Anatomical Adaptation-Early Clinical Evidence of Benefit and Future Needs in Lung Cancer.
Definitive treatment of locally advanced non-small-cell lung cancer with radiation is challenging. During the course of treatment, anatomical changes such as tumor regression, tumor displacement/deformation, pleural effusion, and/or atelectasis can result in a deviation of the administered radiation dose from the intended prescribed treatment and thereby worsen local control and toxicity. Adaptive radiotherapy can help correct for these changes and can be generally categorized into 3 philosophical paradigms: (1) maintenance of prescribed dose to the initially defined target volume; (2) dose reduction to healthy organs while maintaining initial prescribed dose to a regressing tumor volume; or (3) dose escalation to a regressing tumor volume with isotoxicity to healthy organs. Numerous single institution studies have investigated these methods, and results from large prospective clinical trials will hopefully provide consensus on the method, utility, and efficacy of implementing adaptive radiation therapy (ART) in a clinical setting. Additional development into standardization and automation of the ART workflow, specifically in identifying when ART is warranted and in reducing the manual clinical effort needed to produce an adaptive plan, will be paramount to making ART feasible for the broader radiation therapy community.


Mechanisms of acetylcholine receptor loss in myasthenia gravis.
The fundamental abnormality affecting the neuromuscular junctions of myasthenic patients is a reduction of available AChRs, due to an autoimmune attack directed against the receptors. Antibodies to AChR are present in most patients, and there is evidence that they have a predominant pathogenic role in the disease, aided by complement. The mechanism of antibody action involves acceleration of the rate of degradation of AChRs, attributable to cross-linking of the receptors. In addition, antibodies may block AChRs, and may participate in producing destructive changes, perhaps in conjunction with complement. The possibility that cell-mediated mechanisms may play a role in the autoimmune responses of some myasthenic patients remains to be explored. Although the target of the autoimmune attack in myasthenic patients is probably always the acetylcholine receptors, it is not yet clear which of these immune mechanisms are most important. It is likely that the relative role of each mechanism varies from patient to patient. One of the goals of future research will be to identify the relative importance of each of these mechanisms in the individual patient, and to tailor specific immunotherapeutic measures to the abnormalities found.


Discovery of the teleomorph of the hyphomycete, Sterigmatobotrys macrocarpa, and epitypification of the genus to holomorphic status.
Sterigmatobotrys macrocarpa is a conspicuous, lignicolous, dematiaceous hyphomycete with macronematous, penicillate conidiophores with branches or metulae arising from the apex of the stipe, terminating with cylindrical, elongated conidiogenous cells producing conidia in a holoblastic manner. The discovery of its teleomorph is documented here based on perithecial ascomata associated with fertile conidiophores of S. macrocarpa on a specimen collected in the Czech Republic; an identical anamorph developed from ascospores isolated in axenic culture. The teleomorph is morphologically similar to species of the genera Carpoligna and Chaetosphaeria, especially in its nonstromatic perithecia, hyaline, cylindrical to fusiform ascospores, unitunicate asci with a distinct apical annulus, and tapering paraphyses. Identical perithecia were later observed on a herbarium specimen of S. macrocarpa originating in New Zealand. Sterigmatobotrys includes two species, S. macrocarpa, a taxonomic synonym of the type species, S. elata, and S. uniseptata. Because no teleomorph was described in the protologue of Sterigmatobotrys, we apply Article 59.7 of the International Code of Botanical Nomenclature. We epitypify (teleotypify) both Sterigmatobotrys elata and S. macrocarpa to give the genus holomorphic status, and the name S. macrocarpa is adopted for the holomorph. To evaluate the ordinal and familial affinities of Sterigmatobotrys and its relationships with the morphologically similar genera Carpoligna and Chaetosphaeria, phylogenetic relationships were inferred based on aligned sequences of the large subunit nuclear ribosomal DNA (ncLSU rDNA).


Direct measurement of wound and tissue oxygen tension in postoperative patients.
An implanted Silastic catheter technique was used to measure partial pressure of oxygen in mastectomy wounds and needle-induced wounds in the subcutaneous tissue of the arms of 33 postoperative patients to assess tissue-wound oxygenation and perfusion on the day of operation and daily through postoperative day five. Characteristic patterns were observed. Wound hypoxia was common and most pronounced after abdominal, vascular, and cardiac procedures. It was most severe immediately after operation. Tissue hypoxia was not easily detected by clinical evaluation and was unknowingly tolerated by experienced surgeons. The relationship between arterial and tissue PO2 is biphasic and presumably curvilinear at the lower range of PaO2 and rises linearly even above the point of full saturation of hemoglobin. Supplemental bolus fluid infusion elevated depressed tissue PO2 in 19 out of 19 measurements, implicating hypovolemia as a common cause of postoperative tissue hypoxia. Measurements of tissue oxygen tension, coupled with a single arterial oxygen determination, constitute a clinically useful means of monitoring tissue perfusion.


