach can help diagnose any underlying pathology and aid in early management.


Improving animal and human health through understanding liver fluke immunology.
Sheep, goats and cattle represent the most numerous and economically important agricultural species worldwide used as sources for milk, fibre and red meat. In addition, in the developing world, these species often represent the sole asset base for small-holder livestock farmers and cattle/buffaloes often provide the majority of draught power for crop production. Production losses caused by helminth diseases of these animals are a major factor in extending the cycle of poverty in developing countries and a major food security issue for developed economies. Fasciola spp. are one of the most important zoonotic diseases with a global economic impact in livestock production systems and a poorly defined but direct effect on human health. Improvements in human and animal health will require a concerted research effort into the development of new accurate and simple diagnostic tests and increased vaccine and drug development against Fasciola infections. Here, the use of definitive natural host breeds with contrasting resistance to Fasciola infections is discussed as a resource to contrast parasite-host interactions and identify parasite immune evasion strategies. Such studies are likely to boost the discovery of new vaccine, drug and diagnostic candidates and provide the foundation for future genetic selection of resistant animals.


Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer.
Brain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.


Transjugular liver biopsy: a retrospective analysis of 601 cases.
To perform a retrospective analysis of all transjugular liver biopsies (TJLBs) performed during a 77-month period. The authors discuss the technical modifications adopted to achieve better procedural success and histopathologic yield apart from the safety profile of this procedure during the study period. Six hundred one consecutive patients underwent TJLB at the authors' institution during the study period. TJLB was performed when percutaneous biopsy was precluded, being judged unsafe. The left internal jugular vein (IJV) was accessed only when it was not possible to cannulate the right IJV, which was the routine access for this procedure. Biopsy samples were obtained from the right lobe after right hepatic vein cannulation. Left lobe biopsy was done only in select cases. In patients with shrunken liver and unfavorable hepatic veins for cannulation and in those with hepatic veno-occlusive disease, biopsy was performed with a transcaval approach under ultrasonographic (US) guidance, improving our technical success for this procedure over the years. The overall technical success rate for the procedure was 98.8 % (594/601), the histopathologic positivity was 97% (576/594), and the overall complication rate was 2.5% (15/601). With technical modifications such as transcaval liver biopsy and with access to US in the angiography suite, interventionalist can achieve higher technical success rates for this procedure. The authors' institutional experience with this procedure reiterates its high histopathologic positivity and safety profile both in adult and pediatric patients.


Thyroid nodularity after diagnostic administration of iodine-131.
In contrast to external X and gamma radiation, radiation from internally deposited 131I has not been clearly shown to cause thyroid tumors or nodules. Given the wide use of 131I in medicine and concern about health risks associated with the release of radioiodines from nuclear reactors, more information is needed. The purpose of this study was to evaluate the risk of thyroid nodularity among women previously exposed to radioiodine (131I) for diagnostic reasons. A clinical examination survey, including thyroid palpation, was conducted for a sample of women drawn from a cohort of patients exposed to 131I and a comparison group of women attending a mammography screening clinic. The study was conducted during 1991-1993 at Radiumhemmet, Karolinska Hospital, Stockholm, Sweden. A total of 1,005 women referred for a thyroid scintigraph or tracer test during the period 1952-1977 were included in the study. For comparison, 248 nonexposed women attending a mammography screening clinic were also enrolled. The primary outcome measure was the presence or absence of palpable thyroid nodules at the time of the clinical examination. Odds ratios were used as estimates of relative risk (RR). The mean dose to the thyroid from 131I was 0.54 Gy, and the average age at 131I administration was 26 years. The prevalence of thyroid nodularity was 10.6% among women who had been exposed to 131I and 11.7% among the nonexposed women [RR = 0.9; 95% confidence interval (CI) 0.6-1.4]. When analysis was restricted to women exposed to 131I, prevalence was associated positively with thyroid dose (excess RR = 0.9 per Gy; 95% CI 0.2-1.9). However, the excess RR was similar for women exposed before age 20 years and those exposed after age 20, which is contrary to findings for populations exposed to external radiation. While results demonstrated a positive association between diagnostic administration of 131I and the subsequent occurrence of thyroid nodules, it is unclear whether the association is causal, as the possibility of confounding by indication for 131I administration cannot be ruled out. No tumors that were subsequently diagnosed as cancer were found during the thyroid examinations, which supports the view that exposure to 131I administered for diagnostic reasons during adulthood rarely causes thyroid cancer.


Upper Bounds on Device-Independent Quantum Key Distribution.
Quantum key distribution (QKD) is a method that distributes a secret key to a sender and a receiver by the transmission of quantum particles (e.g., photons). Device-independent quantum key distribution (DIQKD) is a version of QKD with a stronger notion of security, in that the sender and receiver base their protocol only on the statistics of input and outputs of their devices as inspired by Bell's theorem. We study the rate at which DIQKD can be carried out for a given bipartite quantum state distributed between the sender and receiver or a quantum channel connecting them. We provide upper bounds on the achievable rate going beyond upper bounds possible for QKD. In particular, we construct states and channels where the QKD rate is significant while the DIQKD rate is negligible. This gap is illustrated for a practical case arising when using standard postprocessing techniques for entangled two-qubit states.


Influence of fluid flow on the stability and wetting transition of submerged superhydrophobic surfaces.
Superhydrophobic surfaces have attracted great attention for drag reduction application. However, these surfaces are subject to instabilities, especially under fluid flow. In this work, we in situ examine the stability and wetting transition of underwater superhydrophobicity under laminar flow conditions by confocal microscopy. The absolute liquid pressure in the flow channel is regulated to acquire the pinned Cassie-Baxter and depinned metastable states. The subsequent dynamic evolution of the meniscus morphology in the two states under shear flow is monitored. It is revealed that fluid flow does not affect the pressure-mediated equilibrium states but accelerates the air exchange between entrapped air cavities and bulk water. A diffusion-based model with varying effective diffusion lengths is used to interpret the experimental data, which show a good agreement. The Sherwood number representing the convection-enhanced mass transfer coefficient is extracted from the data, and is found to follow a classic 1/3-power-law relation with the Reynolds number as has been discovered in channel flows with diffusive boundary conditions. The current work paves the way for designing durable superhydrophobic surfaces under flow conditions.


Elastin metabolism during perinatal lung development in the copper-deficient rat.
Metal-chelating drugs were employed to investigate the role of copper (Cu) in elastin metabolism during the period of alveolarization in rat lung. Six groups of pregnant Sprague-Dawley rats were fed one of six semipurified diets, i.e., sufficient or deficient in copper, or the same basal diet containing 0.2% or 0.4% D-penicillamine (DPA), or the same basal diet containing 0.2% or 0.4% triethylenetetramine (TETA). The dams were fed throughout gestation, parturition, and lactation. The pups were then killed postnatally at day 10 and day 21 for the various analyses. At day 21, liver copper in the Cu-deficient pups was 3-5% control levels. In drug-treated groups, liver copper was 16-30% control levels. In the 21-day-old Cu-deficient rats, the concentration of lung elastin was only 75% of its concentration in control. Lung lysyl oxidase activity was lower in Cu-deficient rats, and data for the relative distribution of lung elastin cross-linking amino acids indicated impaired cross-linking in the pups from both the Cu-deficient and the 0.4% DPA groups. Morphologic examination of the lung also indicated dilation of airways in these two groups. Data on the distribution of cross-linking amino acids in elastin samples were also consistent with previous suggestions that impaired cross-linking observed in copper deficiency or from DPA treatment results from different mechanisms. Since the intakes of DPA and TETA were chosen to be in the therapeutic range of intakes used to treat diseases of abnormal copper metabolism, an important feature of these studies is that DPA and perhaps TETA have the potential of impairing normal lung development.


Ion Channel Disturbances in Migraine Headache: Exploring the Potential Role of the Kynurenine System in the Context of the Trigeminovascular System.
Migraine is a primary headache disorder, which is an enormous burden to the healthcare system. While some aspects of the pathomechanism of migraines remain unknown, the most accepted theory is that activation and sensitization of the trigeminovascular system are essential during migraine attacks. In recent decades, it has been suggested that ion channels may be important participants in the pathogenesis of migraine. Numerous ion channels are expressed in the peripheral and central nervous systems, including the trigeminovascular system, affecting neuron excitability, synaptic energy homeostasis, inflammatory signaling, and pain sensation. Dysfunction of ion channels could result in neuronal excitability and peripheral or central sensitization. This narrative review covers the current understanding of the biological mechanisms leading to activation and sensitization of the trigeminovascular pain pathway, with a focus on recent findings on ion channel activation and modulation. Furthermore, we focus on the kynurenine pathway since this system contains kynurenic acid, which is an endogenous glutamate receptor antagonist substance, and it has a role in migraine pathophysiology.


Na-H exchange regulates intracellular pH in isolated rat hepatocyte couplets.
Intracellular pH (pHi) was measured directly in isolated rat hepatocyte couplets using pH sensitive microelectrodes. The hepatocytes were maintained in a minimal salt buffer without added hormones or serum. Values of pHi (6.99 +/- 0.12, mean +/- SE) were close to their Nernst equilibria. After intracellular acidification with ammonium chloride, pH regulation was inhibited with 1 mM amiloride or by omission of external sodium, consistent with a Na-H exchange mechanism. Mean intracellular buffering power, in the nominal absence of carbon dioxide, was 34.1 +/- 11.4 mM. In the presence of external bicarbonate, amiloride or omission of sodium slowed, but did not completely inhibit recovery from acidification, indicating that additional pHi regulation mechanisms may operate in this preparation. These studies provide a direct measurement of pHi in hepatocyte couplets and indicate that Na-H exchange, together with a bicarbonate dependent system are important mechanisms for pHi regulation in this preparation.


PavA of Streptococcus pneumoniae modulates adherence, invasion, and meningeal inflammation.
Pneumococcal adherence and virulence factor A (PavA) is displayed to the cell outer surface of Streptococcus pneumoniae and mediates pneumococcal binding to immobilized fibronectin. PavA, which lacks a typical gram-positive signal sequence and cell surface anchorage motif, is essential for pneumococcal virulence in a mouse infection model of septicemia. In this report the impact of PavA on pneumococcal adhesion to and invasion of eukaryotic cells and on experimental pneumococcal meningitis was investigated. In the experimental mouse meningitis model, the virulence of the pavA knockout mutant of S. pneumoniae D39, which did not show alterations of subcellular structures as indicated by electron microscopic studies, was strongly decreased. Pneumococcal strains deficient in PavA showed substantially reduced adherence to and internalization of epithelial cell lines A549 and HEp-2. Similar results were obtained with human brain-derived microvascular endothelial cells and human umbilical vein-derived endothelial cells. Attachment and internalization of pneumococci were not significantly affected by preincubation or cocultivations of pneumococci with anti-PavA antisera. Pneumococcal adherence was also not significantly affected by the addition of PavA protein. Complementation of the pavA knockout strain with exogenously added PavA polypeptide did not restore adherence of the mutant. These data suggest that PavA affects pneumococcal colonization by modulating expression or function of important virulence determinants of S. pneumoniae.


Comparison of Anatomic and Clinical Outcomes in Patients Undergoing Alternative Initial Noninvasive Testing Strategies for the Diagnosis of Stable Coronary Artery Disease.
The optimal initial noninvasive diagnostic testing strategy for stable coronary artery disease (CAD) is unknown. Although American guidelines recommend an exercise stress test as the first-line test, European guidelines suggest that stress imaging (myocardial perfusion imaging or stress echocardiography) or coronary computed tomography angiography may be preferable. Understanding the relationship between the initial strategy and downstream yield of obstructive CAD and major adverse cardiac events may provide insight as to the optimal strategy. We conducted a population-based retrospective cohort study of adults in Ontario, Canada, using health administrative and clinical data. The relationship between the initial testing strategy and obstructive CAD on invasive angiography was examined. Patients were then followed from their angiogram onward to determine whether they developed a composite end point of major adverse cardiac events. After adjusting for covariates, patients with initial myocardial perfusion imaging (odds ratio: 0.92; 95% confidence interval, 0.85, 1.00), coronary computed tomography angiography (odds ratio: 1.51; 95% confidence interval, 0.91, 2.49), or stress echo (odds ratio: 0.95; 95% confidence interval, 0.84, 1.08) did not a have significantly different yield of obstructive CAD compared with those with an initial exercise stress test. Furthermore, there was no significant difference in downstream major adverse cardiac events after invasive angiography among the 4 initial testing strategies after adjusting for clinically relevant covariates. Our study found no evidence to suggest significant differences in either yield of obstructive CAD or downstream major adverse cardiac events in patients undergoing an initial noninvasive testing strategy with stress or anatomical imaging compared with those undergoing an initial exercise stress test.


The effect of cell division on the cellular dynamics of microinjected DNA and dextran.
Gene delivery is a multistep process that is being studied to increase its efficiency, a major hurdle for effective gene therapy. Our study focused on the nuclear entry step by microinjecting a mixture of fluorescent dextran and the pEYFP-Nuc plasmid (encoding a nuclear-targeted, enhanced GFP) into the cytoplasm of nondividing and dividing cells that were selected using non-chemical means. After 10 and 1000 ng/microl of plasmid DNA (pDNA) were cytoplasmically injected, 28% and 50% of the cells that had not divided expressed GFP, respectively, compared with 50% and 90% for the cells that had divided. This result suggested that pDNA can enter the nonmitotic nuclei of mononucleated cells, albeit at a lower efficiency than mitotic nuclei. The ability of pDNA to enter the intact nuclei of nondividing cells is consistent with our previous experience using multinucleated myotubes and digitonin-permeabilized cells in culture and using intravascular naked pDNA delivery in vivo. An explanation for the small effect of cell division was provided by studies using fluorescently labeled molecules and confocal fluorescent microscopy. They showed that the bulk of large dextran, and similarly pDNA, was excluded from re-formed nuclei after mitosis, thereby limiting the effect of cell division on the nuclear entry of pDNA.


Potential of xanthones from tropical fruit mangosteen as anti-cancer agents: caspase-dependent apoptosis induction in vitro and in mice.
The pericarp of mangosteen (Garcinia mangostana L.) is rich in various xanthones that are known to possess unique biological activities. In this work, we characterized the anti-proliferative and cytotoxic activities of mangosteen xanthones both in vitro and in mice. In vitro analysis with a human colorectal adenocarcinoma cell line, COLO 205, showed that mangosteen xanthones not only inhibit the proliferation of target cells but also induce their death by apoptosis that involves the activation of the caspase cascade. In vivo analysis using a mouse subcutaneous tumor model with COLO 205 cells showed that, at relatively low doses, the growth of tumors was repressed upon intratumoral administration of mangosteen xanthones. When a higher dose of mangosteen xanthones was administered, the size of tumors was reduced gradually, and, in some mice, the disappearance of tumors was seen. Histopathological evaluation and biochemical analysis of tumors that received mangosteen xanthones indicate the induction of apoptosis in tumors, which resulted in the repression of their growth and the reduction of their sizes. These results demonstrate the potential of mangosteen xanthones to serve as anti-cancer agents for the chemotherapy of cancer.


Molecular characterization of prophenoloxidase-1 (PPO1) and the inhibitory effect of kojic acid on phenoloxidase (PO) activity and on the development of Zeugodacus tau (Walker) (Diptera: Tephritidae).
Phenoloxidase (PO) plays a key role in melanin biosynthesis during insect development. Here, we isolated the 2310-bp full-length cDNA of PPO1 from Zeugodacus tau, a destructive horticultural pest. qRT-polymerase chain reaction showed that the ZtPPO1 transcripts were highly expressed during larval-prepupal transition and in the haemolymph. When the larvae were fed a 1.66% kojic acid (KA)-containing diet, the levels of the ZtPPO1 transcripts significantly increased by 2.79- and 3.39-fold in the whole larvae and cuticles, respectively, while the corresponding PO activity was significantly reduced; in addition, the larval and pupal durations were significantly prolonged; pupal weights were lowered; and abnormal phenotypes were observed. An in vitro inhibition experiment indicated that KA was an effective competitive inhibitor of PO in Z. tau. Additionally, the functional analysis showed that 20E could significantly up-regulate the expression of ZtPPO1, induce lower pupal weight, and advance pupation. Knockdown of the ZtPPO1 gene by RNAi significantly decreased mRNA levels after 24 h and led to low pupation rates and incomplete pupae with abnormal phenotypes during the larval-pupal interim period. These results proved that PO is important for the normal growth of Z. tau and that KA can disrupt the development of this pest insect.