Effects of patient-, environment- and medication-related factors on high-alert medication incidents.
To measure the rate of medication incidents associated with the prescription and administration of high-alert medications and to identify patient-, environment- and medication-related factors associated with these incidents. A retrospective chart audit design was conducted of medical records for patient admissions from 1 January 2010 to 31 December 2010. Five practice settings (cardiac care, emergency care, intensive care, oncology care and perioperative care) at a public teaching hospital in Melbourne, Australia. Patients were considered for inclusion if they were prescribed at least one high-alert medication and if they were admitted to one of five practice settings. High-alert prescribing and administering incidents were measured in each of the five practice settings. Generalized linear mixed modeling was used for data analysis. There were 6984 opportunities for high-alert medication incidents across the five clinical settings. The overall medication incident rate was 1934/6984 (27.69%). There were 1176 prescribing incidents (16.84%) and 758 administering incidents (10.85%). Statistical modeling showed that, in each of the five clinical settings, an increased number of ward transfers was associated with increased odds of prescribing incidents. In addition, statistical modeling demonstrated that an increased number of ward transfers was associated with increased odds of administering incidents in emergency care and perioperative care. Complex relationships were found in managing high-alert medications in specialty clinical settings. Employing measures to address patients' movements across ward settings can reduce high-alert medication incidents and improve quality of care.


Female health workers at the doorstep: a pilot of community-based maternal, newborn, and child health service delivery in northern Nigeria.
Nigeria has one of the highest maternal mortality ratios in the world. Poor health outcomes are linked to weak health infrastructure, barriers to service access, and consequent low rates of service utilization. In the northern state of Jigawa, a pilot study was conducted to explore the feasibility of deploying resident female Community Health Extension Workers (CHEWs) to rural areas to provide essential maternal, newborn, and child health services. Between February and August 2011, a quasi-experimental design compared service utilization in the pilot community of Kadawawa, which deployed female resident CHEWs to provide health post services, 24/7 emergency access, and home visits, with the control community of Kafin Baka. In addition, we analyzed data from the preceding year in Kadawawa, and also compared service utilization data in Kadawawa from 2008-2010 (before introduction of the pilot) with data from 2011-2013 (during and after the pilot) to gauge sustainability of the model. Following deployment of female CHEWs to Kadawawa in 2011, there was more than a 500% increase in rates of health post visits compared with 2010, from about 1.5 monthly visits per 100 population to about 8 monthly visits per 100. Health post visit rates were between 1.4 and 5.5 times higher in the intervention community than in the control community. Monthly antenatal care coverage in Kadawawa during the pilot period ranged from 11.9% to 21.3%, up from 0.9% to 5.8% in the preceding year. Coverage in Kafin Baka ranged from 0% to 3%. Facility-based deliveries by a skilled birth attendant more than doubled in Kadawawa compared with the preceding year (105 vs. 43 deliveries total, respectively). There was evidence of sustainability of these changes over the 2 subsequent years. Community-based service delivery through a resident female community health worker can increase health service utilization in rural, hard-to-reach areas.


Health care reform: managed competition and beyond.
Since the election, the health care reform debate has focused on three broad features: implementation of managed competition, changes in the tax treatment of health insurance, and the imposition of budget caps or targets. The basic element of managed competition is the creation of sponsors who act as collective purchasing agents for large groups of individuals. One of the potentially most politically difficult issues in implementing any health care reform proposal is likely to be defining the minimum standard benefit package. It will determine the costs society bears, the income of providers, the health of many individuals, and the attributes of a workable health care reform package. Managed competition is intended to foster competition among health plans on the basis of cost and quality. The measures of quality actually employed in the health care system will determine in large part the incentives faced by insurers, providers, and consumers. The problem of adverse selection is potentially the most important issue in reforming the health insurance market. If individuals can opt not to purchase health benefits, poorer risks will be more likely to purchase health insurance than good risks, and at minimum the price of these benefits will be higher than would otherwise be the case. Managed competition requires that individuals share at least some of the financial consequences of their choices among health plans. As a result, most managed competition proposals change the tax code by limiting the exclusion of employer contributions to health insurance from worker's taxable income. Changing the health insurance market, mandating employer health benefits, and changing the tax code may have significant effects on the health care delivery system, but they are unlikely to reduce health care cost inflation in the near term. One of the proposals for restraining the growth in health care costs is the imposition of a budget on the amount spent on health care services. The combination of the constraints placed on federal governmental action by the budget and the significant political problems involved in reaching a consensus on the important elements of health care reform may limit the ability of the federal government to implement national health care reform in the near term. As a result, individual states may be encouraged by the federal government to continue to experiment with their own health reform programs.


X-ray emission spectroscopy: an effective route to extract site occupation of cations.
Cation site occupation is an important determinant of materials properties, especially in a complex system with multiple cations such as in ternary spinels. Many methods for extracting the cation site information have been explored in the past, including analysis of spectra obtained through K-edge X-ray absorption spectroscopy (XAS). In this work, we measure the effectiveness of X-ray emission spectroscopy (XES) for determining the cation site occupation. As a test system we use spinel phase CoxMn3-xO4 nanoparticles contaminated with CoO phases because Co and Mn can occupy all cation sites and the impurity simulates typical products of oxide syntheses. We take advantage of the spin and oxidation state sensitive Kβ1,3 peak obtained using XES and demonstrate that XES is a powerful and reliable technique for determining site occupation in ternary spinel systems. Comparison between the extended X-ray absorption fine structure (EXAFS) and XES techniques reveals that XES provides not only the site occupation information as EXAFS, but also additional information on the oxidation states of the cations at each site. We show that the error for EXAFS can be as high as 35% which makes the results obtained ambiguous for certain stoichiometries, whereas for XES, the error determined is consistently smaller than 10%. Thus, we conclude that XES is a superior and a far more accurate method than XAS in extracting cation site occupation in spinel crystal structures.


[Treatment of inflammatory diseases of the brain with kanamycin].
On the basis of clinical trials with 20 patients suffering from acute inflammatory diseases of the brain recommendations for determination of indications for rational use of kanamycin were formulated. Kanamycin proved to be effective in treatment of severe forms of neuroinfections caused by gramnegative bacteria, as well as mixed and resistant staphylococcal infections. With the account of the clinical state the use of the drug should be preceded by bacteriological tests with qualitative and quantitative determination of sensitivity of the isolates to the antibiotics.


Research on the influence path of the unit environment of medical and health institutions on achievement transformation output.
To analyze the influence path of the interaction between the unit environment, achievement transformation willingness, and achievement transformation cognition on achievement transformation output to provide a basis for optimizing the achievement transformation environment of medical and health institutions and improving the efficiency of scientific and technological achievements transformation. Through the questionnaire survey, 292 data points were obtained. SPSS20.0 was used to conduct cross-table chi-square analysis and binary logistic regression analysis on the willingness, cognition, and output of scientific and technological achievements transformation. The process 14.0 plug-in is used to analyze the mediating effect of transformation cognition and the moderating effect of the unit environment. Achievement transformation willingness has a significant positive impact on achievement transformation cognition and achievement transformation output. Achievement transformation cognition has a positive impact on achievement transformation output, and the mediating effect of transformation cognition is significant and partial. The unit environment has a negative moderating effect on the influence of achievement transformation willingness on achievement transformation cognition, and a positive moderating effect on the influence of achievement transformation willingness on achievement transformation output. Personal factors and unit achievement transformation environment have an obvious influence on the willingness and cognition of achievement transformation. It is necessary to optimize the environment of unit scientific and technological achievements transformation, improve the policy system of benefiting from the achievements of scientific and technological achievements transformation of medical and health personnel, implement the disposal right, income right and distribution right of scientific and technological achievements transformation of medical and health institutions, and stimulate the enthusiasm of scientific and technological achievements transformation of medical and health personnel.


Occurrence of plasmid-mediated quinolone resistance determinants and rmtB gene in Salmonella enterica serovar enteritidis and Typhimurium isolated from food-animal products in Tunisia.
Four hundred and thirty Salmonella isolates, recovered from various food-animal products, were tested for nalidixic acid resistance, plasmid-mediated quinolone resistance, and genetic relationship. One hundred fifteen isolates (113 Salmonella serovar Enteritidis and two Salmonella serovar Typhimurium isolates) of 430 (26.7%) Salmonella isolates exhibited nalidixic acid resistance. Polymerase chain reaction screening for qnrA, qnrB, qnrS, qepA (encoding fluoroquinolones resistance) and rmtB (encoding aminoglycosides resistance) showed that 5 (1.16%) isolates were positive for qnr- and qepA-type genes, and the aac(6')-Ib-cr gene was observed in two (1.7%) Enteritidis isolates concomitantly with qnrA or qnrB. The co-occurrence of qepA and rmtB in one Typhimurium isolate is noteworthy. Pulsed-field gel electrophoresis revealed a high genetic homogeneity of nalidixic-resistant isolates and the persistence of clonal clusters over 4 years in different regions in Tunisia and from various food-animal products. To the best of our knowledge, this is the first report of co-occurrence of qepA and rmtB in a Salmonella strain.