ANMCO/SIC Consensus Document: cardiology networks for outpatient heart failure care.
Changing demographics and an increasing burden of multiple chronic comorbidities in Western countries dictate refocusing of heart failure (HF) services from acute in-hospital care to better support the long inter-critical out-of- hospital phases of HF. In Italy, as well as in other countries, needs of the HF population are not adequately addressed by current HF outpatient services, as documented by differences in age, gender, comorbidities and recommended therapies between patients discharged for acute hospitalized HF and those followed-up at HF clinics. The Italian Working Group on Heart Failure has drafted a guidance document for the organisation of a national HF care network. Aims of the document are to describe tasks and requirements of the different health system points of contact for HF patients, and to define how diagnosis, management and care processes should be documented and shared among health-care professionals. The document classifies HF outpatient clinics in three groups: (i) community HF clinics, devoted to management of stable patients in strict liaison with primary care, periodic re-evaluation of emerging clinical needs and prompt treatment of impending destabilizations, (ii) hospital HF clinics, that target both new onset and chronic HF patients for diagnostic assessment, treatment planning and early post-discharge follow-up. They act as main referral for general internal medicine units and community clinics, and (iii) advanced HF clinics, directed at patients with severe disease or persistent clinical instability, candidates to advanced treatment options such as heart transplant or mechanical circulatory support. Those different types of HF clinics are integrated in a dedicated network for management of HF patients on a regional basis, according to geographic features. By sharing predefined protocols and communication systems, these HF networks integrate multi-professional providers to ensure continuity of care and patient empowerment. In conclusion, This guidance document details roles and interactions of cardiology specialists, so as to best exploit the added value of their input in the care of HF patients and is intended to promote a more efficient and effective organization of HF services.


[Cell composition and ultrastructure of the thymus in offspring during changes in the hormonal background in the mother-fetus functional system].
Micro- and ultrastructure has been studied in newborn rats, developed under conditions of an altered hormonal background in the functional system mother--fetus (FSMF), when hydrocortisone acetate is injected on the 17th-18th days of pregnancy, and at bilateral adrenalectomy of pregnant females. A number of similar changes in the offspring thymus are revealed under both procedure: the portion of mitotically dividing and blast forms of cells decreases, there is a certain tendency to increasing destructively altered cells and intensity of the processes in differentiation of cellular elements and subcellular structures, that is, evidently, depended on increasing contents of corticosteroids in the developing organism. When hydrocortisone acetate is injected to the pregnant rats, some amount of the drug can penetrate across the placenta and a superfluous concentration of glucocorticoids is created in the fetus blood. When adrenalectomy is performed in the pregnant rats, the main cause of elevated secretion of corticosteroids in the fetuses is, evidently, stimulation of the adrenals with their own ACTH, that is produced as a response to a decreased concentration of corticosteroids in FSMF. Nevertheless, in the fetal thymus reaction to the effects mentioned there are some differences. In the experiments with adrenalectomy in the pregnant rats, in the offspring thymus signs of degradation of lymphocytes and reticuloepitheliocytes are manifested more distinctly; that can be connected with a high concentration of endogenic corticosteroids in the fetus blood and with a qualitative composition of the hormones.


Type 2 diabetes mellitus in Canada's first nations: status of an epidemic in progress.
This review provides a status report on the epidemic of type 2 diabetes mellitus that is affecting many of Canada's First Nations. We focus on the published literature, especially reports published in the past 2 decades, and incorporate data from the Aboriginal Peoples Survey and the First Nations and Inuit Regional Health Survey. We look at the extent and magnitude of the problem, the causes and risk factors, primary prevention and screening, clinical care and education, and cultural concepts and traditional knowledge. The epidemic of type 2 diabetes is still on the upswing, with a trend toward earlier age at onset. Genetic-environmental interactions are the likely cause. Scattered intervention projects have been implemented and evaluated, and some show promise. The current health and social repercussions of the disease are considerable, and the long-term outlook remains guarded. A national Aboriginal diabetes strategy is urgently needed.


Whole-leaf wash improves chlorine efficacy for microbial reduction and prevents pathogen cross-contamination during fresh-cut lettuce processing.
Currently, most fresh-cut processing facilities in the United States use chlorinated water or other sanitizer solutions for microbial reduction after lettuce is cut. Freshly cut lettuce releases significant amounts of organic matter that negatively impacts the effectiveness of chlorine or other sanitizers for microbial reduction. The objective of this study is to evaluate whether a sanitizer wash before cutting improves microbial reduction efficacy compared to a traditional postcutting sanitizer wash. Romaine lettuce leaves were quantitatively inoculated with E. coli O157:H7 strains and washed in chlorinated water before or after cutting, and E. coli O157:H7 cells that survived the washing process were enumerated to determine the effectiveness of microbial reduction for the 2 cutting and washing sequences. Whole-leaf washing in chlorinated water improved pathogen reduction by approximately 1 log unit over traditional cut-leaf sanitization. Similar improvement in the reduction of background microflora was also observed. Inoculated "Lollo Rossa" red lettuce leaves were mixed with noninoculated Green-Leaf lettuce leaves to evaluate pathogen cross-contamination during processing. High level (96.7% subsamples, average MPN 0.6 log CFU/g) of cross-contamination of noninoculated green leaves by inoculated red leaves was observed when mixed lettuce leaves were cut prior to washing in chlorinated water. In contrast, cross-contamination of noninoculated green leaves was significantly reduced (3.3% of subsamples, average MPN <or=-0.3 log CFU/g) when the mixed leaves were washed in chlorinated water before cutting. This result suggests that whole-leaf sanitizing washes could be a practical strategy for enhancing the efficacy of chlorine washes for pathogen reduction and cross-contamination prevention.


The Weighted Peak Method in the Time Domain Compared With Alternative Methods for Assessing LF Electric and Magnetic Fields.
Directive 2013/35/EU of the European Parliament and Council recommends the weighted peak method for assessing non-thermal effects of low frequency (LF) electric and magnetic fields. This article shows that this method is very practical and user friendly and is absolutely reliable to lead to correct results when applied in the time domain. The method can be used without limitations for any field profile and emulates the underlying physical and biological effects significantly better than all other presently known methods. For this reason, this method is described and recommended in many technical standards for assessing the non-thermal effects of electromagnetic fields and is recognized by the international scientific community. The disadvantages of competing methods are demonstrated. Some technical aspects of real measurement systems are also examined.


Two-dimensional gel electrophoresis analysis of the leiomyoma interstitial fluid reveals altered protein expression with a possible involvement in pathogenesis.
Uterine leiomyoma is the most common smooth benign neoplasm. In the present study, we analyzed the global interstitial fluid (IF) profile of leiomyoma vs. normal myometrium to identify protein dysregulation involved in leiomyoma pathogenesis. Two-dimensional gel electrophoresis and mass spectrometry were used to generate and compare the global interstitial fluid profiles of the leiomyoma and of the normal tissue. Two proteins were validated by immunohistochemistry. By comparing the interstitial fluid profile of the leiomyoma with that of the normal myometrium, the levels of seven proteins were found to be significantly different: four structural organization proteins (desmin, prelamin-A/C, transgelin and α-actinin-1), an inflammatory response (α1-antitrypsin), a response to oxidative stress (peroxiredoxin-2), and a folding protein (heat shock 70 kDa protein 1A/1B). Desmin, α1-antitrypsin and peroxiredoxin-2 were upregulated in the leiomyoma, whereas heat shock 70 kDa protein 1A/1B, α-actinin-1, prelamin-A/C and transgelin were downregulated. Desmin and α1-antitrypsin were further validated by immunohistochemistry. By identifying proteins with altered expression levels compared to the myometrium from several pathways of the leiomyoma pathogenesis, we found the leiomyoma interstitial fluid to have a characteristic proteomic profile. A better appreciation of the pathophysiology of the disease can be useful in the development of conservative treatments that serve as viable alternatives to hysterectomy.