Targeted nucleotide exchange in the alkaline phosphatase gene of HuH-7 cells mediated by a chimeric RNA/DNA oligonucleotide.
Although a variety of methods has been devised for modification of hepatic genes, none has been effective for long-term correction of genetic disorders. In this study, we employed a recently described novel experimental strategy for site-directed nucleotide exchange in genomic DNA of HuH-7 human hepatoma cells. A chimeric 2'-O-methylated-RNA/DNA oligonucleotide containing sequences complementary to 25 bases of the alkaline phosphatase gene was constructed as a duplex containing a G to A substitution at nucleotide 935. Cells were transfected with oligonucleotides for 48 hours, then harvested for DNA isolation and polymerase chain reaction (PCR) amplification of exon 6 of the alkaline phosphatase gene. Colony lifts were hybridized to 17 mer 32P-labeled oligonucleotide probes specific to the 935-G and 935-A sequences. Hybridizing colonies were grown, plasmid DNA isolated, and sequenced. Transfection efficiency was determined at 24 hours by nuclear uptake of fluorescein-12-dUTP-labeled chimeric oligonucleotides. Colonies hybridizing with the 935-A probe were identified only from cells transfected with the specific chimeric oligonucleotide; and there was no evidence of cross-hybridization. Conversion of G to A at nucleotide 935 occurred at an overall frequency of up to 11.9% and when corrected for transfection efficiency approached 43%. No other alterations were detected in the sequence of exon 6 with the targeted nucleotide exchange. These results show that a single base pair alteration in the alkaline phosphatase gene of HuH-7 cells can be introduced at a relatively high frequency following transfection with chimeric RNA/DNA oligonucleotides. This technique offers a novel and potentially powerful strategy for site-directed hepatic gene alteration without the use of viral-based vectors.


Neutralization of CXCL12 attenuates established pulmonary hypertension in rats.
The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models. Male Wistar rats were injected with monocrotaline (MCT) or were subjected to SU5416 followed by 3-week hypoxia to induce severe PH. After PH establishment, assessed by pulsed-wave Doppler echocardiography, MCT-injected or SU5416 plus chronic hypoxia (SuHx) rats were randomized to receive CXCL12 neutraligands chalcone 4 or LIT-927 (100 mg/kg/day), the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100 (5 mg/kg/day), or vehicle, for 2 or 3 weeks, respectively. At the end of these treatment periods, echocardiographic and haemodynamic measurements were performed and tissue samples were collected for protein expression and histological analysis. Daily treatment of MCT-injected or SuHx rats with established PH with chalcone 4 or LIT-927 partially reversed established PH, reducing total pulmonary vascular resistance, and remodelling of pulmonary arterioles. Consistent with these observations, we found that neutralization of CXCL12 attenuates right ventricular hypertrophy, pulmonary vascular remodelling, and decreases pulmonary artery smooth muscle cell (PA-SMC) proliferation in lungs of MCT-injected rats and SuHx rats. Importantly, CXCL12 neutralization with either chalcone 4 or LIT-927 inhibited the migration of PA-SMCs and pericytes in vitro with a better efficacy than AMD3100. Finally, we found that CXCL12 neutralization decreases vascular pericyte coverage and macrophage infiltration in lungs of both MCT-injected and SuHx rats. We report here a greater beneficial effect of CXCL12 neutralization vs. the conventional CXCR4 blockade with AMD3100 in the MCT and SuHx rat models of severe PH, supporting a role for CXCL12 in the progression of vascular complications in PH and opening to new therapeutic options.


Effect of climate on the distribution of Fusarium spp. causing crown rot of wheat in the Pacific Northwest of the United States.
Fusarium crown rot (FCR) is one of the most widespread root and crown diseases of wheat in the Pacific Northwest (PNW) of the United States. Our objectives were to characterize crown rot severity and distribution throughout the PNW by conducting a survey of 210 fields covering the diverse dryland wheat-producing areas of Washington and Oregon and to utilize a factor analysis statistical approach to determine the effects of climate and geography on species distribution and disease severity. Climatic variables were based on 30-year averages and 2008 and 2009 separately (the 2 years of the survey). Mean annual temperature, mean temperature in the coldest month, mean temperature in the warmest month, mean annual precipitation, snowfall, elevation, soil type, and cropping intensity were highly intercorrelated. The factor analysis of the climate variables resulted in the development of two latent factors that could be used as predictor variables in logistic regression models for the presence or absence of Fusarium spp. and of FCR disease scores. Isolates of Fusarium spp. were recovered from 99% of 105 fields sampled in 2008 and 97% of fields in 2009. There were differences between years for responses of FCR and nodes scores, and isolations of Fusarium pseudograminearum with more significant results in 2008, due to warmer drier weather. Results of the factor analysis showed that the distribution of F. pseudograminearum occurred in a greater frequency in areas of the PNW at lower elevations with lower moisture and higher temperatures in 2008, whereas F. culmorum occurred in greater frequency in areas at higher elevations with moderate to high moisture and cooler temperatures consistently across both years. Disease scores increased with increasing levels of factors 1 (primarily temperature) and 2 (primarily precipitation). Both the frequency of pathogen species and disease scores were influenced by the year, indicating that soilborne pathogens are responsive to short-term changes in environment. This factor analysis approach can be utilized in studies to determine the effects of climate and other environmental (soil, cropping system, and so on) factors on the distribution and severity of root diseases.


Biochemical analysis of p120/130: a protein-tyrosine kinase substrate restricted to T and myeloid cells.
T cell activation is mediated by a cascade of intracellular events involving protein-tyrosine kinases and their substrates. p56(lck) and p59(fyn) are protein-tyrosine kinases that associate with CD4/CD8 and the TCRzeta/CD3 complex, respectively. We previously reported the appearance of a protein doublet at 120 and 130 kDa that preferentially associates with p59(fyn) and undergoes tyrosine phosphorylation upon receptor ligation. In this paper, we demonstrate that p120/130 is a novel protein that is restricted in expression to T cells, thymocytes and myeloid cells. Internal peptide sequencing and immunoblotting using an anti-p120/130 antisera showed that p120/130 is a unique protein that is distinct from p130(cas) and p125(cbl). By contrast, p120 and p130 shared similar peptide patterns and are structurally related. Alkaline phosphatase digestion of precipitates showed that they are not related due to phosphorylation. p120/130 was found to associate constitutively with a 55-kDa protein of unknown identity, but which is distinct from p56(lck) and Shc. p120/130 also undergoes a unique kinetics of phosphorylation and associates with the Ag receptor in response to TCR ligation. In keeping with the association with p59(fyn), T cells from p59(fyn)-negative mice exhibit reduced phosphorylation of the protein. p120/130 therefore represents a novel TCR associated intracellular molecule with potential to play a role in T cell signaling.


Synergistic effects of the hybridization between boron-doped carbon quantum dots and n/n-type g-C3N4 homojunction for boosted visible-light photocatalytic activity.
Dye wastewater has raised a prevalent environmental concern due to its ability to prevent the penetration of sunlight through water, thereby causing a disruption to the aquatic ecosystem. Carbon quantum dots (CQDs) are particularly sought after for their highly tailorable photoelectrochemical and optical properties. Simultaneously, graphitic carbon nitride (g-C3N4) has gained widespread attention due to its suitable band gap energy as well as excellent chemical and thermal stabilities. Herein, a novel boron-doped CQD (BCQD)-hybridized g-C3N4 homojunction (CN) nanocomposite was fabricated via a facile hydrothermal route. The optimal photocatalyst sample, 1-BCQD/CN (with a 1:3 mass ratio of boron to CQD) accomplished a Rhodamine B (RhB, 10 mg/L) degradation efficiency of 96.8% within 4 h under an 18 W LED light irradiation. The kinetic rate constant of 1.39 × 10-2 min-1 achieved by the optimum sample was found to be 3.6- and 2.8-folds higher than that of pristine CN and un-doped CQD/CN, respectively. The surface morphology, crystalline structure, chemical composition and optical properties of photocatalyst samples were characterized via TEM, FESEM-EDX, XRD, FTIR, UV-Vis DRS and FL spectrometer. Based on the scavenging tests, it was revealed that the photogenerated holes (h+), superoxide anions (∙O2-) and hydroxyl radicals (∙OH) were the primary reactive species responsible for the photodegradation process. Overall, the highly efficient 1-BCQD/CN composite with excellent photocatalytic activity could provide a cost-effective and robust means to address the increasing concerns over global environmental pollution.


15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity.
To report the ocular structure and visual acuity outcomes at age 15 years, and the incidence of retinal detachment between 10 and 15 years of age, for patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP). Subjects were 254 survivors from 291 preterm children with birth weights less than 1251 g and severe (threshold) retinopathy of prematurity (ROP) in one or both eyes, who participated in the CRYO-ROP trial. At age 15 years, unfavorable ocular structure was posterior retinal fold or worse judged by study-certified ophthalmologists. Unfavorable distance visual acuity was 20/200 or worse measured by study-certified testers using Early Treatment of Diabetic Retinopathy Study recognition acuity charts. Thirty percent of treated eyes and 51.9% of control eyes (P<.001) had unfavorable structural outcomes. Between 10 and 15 years of age, new retinal folds, detachments, or obscuring of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes. Unfavorable visual acuity outcomes were found in 44.7% of treated and 64.3% of control eyes (P<.001). The benefit of cryotherapy for treatment of threshold ROP, for both structure and visual function, was maintained across 15 years of follow-up. New retinal detachments, even in eyes with relatively good structural findings at age 10 years, suggest value in long-term, regular follow-up of eyes that experience threshold ROP.