A new simple method to detect an air-leaking lung field in pneumothorax by a flexible bronchofiberscope.
A new simple method was designed to detect an air-leaking lung field in refractory pneumothorax. A constant volume of 100% helium gas was introduced into each lobe bronchus of two patients with pneumothorax via a flexible bronchofiberscope. In both patients, only when helium gas was introduced into the communicating bronchus with a ruptured emphysematous bullae, a high concentration of helium was detected in the intrathoracic gas. Thoracotomy has been used for patients with pneumothorax in which an air-leakage has persistently as well as recurrently continued, but this therapeutical approach has been frequently limited by a patient-age and an underlying disease. An exact detecting of the site of air leakage makes much expectant of an effectiveness of the outlet-closing treatment under a thoracoscope and finally leads to a new transbronchial treatment of pneumothorax.


Exploration, normalization, and summaries of high density oligonucleotide array probe level data.
In this paper we report exploratory analyses of high-density oligonucleotide array data from the Affymetrix GeneChip system with the objective of improving upon currently used measures of gene expression. Our analyses make use of three data sets: a small experimental study consisting of five MGU74A mouse GeneChip arrays, part of the data from an extensive spike-in study conducted by Gene Logic and Wyeth's Genetics Institute involving 95 HG-U95A human GeneChip arrays; and part of a dilution study conducted by Gene Logic involving 75 HG-U95A GeneChip arrays. We display some familiar features of the perfect match and mismatch probe (PM and MM) values of these data, and examine the variance-mean relationship with probe-level data from probes believed to be defective, and so delivering noise only. We explain why we need to normalize the arrays to one another using probe level intensities. We then examine the behavior of the PM and MM using spike-in data and assess three commonly used summary measures: Affymetrix's (i) average difference (AvDiff) and (ii) MAS 5.0 signal, and (iii) the Li and Wong multiplicative model-based expression index (MBEI). The exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values. We evaluate the four expression summary measures using the dilution study data, assessing their behavior in terms of bias, variance and (for MBEI and RMA) model fit. Finally, we evaluate the algorithms in terms of their ability to detect known levels of differential expression using the spike-in data. We conclude that there is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities.


Characteristics of Lower Leg Muscle Activity in Patients with Cerebral Palsy during Cycling on an Ergometer.
Cycling on ergometer is often part of rehabilitation programs for patients with cerebral palsy (CP). The present study analyzed activity patterns of individual lower leg muscle during active cycling on ergometer in patients with CP and compared them to similar recordings in healthy participants. Electromyographic (EMG) recordings of lower leg muscle activity were collected from 14 adult patients and 10 adult healthy participants. Activity of the following muscles was recorded: Musculus tibialis anterior, Musculus gastrocnemius, Musculus rectus femoris, and Musculus biceps femoris. Besides qualitative analysis also quantitative analysis of individual muscle activity was performed by computing the coefficient of variation of EMG signal amplitude. More irregular EMG patterns were observed in patients in comparison to healthy participants: agonist-antagonist cocontractions were more frequent, muscle activity measured at specific points of the cycle path was more variable, and dynamic range of muscle activity along the cycle path was narrower in patients. Hypertonicity was also more frequent in patients. Muscle activity patterns during cycling differed substantially across patients. It showed irregular nature and occasional sharp high peaks. Dynamic range was also narrower than in controls. Observations underline the need for individualized cycling training to optimize rehabilitation effects.


Trends in health care practitioner credentialing.
Once a risk management process limited to hospitals, the practice of practitioner credentialing has expanded to include many other health care organizations, including insurers, health maintenance organizations, preferred provider organizations, management services organizations, medical groups, and independent practice associations. Standards set by recognized accreditation bodies, including the Joint Commission on Accreditation of Healthcare Organizations (Joint Commission), National Committee for Quality Assurance (NCQA), and American Accreditation Health Care Commission/Utilization Review Accreditation Committee mandate a substantial effort to properly evaluate the credentials of health care practitioners. A sector of commerce called the credentials verification organization (CVO) industry has undertaken the mission to make the process of practitioner credentialing more consistent and efficient, faster, and less expensive.


The mechanical consequences of mineralization in embryonic bone.
The purpose of this study was to examine the effect of mineralization on the mechanical properties of embryonic bone rudiments. For this purpose, four-point bending experiments were performed on unmineralized and mineralized embryonic mouse ribs at 16 and 17 days of gestational age. Young's modulus was calculated using force-displacement data from the experiment in combination with finite element analysis (FEA). For the unmineralized specimens, a calculated average for the Young's modulus of 1.11 (+/- 0.62) MPa was established after corrections for sticking to the four-point bending device and aspect ratio, which is the ratio between the length of the bone and its diameter. For the mineralized specimens, the value was 117 (+/- 62) MPa after corrections. Hence, Young's moduli of embryonic bone rudiments increase by two orders of magnitude within 1 day, during endochondral ossification. As an effect, the hypertrophic chondrocytes in the calcifying cartilage experience a significant change in their mechanical environment. The chondrocytes are effectively stress shielded, which means that they do not carry stresses since stresses are supported by the stiffest parts of the tissue, which are in this case the diaphyseal cortex and the calcified matrix. The deformability of the hypertrophic chondrocytes is, therefore, severely reduced. Since the transition is so sudden and enormous, it can be seen as a process of 'catastrophic' proportion for the hypertrophic chondrocytes. The subsequent resorption of calcified cartilage and the expansion of the marrow cavity could be consequential to stress shielding.


Exploring Health Care Professionals' Perceptions of Incidents and Incident Reporting in Rehabilitation Settings.
Research exploring patient safety in rehabilitation settings is limited. This study's aim was to describe team members' perceptions of incidents and incident reporting in rehabilitation settings. Semistructured interviews were conducted with 18 health care professionals from multiple rehabilitation units (medical, neurological, and orthopedic) at 2 inner-city rehabilitation centers. Five hypothetical scenarios were presented to participants during the interviews. Participants were asked to classify the scenarios and whether they would report any identified incidents. Data were analyzed using a descriptive thematic approach. Participants classified events based on 2 parameters: the nature of the outcome and deviation from professional practice. Factors influencing participants' decisions to file incident reports included their classification of the events in the scenarios (i.e., events classified as critical incidents were more often reported than those classified as incident or near miss); the severity of the impact on the client; and their profession's perceived role in reporting specific incidents. When participants said they would report incidents, all agreed that they would report only objective facts. The study findings demonstrate gaps between incident-reporting policy and practice, and opportunities to address these gaps. Organizational leaders can work with all health care professions to support their roles in reporting. Interprofessional team building, focused on valuing all team members, may improve interprofessional communication and reporting. Setting standards for classifying events could increase consistency in reporting. Ultimately, encouraging reporting of near misses and incidents can create a culture of learning focused on problem solving and improved patient safety.


Long-term follow-up of cortisol awakening response in patients treated for stress-related exhaustion.
Studies on hypothalamus-pituitary-adrenal (HPA) axis activity in stress-related exhaustion and burnout have revealed incongruent results, and few longitudinal studies on clinical populations have been performed. This study was designed to investigate differences in HPA axis activity between patients with stress-related exhaustion and healthy controls and to investigate longitudinal changes in HPA axis activity in the patient group as they entered a multimodal treatment programme. HPA axis activity was assessed through the cortisol awakening response (CAR). Salivary cortisol was sampled at awakening and after 15 min. Follow-up measurements were performed in the patient group after 3, 6, 12 and 18 months. An outpatient clinic specialising in stress-related illness. Patients with clinically diagnosed stress-related exhaustion (n=162) and healthy controls (n=79). The primary measure was CAR measured as the difference between the two salivary cortisol samples. Changes in CAR during follow-up were related to changes in symptoms of burnout, depression and anxiety. Patients showed similar CAR as the controls and their CAR did not change significantly during treatment. No association was found between CAR and symptom development during treatment. The authors conclude that CAR does not seem to discriminate clinically defined patients with exhaustion from healthy controls and it appears not to change during treatment. CAR, measured as salivary cortisol, at awakening and after 15 min, is thus not a valid marker for stress-related exhaustion.