Effects of Poly-L-Lactic Acid on Adipogenesis and Collagen Gene Expression in Cultured Adipocytes Irradiated with Ultraviolet B Rays.
Poly-L-lactic acid (PLLA), a synthetic, biocompatible, and biodegradable polymer, has been safely used in several clinical applications. Recently, PLLA has been widely used in the field of dermatology to treat wrinkles in aging skin. Reportedly, PLLA directly acts on dermal fibroblasts causing a significant increase in the expression of type I collagen. However, little is known about the effect of PLLA on adipocytes. This study aimed to analyze the effect of PLLA on adipocytes and examine its potential in treating deep wrinkles engendered by the loss of subcutaneous fat because of aging and photoaging. To elucidate the effect of PLLA on skin photoaging, cultured 3T3-L1 adipocytes were irradiated with ultraviolet B (UVB) rays. Oil red O staining was used to detect lipid accumulation in the adipocytes. Real-time quantitative polymerase chain reaction and Western blotting were performed to detect types IV and VI collagen mRNA and protein levels, respectively, under different conditions. The differentiation of 3T3-L1 cells enhanced adipogenesis and the expression of types IV and VI collagens, both of which were inhibited by UVB irradiation. Following this irradiation, PLLA stimulated adipogenesis and the expression of types IV and VI collagens. PLLA may provide the beneficial effect on adipocytes from the aspect of adipogenesis and collagen expression in the subcutaneous adipose tissues.


Future of Personalized Cardiovascular Medicine: JACC State-of-the-Art Review.
Previous decades have seen significant progress in the biological understanding of cardiovascular disease, as well as major advances in computational and information technologies. However, anticipated improvements in outcomes, quality, and cost of cardiovascular medicine at the individual and population levels from these advances have lagged expectations. Further, trends showing widening gaps in the pace of technological development and its successful uptake and application in practice suggests that substantial systemic changes are needed. Recent declines in key U.S. health outcomes have added further urgency to seek scalable approaches that deliver the right treatment to the right patient and to develop information-driven policies that improve health. The clinical care and research enterprises are currently in the midst of assimilating changes entrained by a "fourth industrial revolution" marked by the convergence of biology, physical sciences, and information science. These changes, if managed appropriately, can simultaneously enable cost-effective personalized medical care as well as more effective and targeted population health interventions. In this paper derived from a lecture in honor of cardiologist Paul Dudley White, the author explores how White's prescient insights into prevention and treatment continue to resonate today as we seek to assimilate ubiquitous computing, sophisticated sensor technologies, and bidirectional digital communication into the practice of cardiology. How the ongoing acceleration in basic science and information technologies can be wedded to the principles articulated by White as we pursue scalable approaches to personalized medicine is also examined.


Myasthenia gravis: selective enrichment of antiacetylcholine receptor antibody production in untransformed human B cell cultures.
B cells producing antibodies against the acetylcholine receptor (AchR) play a central role in the pathogenesis of myasthenia gravis (MG). Although anti-AchR autoantibodies have been studied extensively, not much is known about autoimmune B cells and their antigen-driven activation. This has mainly been due to difficulties in establishing and maintaining untransformed antigen-specific B cells in vitro. In this study, we show that highly enriched B cells from peripheral blood and thymus of MG patients can be maintained in culture over a period of 4 weeks when grown on the AchR-expressing rhabdomyosarcoma cell line TE671 together with an anti-CD40 stimulus and lymphokines. Anti-AchR antibody secretion could be detected in the majority of B cell cultures on TE671 cells up to 4 weeks. In contrast, B cells cultured on CDw32-transfected L cells binding anti-CD40 antibodies (the CD40 system) produced only small amounts of anti-AchR antibodies at single time points, whereas the overall IgG production was higher than on TE671 cells. The expression of the relevant autoantigen on the adherent cell line in addition to other growth stimuli could account for this difference and may provide a useful tool for investigating antigen-dependent B cell activation in MG and other B cell-mediated autoimmune conditions.


p38 MAP kinase signalling is required for hypertrophic chondrocyte differentiation.
Longitudinal growth of endochondral bones is accomplished through the co-ordinated proliferation and hypertrophic differentiation of growth plate chondrocytes. The molecular mechanisms and signalling cascades controlling these processes are not well understood. To analyse the expression and roles of p38 mitogen-activated protein kinases in this process, we have established a micromass system for the reproducible hypertrophic differentiation of mouse mesenchymal limb bud cells. Our results show that all four mammalian p38 kinase genes are expressed during the chondrogenic programme, as well as their upstream regulators MKK3 (mitogen-activated protein kinase kinase 3) and MKK6. Treatment of micromass cultures with pharmacological inhibitors of p38 results in a marked delay in hypertrophic differentiation in micromass cultures, indicating a requirement for p38 signalling in chondrocyte differentiation. Inhibition of p38 kinase activity leads to reduced and delayed induction of alkaline phosphatase activity and matrix mineralization. In addition, p38 inhibition causes reduced expression of hypertrophic marker genes such as collagen X, matrix metalloproteinase 13 and bone sialoprotein. The function of p38 in hypertrophic differentiation appears to be mediated, at least in part, by the transcription factor myocyte enhancer factor 2C. In summary, we have demonstrated a novel requirement for p38 signalling in hypertrophic differentiation of chondrocytes and identified myocyte enhancer factor 2C as an important regulator of chondrocyte gene expression.


A comparison of Naprelan and Naprosyn in the treatment of osteoarthritis of the knee.
This double-blind, double-dummy, placebo-controlled, randomized study compared the safety and efficacy of Naprelan (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania), a once-daily, controlled-release formulation of naproxen sodium with that of Naprosyn (Syntex Laboratories, Inc., Palo Alto, California), a conventional naproxen formulation. A total of 347 patients with osteoarthritis (OA) of the knee were assigned to receive Naprelan 1,000 mg once daily, Naprosyn 500 mg BID, or placebo for 12 weeks. Two hundred twenty-eight patients who completed the study then entered an open-label extension in which they received Naprelan 1,000 mg daily for as many as 9 additional months. In the double-blind phase, Naprelan and Naprosyn demonstrated comparable efficacy with no significant differences in mean efficacy scores. After 12 weeks, three primary variables significantly favored Naprelan and Naprosyn over placebo, while a fourth approached significance. Statistical analysis confirmed that Naprelan and Naprosyn were equally effective. Significantly more Naprosyn--than placebo-treated patients had at least one drug-related adverse event (AE) and at least one drug-related gastrointestinal (GI) system AE, but there were no significant differences between Naprelan and placebo. During the open-label phase, patients initially treated with Naprelan or Naprosyn maintained the improvement achieved in the double-blind phase, while those initially treated with placebo showed significantly greater improvement after the first month of Naprelan treatment than the other two groups. As assessed by one of two primary efficacy measures, the greater improvement in those initially treated with placebo was maintained until the end of the study. The AE profile for patients treated with Naprelan for up to 1 year was not significantly different than that for the double-blind phase. The results of this study have confirmed the efficacy of Naprelan 1,000 mg once daily in the treatment of OA as superior to placebo and equivalent to Naprosyn 500 mg BID.


CoCanCPG. Coordination of cancer clinical practice in Europe.
All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, stepwise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.


Long-term follow-up of patients with necrotizing enterocolitis.
Despite the rise in the incidence of necrotizing enterocolitis (NEC), there is a paucity of data regarding long-term patient outcome. The authors examined functional outcome of infants with NEC (n = 103) treated at our institution between 1991 and 1995. The authors reviewed the medical records of infants who were treated both operatively and nonoperatively, n = 103. Variables examined included gestational age, birth weight, Bell stage (I through III), operations performed, and mortality rate. Telephone interviews assessed school enrollment, developmental delay, bowel function, and nutritional status. Children treated operatively had a lower gestational age than those in the nonoperative group. Likewise, birth weight in the operative group was significantly lower. Sixty-three percent of patients had stage III, and the remainder had stage II disease. The telephone response rate was 61%. Mean age at follow-up was 7.5 +/- 2.5 years. All children ate by mouth. Nearly all children were toilet trained. All children were less than the 50th percentile for height and weight, and the majority (83%) were enrolled in school full time. Infants with stage II and III NEC who are treated operatively or nonoperatively have a favorable long-term outcome.


Comparison of the optic nerve head in high- and low-tension glaucoma.
The optic nerves of 34 eyes of 34 patients with low-tension glaucoma were compared with those of 41 eyes of 41 patients with high-tension glaucoma. Mean intraocular pressure in the low-tension group was 16.9 +/- 0.7 mm Hg (mean +/- SEM) compared with 31.7 +/- 0.8 mm Hg in the high-tension group. Mean total visual field loss was not significantly different in the two groups, as determined by computerized threshold perimetry (OCTOPUS). The optic disc rim in low-tension eyes was significantly thinner than in high-tension eyes (P = .018); the largest difference occurred inferiorly and inferotemporally (P less than .001). The appearance of the optic nerve is useful to distinguish between these two subtypes of glaucoma and may be a more meaningful indicator than intraocular pressure. Our findings support the hypothesis that there are at least two different mechanisms for optic nerve damage in glaucoma.