Characteristics of interpersonal hostile-dominance in psychiatric inpatients.
This study assessed the extent to which psychiatric symptoms and aggression-related personality as well as cognitive and affective variables predicted interpersonal hostile-dominance (HD) in psychiatric inpatients. Two hundred patients admitted to hospital for psychiatric treatment were recruited, including 132 men and 68 women, with an age range of 19-64 years (M = 38.32 years, SD = 11.13 years). Each participant was assessed within five days of admission using the Impact Message Inventory-Circumplex (IMI-C), the Psychopathy Checklist: Screening Version (PCL:SV), the State-Trait Anger Expression Inventory-2 (STAXI-2), the Schedule of Imagined Violence (SIV), the Measures of Criminal Attitudes and Associates (MCAA), and the Positive and Negative Syndrome Scale (PANSS). Hierarchical multiple regression was used to assess the ability of psychiatric symptoms to predict HD, after controlling for the influence of psychopathy (Factor 1 [F1] and Factor 2 [F2]), trait anger, aggressive script rehearsal, and normative beliefs supporting aggression. Psychopathy (F1 and F2), the tendency to rehearse aggressive scripts, and psychiatric symptomatology (PANSS Positive, Negative, Disorganized, and Excited) all predicted HD, with the final model explaining 71.30% of the variance in HD. Trait anger, positive attitudes toward violence, and PANSS Emotional Distress did not predict HD. HD reflects a characteristic tendency toward interpersonal, affective, and behavioral problems marked by hostility and dominance, combined with a tendency toward frequent aggressive script rehearsal and more severe psychiatric symptomatology.


Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy.
Mutations in receptors, ion channels, and enzymes are frequently recognized by the cellular quality control system as misfolded and retained in the endoplasmic reticulum (ER) or otherwise misrouted. Retention results in loss of function at the normal site of biological activity and disease. Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action. Pharmacoperones of the gonadotropin releasing hormone receptor (GnRHR) have efficacy in cell culture systems, and their cellular and biochemical mechanisms of action are known. Here, we show the efficacy of a pharmacoperone drug in a small animal model, a knock-in mouse, expressing a mutant GnRHR. This recessive mutation (GnRHR E(90)K) causes hypogonadotropic hypogonadism (failed puberty associated with low or apulsatile luteinizing hormone) in both humans and in the mouse model described. We find that pulsatile pharmacoperone therapy restores E(90)K from ER retention to the plasma membrane, concurrently with responsiveness to the endogenous natural ligand, gonadotropin releasing hormone, and an agonist that is specific for the mutant. Spermatogenesis, proteins associated with steroid transport and steroidogenesis, and androgen levels were restored in mutant male mice following pharmacoperone therapy. These results show the efficacy of pharmacoperone therapy in vivo by using physiological, molecular, genetic, endocrine and biochemical markers and optimization of pulsatile administration. We expect that this newly appreciated approach of protein rescue will benefit other disorders sharing pathologies based on misrouting of misfolded protein mutants.


The Hippo pathway transcriptional co-activator, YAP, confers resistance to cisplatin in human oral squamous cell carcinoma.
Cisplatin (CDDP) is widely used to treat oral squamous cell carcinoma (OSCC), however, many patients exhibit acquired drug resistance. Yes-associated protein (YAP) is a transcriptional co-activator of the Hippo pathway that regulates organ size and promotes cell proliferation. YAP overexpression correlates with epithelial-mesenchymal transition and nodal metastasis, resulting in anti-tubulin drug resistance. Whether YAP overexpression is the cause of CDDP resistance in cancer cells is unclear, therefore, we investigated the correlation between YAP expression and CDDP sensitivity. We established three CDDP-resistant cell lines (OSC-19-R, SCCKN-R and HSC-3-R) from the OSCC parental cell lines. We also examined the expression levels of ATP7B, GST-π and ERCC1, which are strongly associated with CDDP resistance, and Hippo pathway-related proteins by western blotting. Using immunocytochemistry, we examined the cellular localization of YAP. Additionally, following knockdown of YAP using short interfering RNAs (siRNAs), we analyzed changes in sensitivity to CDDP. Compared with parental OSC-19 cells, OSC-19-R cells were obviously larger. Expression levels of YAP were not significantly different between OSC-19 and OSC-19-R. However, expression levels of phosphorylated YAP in OSC-19-R were decreased. We observed translocation of YAP from the cytoplasm to the nucleus in OSC-19-R cells. Knockdown of YAP using siRNAs revealed that sensitivity to CDDP was significantly increased. Translocation of YAP correlated with the acquisition of CDDP resistance. YAP could be a new therapeutic target for the treatment of patients with cancer that are resistant to CDDP.


Lymphatic vessels in human eyelids: an immunohistological study in dermatochalasis and chalazion.
We investigated lymphatic morphology and expression of endothelin (ET-1) axis molecules in human eyelids affected by an inflammatory state (chalazion) and an age-related degenerative condition (dermatochalasis). Lymphatics were immunohistologically detected by D2-40/LYVE-1 staining. Absorbing lymphatic vessels were localized in papillary dermis and around skin appendages with distinctive morphology. In chalazion, D2-40 reactive flattened lymphatic profiles were compressed by inflammatory infiltrate; in dermatochalasis, large fully opened lymphatics were observed, with a significantly wider total area (lymphatic lumina/200x field; p < 0.05). The lymphatic density (number/200x field) in the two groups was within the same range. Lymphatic dilation is possibly dependent on reduction and fragmentation of the dermal elastic network as well as of oxytalanic fibers in the papillary dermis of dermatochalasis, as shown by Weigert's reaction. Multifunctional peptide ET-1, involved in vasomotion, inflammation and connective proliferation, was faintly and discontinuously localized on lymphatics, as was its type A receptor. In contrast, the consistent expression of type B receptor indicates that lymphatic endothelium is a physiological target for ET-1, whose effects are modulated by multiple pathophysiological conditions. Thus, vasoactive factors play a role in the physiology of richly vascularized eyelids, and therefore, morphofunctional characterization of lymphatic vessels may be useful in suggesting treatment options.


A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study).
Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.


Evaluation of medical ethics competencies in rheumatology: local experience during national accreditation process.
Rheumatologists are the primary healthcare professionals responsible for patients with rheumatic diseases and should acquire medical ethical competencies, such as the informed consent process (ICP). The objective clinical structured examination is a valuable tool for assessing clinical competencies. We report the performance of 90 rheumatologist trainees participating in a station designed to evaluate the ICP during the 2018 and 2019 national accreditations. The station was validated and represented a medical encounter in which the rheumatologist informed a patient with systemic lupus erythematosus with clinically active nephritis about renal biopsy. A trained patient-actor and an evaluator were instructed to assess ICP skills (with a focus on kidney biopsy benefits, how the biopsy is done and potential complications) in obtaining formal informed consent, delivering bad news and overall communication with patients. The evaluator used a tailored checklist and form. Candidate performance varied with ICP content and was superior for potential benefit information (achieved by 98.9% of the candidates) but significantly reduced for potential complications (37.8%) and biopsy description (42.2%). Only 17.8% of the candidates mentioned the legal perspective of ICP. Death (as a potential complication) was omitted by the majority of the candidates (93.3%); after the patient-actor challenged candidates, only 57.1% of them gave a clear and positive answer. Evaluators frequently rated candidate communications skills as superior (≥80%), but ≥1 negative aspect was identified in 69% of the candidates. Ethical competencies are mandatory for professional rheumatologists. It seems necessary to include an ethics competency framework in the curriculum throughout the rheumatology residency.


"We are a family with diabetes": Parent perspectives on siblings of youth with type 1 diabetes.
Having a child with type 1 diabetes (T1D) impacts the entire family system. Parental distress and burden have been well studied, but other family members, including siblings, have received little attention. Based on research about family life and sibling experiences in other chronic condition populations (e.g., autism, cancer), we expected parents of youth with T1D would report that siblings participated in T1D management and that T1D had a psychological impact on siblings. As part of a larger qualitative study, parents of youth with T1D age 5-17 (M = 10.8 ± 3.6 years) participated in semistructured interviews about T1D-specific health-related quality of life. For this study, we conducted secondary analyses on transcripts from 20 parents (95% mothers) from households with at least 1 sibling of the child with T1D. Three themes emerged: (a) siblings share the workload and help with T1D management, (b) T1D takes an emotional toll on siblings, and (c) parents feel guilty about prioritizing T1D over siblings' needs and desires. Parents recognized siblings have impactful roles in T1D management and family functioning. Future research into these themes can guide clinical and research efforts to develop sibling-inclusive resources and interventions for families with T1D. Enhancing family-focused interventions to recognize and support the needs of siblings may ultimately improve family T1D-related quality of life. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Differences between chimpanzees and bonobos in neural systems supporting social cognition.
Our two closest living primate relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus), exhibit significant behavioral differences despite belonging to the same genus and sharing a very recent common ancestor. Differences have been reported in multiple aspects of social behavior, including aggression, sex, play and cooperation. However, the neurobiological basis of these differences has only been minimally investigated and remains uncertain. Here, we present the first ever comparison of chimpanzee and bonobo brains using diffusion tensor imaging, supplemented with a voxel-wise analysis of T1-weighted images to specifically compare neural circuitry implicated in social cognition. We find that bonobos have more gray matter in brain regions involved in perceiving distress in both oneself and others, including the right dorsal amygdala and right anterior insula. Bonobos also have a larger pathway linking the amygdala with the ventral anterior cingulate cortex, a pathway implicated in both top-down control of aggressive impulses as well as bottom-up biases against harming others. We suggest that this neural system not only supports increased empathic sensitivity in bonobos, but also behaviors like sex and play that serve to dissipate tension, thereby limiting distress and anxiety to levels conducive with prosocial behavior.


Equal dependence of the high prevalence of health problems on age and family income in rural southern areas.
People who have periods of low family income are at risk for increased health problems in the future, even if they present a similar clinical picture before the reduction in family income. The association between low income and health status was studied in residents of an area with relatively low-average family income and with a historically unstable economy. We surveyed a stratified, clustered sample of residents of Johnson County, Tennessee, using a structured interview. The responses were analyzed in conjunction with national and regional data (National Health Interview Survey). Residents of the geographic area under study had a markedly higher prevalence of self-reported health problems than either the national average or rural areas in the southeast United States. The higher prevalence was accounted for by the combination of age and family income, which had equal effects on health status, but not by age differences alone. Family income and economic development are critically important to improving community health. Sensible capitation rates in managed care arrangements can be obtained only if the income distribution of an insured population is considered along with their age, sex, and physical health status.


The effect of strain rate on the mechanical properties of human cortical bone.
Bone mechanical properties are typically evaluated at relatively low strain rates. However, the strain rate related to traumatic failure is likely to be orders of magnitude higher and this higher strain rate is likely to affect the mechanical properties. Previous work reporting on the effect of strain rate on the mechanical properties of bone predominantly used nonhuman bone. In the work reported here, the effect of strain rate on the tensile and compressive properties of human bone was investigated. Human femoral cortical bone was tested longitudinally at strain rates ranging between 0.14-29.1 s(-1) in compression and 0.08-17 s(-1) in tension. Young's modulus generally increased, across this strain rate range, for both tension and compression. Strength and strain (at maximum load) increased slightly in compression and decreased (for strain rates beyond 1 s(-1)) in tension. Stress and strain at yield decreased (for strain rates beyond 1 s(-1)) for both tension and compression. In general, there seemed to be a relatively simple linear relationship between yield properties and strain rate, but the relationships between postyield properties and strain rate were more complicated and indicated that strain rate has a stronger effect on postyield deformation than on initiation of yielding. The behavior seen in compression is broadly in agreement with past literature, while the behavior observed in tension may be explained by a ductile to brittle transition of bone at moderate to high strain rates.


Analysis of Training Plans in Basketball: Gender and Formation Stage Differences.
Scientific literature has stated the presence of various stages in athletes sportive development, with different objectives in each one of them. This should lead coaches to different training plans according to the athlete's formation stage. The aim of this study was to analyse training plans and identify differences in basketball objectives according to formative stages (U'12 and U'14) in boys and girls. A total of 1,976 training tasks were collected and analysed, for a total of four teams (girls and boys of U'12 and U'14 categories) during an entire season. Pedagogical variables, game phases, game situations, training means and content were studied. The results showed significant differences between genders. Girls' teams performed more tasks on offense and technical skills. By contrast, boys' teams performed more defensive tasks and tactical contents. The 1-on-0 and 1-on-1 were the most repeated game situations in all teams. Coaches used different training tasks according to gender and age. In male U'12 teams, drills predominated, whereas in the other categories, games predominated. For boys' teams, the contents were tactical oriented, and for girls' teams, the contents were oriented toward skill acquisition. Studying the pedagogical variables of the training process allowed for identification of the utility of training, assessment, and modification of this process.


Genome-Wide Identification of the Vacuolar H+-ATPase Gene Family in Five Rosaceae Species and Expression Analysis in Pear (Pyrus bretschneideri).
Vacuolar H+-ATPases (V-ATPase) are multi-subunit complexes that function as ATP hydrolysis-driven proton pumps. They play pivotal roles in physiological processes, such as development, metabolism, stress, and growth. However, there have been very few studies on the characterisation of V-ATPase (VHA) genes in Rosaceae species. Therefore, in the present study, we performed a genome-wide analysis and identified VHA gene family members in five Rosaceae species (Pyrus bretschneideri, Malus domestica, Prunus persica, Fragaria vesca, and Prunus mume). A total of 159 VHA genes were identified, and were classified into 13 subfamilies according to the phylogenetic analysis. The structure of VHA proteins revealed high similarity among different VHA genes within the same subgroup. Gene duplication event analysis revealed that whole-genome duplications represented the major pathway for expansion of the Pyrus bretschneideri VHA genes (PbrVHA genes). The tissue-specific expression analysis of the pear showed that 36 PbrVHA genes were expressed in major tissues. Seven PbrVHA genes were significantly downregulated when the pollen tube growth stopped. Moreover, many PbrVHA genes were differentially expressed during fruit development and storage, suggesting that VHA genes play specific roles in development and senescence. The present study provides fundamental information for further elucidating the potential roles of VHA genes during development and senescence.


The effect of alendronate therapy on osteoporotic fracture in the vertebral fracture arm of the Fracture Intervention Trial.
Results from the now-complete Vertebral Fracture Study have been reported elsewhere. The purpose of this report is to review these results in the context of the overall design and implementation of the Fracture Intervention Trial (FIT), and to comment on their implications for clinical practice. The FIT results have important implications for the treatment of osteoporosis in clinical practice. The 51% decrease in the incidence of hip fracture represents the first documentation of any medication's ability to prevent fractures of the hip in community-dwelling women. The 48% reduction in the incidence of morphometrically documented vertebral fracture is also important, as these types of fracture are associated with significant pain and disability and are predictive of future vertebral and hip fractures.


The use of natural bio-agents for the control of cotton phytopathogens.
The use of natural antagonists as means of pre-sowing seed treatment showed high biological efficacy by improving seed germination, growth and productivity of cotton plants, and by decreasing infection by major cotton pathogens: Xanthomonas malvacearum, Rhizoctonia solani, Fusarium oxysporum f. sp. vasinfectum, Verticillium dahliae. Studies of anti-microbial properties of antagonists revealed significant inhibitory activity of Bacillus subtilis strains and their metabolites against cotton pathogens. Obtained results prove the prospective from the use of B. subtilis for developing complex, ecological products for biological control of cotton and other agricultural plants.


The Relationship between Total Water Intake and Cognitive Control among Prepubertal Children.
Cognitive control (also known as executive function) encompasses mental processes that underlie goal-directed behavior, and it enables us to adjust our behavior according to changing environmental demands. Previous research among children has demonstrated that aerobic fitness and obesity have contrasting and selective effects on cognitive control. However, the relationship between water intake and childhood cognitive control remains inadequately studied. This study investigated the relationship between total water intake and cognitive control among prepubertal children (8-9-year olds). Children between 8 and 9 years of age (n = 63) performed a modified flanker task to assess cognitive control related to inhibition (ability to resist distractions and maintain focus). Diet was measured using 3-day food records. Total water was defined as water consumed from drinking water, beverages, and food. A comparison of task performance across the median intake of total water revealed that children above the median exhibited shorter reaction times across multiple conditions of the flanker task, requiring variable amounts of cognitive control. Further, after adjustment of age, IQ, socioeconomic status, weight status, and aerobic fitness level, the proportion of intake comprised of water (%TW) was negatively correlated with reaction time interference, that is, the ability to maintain task performance when task conditions demanded greater inhibition. These results indicate an association between water intake and cognitive control using a task that modulates inhibition. Specifically, higher water intake correlated with greater ability to maintain task performance when inhibitory demands are increased. Future work is needed to determine the mechanism by which water influences cognitive control among children.


Effects of Flavonoids on Cancer, Cardiovascular and Neurodegenerative Diseases: Role of NF-κB Signaling Pathway.
Flavonoids are polyphenolic phytochemical compounds found in many plants, fruits, vegetables, and leaves. They have a multitude of medicinal applications due to their anti-inflammatory, antioxidative, antiviral, and anticarcinogenic properties. Furthermore, they also have neuroprotective and cardioprotective effects. Their biological properties depend on the chemical structure of flavonoids, their mechanism of action, and their bioavailability. The beneficial effects of flavonoids have been proven for a variety of diseases. In the last few years, it is demonstrated that the effects of flavonoids are mediated by inhibiting the NF-κB (Nuclear Factor-κB) pathway. In this review, we have summarized the effects of some flavonoids on the most common diseases, such as cancer, cardiovascular, and human neurodegenerative diseases. Here, we collected all recent studies describing the protective and prevention role of flavonoids derived from plants by specifically focusing their action on the NF-κB signaling pathway.


A machine learning driven monogram for predicting chronic kidney disease stages 3-5.
Chronic kidney disease (CKD) remains one of the most prominent global causes of mortality worldwide, necessitating accurate prediction models for early detection and prevention. In recent years, machine learning (ML) techniques have exhibited promising outcomes across various medical applications. This study introduces a novel ML-driven monogram approach for early identification of individuals at risk for developing CKD stages 3-5. This retrospective study employed a comprehensive dataset comprised of clinical and laboratory variables from a large cohort of diagnosed CKD patients. Advanced ML algorithms, including feature selection and regression models, were applied to build a predictive model. Among 467 participants, 11.56% developed CKD stages 3-5 over a 9-year follow-up. Several factors, such as age, gender, medical history, and laboratory results, independently exhibited significant associations with CKD (p < 0.05) and were utilized to create a risk function. The Linear regression (LR)-based model achieved an impressive R-score (coefficient of determination) of 0.954079, while the support vector machine (SVM) achieved a slightly lower value. An LR-based monogram was developed to facilitate the process of risk identification and management. The ML-driven nomogram demonstrated superior performance when compared to traditional prediction models, showcasing its potential as a valuable clinical tool for the early detection and prevention of CKD. Further studies should focus on refining the model and validating its performance in diverse populations.


Comprehensive evaluation of treatment and outcomes of low-grade diffuse gliomas.
Low-grade gliomas affect younger adults and carry a favorable prognosis. They include a variety of biological features affecting clinical behavior and treatment. Having no guidelines on treatment established, we aim to describe clinical and treatment patterns of low-grade gliomas across the largest cancer database in the United States. We analyzed the National Cancer Database from 2004 to 2015, for adult patients with a diagnosis of World Health Organization grade II diffuse glioma. We analyzed 13,621 cases with median age of 41 years. Over 56% were male, 88.4% were white, 6.1% were black, and 7.6% Hispanic. The most common primary site location was the cerebrum (79.9%). Overall, 72.2% received surgery, 36.0% radiation, and 27.3% chemotherapy. Treatment combinations included surgery only (41.5%), chemotherapy + surgery (6.6%), chemotherapy only (3.1%), radiation + chemotherapy + surgery (10.7%), radiation + surgery (11.5%), radiation only (6.1%), and radiotherapy + chemotherapy (6.7%). Radiation was more common in treatment of elderly patients, 1p/19q co-deletion (37.3% versus 24.3%, p<0.01), and tumors with midline location. Median survival was 11 years with younger age, 1p/19q co-deletion, and cerebrum location offered survival advantage. Tumor location, 1p/19q co-deletion, and age were the main determinants of treatment received and survival, likely reflecting tumor biology differences. Any form of treatment was preferred over watchful waiting in the majority of the patients (86.1% versus 8.1%). Survival of low-grade gliomas is higher than previously reported in the majority of clinical trials and population-based analyses. Our analysis provides a real world estimation of treatment decisions, use of molecular data, and outcomes.


The Effect of the Addition of Apulian black Chickpea Flour on the Nutritional and Qualitative Properties of Durum Wheat-Based Bakery Products.
Historically cultivated in Apulia (Southern Italy), Apulian black chickpeas are rich in bioactive compounds such as anthocyanins. This type of chickpea is being replaced by modern cultivars and is at risk of genetic erosion; therefore, it is important to explore its potential for new food applications. The aim of this work was to assess the effect of the addition of Apulian black chickpea wholemeal flour on the nutritional and qualitative properties of durum wheat-based bakery products; namely bread, "focaccia" (an Italian traditional bakery product similar to pizza), and pizza crust. Composite meals were prepared by mixing Apulian black chickpea wholemeal flour with re-milled semolina at 10:90, 20:80, 30:70, and 40:60. The rheological properties, evaluated by farinograph, alveograph, and rheofermentograph, showed a progressive worsening of the bread-making attitude when increasing amounts of chickpea flour were added. The end-products expanded less during baking, and were harder and darker than the corresponding conventional products, as assessed both instrumentally and by sensory analysis. However, these negative features were balanced by higher contents of fibre, proteins, and bioactive compounds, as well as higher antioxidant activity.


Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox.
Endothelial cells (ECs) and platelets, which respectively produce antithrombotic prostacyclin and prothrombotic thromboxane A2, both express COX1 (cyclooxygenase1). Consequently, there has been no way to delineate any antithrombotic role for COX1-derived prostacyclin from the prothrombotic effects of platelet COX1. By contrast, an antithrombotic role for COX2, which is absent in platelets, is straightforward to demonstrate. This has resulted in an incomplete understanding of the relative importance of COX1 versus COX2 in prostacyclin production and antithrombotic protection in vivo. We sought to identify the role, if any, of COX1-derived prostacyclin in antithrombotic protection in vivo and compare this to the established protective role of COX2. We developed vascular-specific COX1 knockout mice and studied them alongside endothelial-specific COX2 knockout mice. COX1 immunoreactivity and prostacyclin production were primarily associated with the endothelial layer of aortae; freshly isolated aortic ECs released >10-fold more prostacyclin than smooth muscle cells. Moreover, aortic prostacyclin production, the ability of aortic rings to inhibit platelet aggregation and plasma prostacyclin levels were reduced when COX1 was knocked out in ECs but not in smooth muscle cells. When thrombosis was measured in vivo after FeCl3 carotid artery injury, endothelial COX1 deletion accelerated thrombosis to a similar extent as prostacyclin receptor blockade. However, this effect was lost when COX1 was deleted from both ECs and platelets. Deletion of COX2 from ECs also resulted in a prothrombotic phenotype that was independent of local vascular prostacyclin production. These data demonstrate for the first time that, in healthy animals, endothelial COX1 provides an essential antithrombotic tone, which is masked when COX1 activity is lost in both ECs and platelets. These results help us define a new 2-component paradigm wherein thrombotic tone is regulated by both COX1 and COX2 through complementary but mechanistically distinct pathways.


Crystal structure of the avian reovirus inner capsid protein sigmaA.
Avian reovirus, an important avian pathogen, expresses eight structural and four nonstructural proteins. The structural sigmaA protein is a major component of the inner capsid, clamping together lambdaA building blocks. sigmaA has also been implicated in the resistance of avian reovirus to the antiviral action of interferon by strongly binding double-stranded RNA in the host cell cytoplasm and thus inhibiting activation of the double-stranded RNA-dependent protein kinase. We have solved the structure of bacterially expressed sigmaA by molecular replacement and refined it using data to 2.3-A resolution. Twelve sigmaA molecules are present in the P1 unit cell, arranged as two short double helical hexamers. A positively charged patch is apparent on the surface of sigmaA on the inside of this helix and mutation of either of two key arginine residues (Arg155 and Arg273) within this patch abolishes double-stranded RNA binding. The structural data, together with gel shift assay, electron microscopy, and sedimentation velocity centrifugation results, provide evidence for cooperative binding of sigmaA to double-stranded RNA. The minimal length of double-stranded RNA required for sigmaA binding was observed to be 14 to 18 bp.


Crosstalk between MSH2-MSH3 and polβ promotes trinucleotide repeat expansion during base excision repair.
Studies in knockout mice provide evidence that MSH2-MSH3 and the BER machinery promote trinucleotide repeat (TNR) expansion, yet how these two different repair pathways cause the mutation is unknown. Here we report the first molecular crosstalk mechanism, in which MSH2-MSH3 is used as a component of the BER machinery to cause expansion. On its own, pol β fails to copy TNRs during DNA synthesis, and bypasses them on the template strand to cause deletion. Remarkably, MSH2-MSH3 not only stimulates pol β to copy through the repeats but also enhances formation of the flap precursor for expansion. Our results provide direct evidence that MMR and BER, operating together, form a novel hybrid pathway that changes the outcome of TNR instability from deletion to expansion during the removal of oxidized bases. We propose that cells implement crosstalk strategies and share machinery when a canonical pathway is ineffective in removing a difficult lesion.


Projected long-term costs of coronary stenting in multivessel coronary disease based on the experience of the Bypass Angioplasty Revascularization Investigation (BARI).
Stents are now used in the majority of percutaneous coronary revascularization procedures. It is not clear whether the higher initial cost of stenting is later repaid by reducing costly complications and repeat revascularization procedures, especially for patients with multivessel disease. To project the long-term costs of using coronary stents, angioplasty, or bypass surgery to treat patients with multivessel coronary artery disease, we developed a decision model based on the outcomes documented in the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial of coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA). We studied 2 clinical strategies: provisional stenting of suboptimal PTCA results and primary stenting of all angiographically eligible lesions. The cost of CABG was also updated to reflect contemporary practice. Provisional stenting had lower projected costs over a 4-year period than either traditional PTCA (-$1742, or -3.4%) or contemporary CABG (-$832, or -1.7%), mostly because of reductions in emergency CABG after PTCA. In contrast, primary stenting had higher projected costs over a 4-year period than either PTCA (+$333, or +0. 7%) or contemporary CABG (+$1243, or +2.5%), mainly because of the higher initial procedure costs. These results were not substantially altered when we systematically varied the key parameters of the models in 1-way and 2-way sensitivity analyses. A primary stenting strategy in patients with multivessel disease has higher projected long-term costs than CABG. In contrast, a provisional stenting strategy in multivessel disease has lower projected costs than either PTCA or CABG.


Role of Fc fragments in antibody-mediated recovery from ocular and subcutaneous herpes simplex virus infections.
The contributions of the Fc fragment of virus-specific antibody in the resistance of mice to peripheral herpes simplex virus infection were investigated. Rabbit anti-herpes simplex virus-specific F(ab')2 fragments prepared by pepsin digestion of immune immunoglobulin G (IgG) were found to be inactive in complement-mediated cytolysis while retaining their capacity to neutralize virus infectivity in vitro. When F(ab')2 fragments were passively transferred either before or simultaneously with virus inoculation, they were as efficient as intact IgG was in protecting animals from virus challenge. However, if passive transfer was delayed until 8 h after herpes simplex virus infection, only IgG antibody was protective. The loss of protective activity could not be attributed to a rapid disappearance of F(ab')2 fragments, because comparable levels of F(ab')2 fragments and IgG antibody were maintained in the blood of recipients during the time that antibody mediated its protective effects. The inability of F(ab')2 subunits to activate complement was also not a factor, because complement-deficient A/J mice and complement-sufficient SJL/J mice recovered from herpes simplex virus infection after the passive transfer of IgG. We concluded that the Fc component of the antibody molecule is needed to resolve intracellular infection and that the mechanism by which antibody mediates recovery remains undefined but does not appear to involve virus neutralization or complement activation.


Influence of adriamycin and adriamycin-radiation combination on jejunal proliferation in the mouse.
The influence of adriamycin and adriamycin-radiation combinations on posttreatment proliferative activity of the mouse jejunum was examined by measuring [3H]thymidine incorporation. Single doses of 5 or 10 mg/kg produced a transient reduction in the proliferative activity, while 1 mg/kg had little effect. After 10 mg/kg, there was a rapid decrease in the number of mitotic figures, followed by a gradual decrease in the number of and rate of DNA synthesis in S-phase cells. A compensatory epithelial hyperplasia characterized by an enlarged crypt proliferative population and shortened mitotic cycle duration was observed beginning 48 hr after treatment. Multiple doses of adriamycin totalling 10 mg/kg inhibited cell production to a greater extent than the equivalent single dose. In combination with 1000 R, adriamycin (5 mg/kg) given from 96 hr before to 72 hr after irradiation reduced the amount of postirradiation proliferation.


Development of a tool to assess and advance the effectiveness of preceptors: The Habits of Preceptors Rubric.
Present the research performed to identify and describe habits of effective pharmacy preceptors and provide a framework for targeted preceptor assessment and development. A 5-round Delphi consensus-building process was used to refine the initial Habits of Preceptors Rubric (HOP-R) developed by the research team. Twenty experts in pharmacy experiential education participated. During the Delphi process, feedback and agreement on all parts of the HOP-R were sought, including the premise, introductory content, framework, preceptor domains, habits, habit level descriptions, and continuous professional development (CPD) plan. After each Delphi round, the research team grouped responses into themes and modified the draft rubric accordingly. These themes were used to frame the response document sent to the expert panel for the following Delphi round; this document explained modifications made to the HOP-R. Consensus was defined as a mean score of ≥3.25 on a 4-point scale (4 = strongly agree, 1 = strongly disagree) for posed statements or ≥70% agreement for ranked items. In the final Delphi round (response rate, 95%), consensus was achieved for all HOP-R individual structural and content elements except the habit level descriptors, for which a secondary rank order analysis was performed. The final HOP-R has 3 domains encompassing 11 preceptor habits that can be displayed across 4 habit levels progressing from developing to master. The HOP-R was developed to assess, quantify, and demonstrate growth across a wide variety of pharmacy preceptor habits. Potential utility includes use as a framework to articulate the knowledge, skills, and behaviors of effective preceptors, facilitate the creation of individualized CPD plans, and assess the impact of participation in teaching and learning curricula.


Proposal to construct the operational base of the educative work process in collective health.
This study aimed to construct the operational base of the educative work in health from a Marxist perspective. Reports of nursing experiences in the basic health services, published between 1988-2003, served as empirical base. The object was captured from: the participants; the action agents; the objective; health and education conceptions; and the generating necessity. The means/instruments were identified through: physical space; didactic resources; frequency of meetings; and the conception of health education. The type of evaluation; to whom it was directed; the goal to be reached and articulation between the theoretical and operational knowledge were identified in order to capture the purpose. The educative work in collective health can strengthen social groups when it becomes praxis that assumes the participant as a dialogical co-producer of the work in health.


[A microsatellite marker linked to the stripe rust resistance gene YrV23 in the wheat variety Vilmorin23].
Vilmorin23 is an internationally used differential host variety for studies on the interactions between wheat stripe rust and wheat. It contains the stripe rust resistance gene YrV23 and is potentially an important source of stripe rust resistance worldwide. SSR analysis was performed on the wheat NIL Taichuang 29*6/YrV23 carrying the resistant gene YrV23 against stripe rust, Vilmorin 23 and its recurrent parent Taichung 29. Fifty pairs of SSR primers on wheat chromosome 2B were screened and a reproducible polymorphic DNA fragment amplified by Xwmc356 was found. Genetic linkage was tested on 150 segregating F2 plants. It showed that the microsatellite marker Xwmc356 was linked to the resistance gene YrV23 with a genetic distance of 9.4 cM.