Life support in the intensive care unit: a qualitative investigation of technological purposes. Canadian Critical Care Trials Group.
The ability of many intensive care unit (ICU) technologies to prolong life has led to an outcomes-oriented approach to technology assessment, focusing on morbidity and mortality as clinically important end points. With advanced life support, however, the therapeutic goals sometimes shift from extending life to allowing life to end. The objective of this study was to understand the purposes for which advanced life support is withheld, provided, continued or withdrawn in the ICU. In a 15-bed ICU in a university-affiliated hospital, the authors observed 25 rounds and 11 family meetings in which withdrawal or withholding of advanced life support was addressed. Semi-structured interviews were conducted with 7 intensivists, 5 consultants, 9 ICU nurses, the ICU nutritionist, the hospital ethicist and 3 pastoral services representatives, to discuss patients about whom life support decisions were made and to discuss life-support practices in general. Interview transcripts and field notes were analysed inductively to identify and corroborate emerging themes; data were coded following modified grounded theory techniques. Triangulation methods included corroboration among multiple sources of data, multidisciplinary team consensus, sharing of results with participants and theory triangulation. Although life-support technologies are traditionally deployed to treat morbidity and delay mortality in ICU patients, they are also used to orchestrate dying. Advanced life support can be withheld or withdrawn to help determine prognosis. The tempo of withdrawal influences the method and timing of death. Decisions to withhold, provide, continue or withdraw life support are socially negotiated to synchronize understanding and expectations among family members and clinicians. In discussions, one discrete life support technology is sometimes used as an archetype for the more general concept of technology. At other times, life-support technologies are discussed collectively to clarify the pursuit of appropriate goals of care. The orchestration of death involves process-oriented as well as outcome-oriented uses of technology. These uses should be considered in the assessment of life-support technologies and directives for their appropriate use in the ICU.


Giant voltage-induced modification of magnetism in micron-scale ferromagnetic metals by hydrogen charging.
Owing to electric-field screening, the modification of magnetic properties in ferromagnetic metals by applying small voltages is restricted to a few atomic layers at the surface of metals. Bulk metallic systems usually do not exhibit any magneto-electric effect. Here, we report that the magnetic properties of micron-scale ferromagnetic metals can be modulated substantially through electrochemically-controlled insertion and extraction of hydrogen atoms in metal structure. By applying voltages of only ~ 1 V, we show that the coercivity of micrometer-sized SmCo5, as a bulk model material, can be reversibly adjusted by ~ 1 T, two orders of magnitudes larger than previously reported. Moreover, voltage-assisted magnetization reversal is demonstrated at room temperature. Our study opens up a way to control the magnetic properties in ferromagnetic metals beyond the electric-field screening length, paving its way towards practical use in magneto-electric actuation and voltage-assisted magnetic storage.


Male reproductive effect of nickel sulphate in mice.
Nickel sulphate was administered orally to adult male mice at dose level of 5 and 10 mg/kg body weight (5 days per week) for 35 days. There was no change in body weight. However a significant decrease in absolute and organ-to-body weight ratios of testes, epididymides, seminal vesicles and prostate gland was observed. The sperm abnormality, associated with decrease in sperm motility and sperm count was also observed. Significant alterations in the activities of marker testicular enzymes, viz. sorbitol dehydrogenase (decreases), lactate dehydrogenase (increases) and gamma-glutamyl transpeptidase (increases) associated with histopathological changes in testes, epididymides and seminal vesicles, were also observed. Accumulation of nickel in testes, epididymides and seminal vesicles was also observed. The study reveals that the oral exposure to nickel may affect the histology of testes, epididymides, seminal vesicles and sperms morphology. These testicular and spermatotoxic changes may be responsible for observed male mediated developmental toxic effects.


Childhood depression: pharmacological therapy/treatment (pharmacotherapy of childhood depression).
Critiqued the published double-blind, placebo-controlled studies of antidepressant pharmacotherapy in child and adolescent major depressive disorder to assess their overall efficacy. The pharmacological mechanism of antidepressant action also was discussed. At best, antidepressant treatment for depressed youths is only modestly effective. In particular, the tricyclic antidepressants are not superior to placebo; however, early evidence with the selective serotonin reuptake inhibitors is more encouraging. The theoretical basis for this response pattern is discussed from a methodological perspective, from a neurodevelopmental status, and from a biological viewpoint. Study modifications are suggested which could improve some of the methodological limitations apparent in previous clinical drug trials.


ASSESSING THE CONTRIBUTION OF CROSS-SECTIONS TO THE UNCERTAINTY OF MONTE CARLO CALCULATIONS IN MICRO- AND NANODOSIMETRY.
Within EURADOS Working Group 6 'Computational Dosimetry', the micro and nanodosimetry task group 6.2 has recently conducted a Monte Carlo (MC) exercise open to participants around the world. The aim of this exercise is to quantify the contribution to the uncertainty of micro and nanodosimetric simulation results arising from the use of different electron-impact cross-sections, and hence physical models, employed by different MC codes (GEANT4-DNA, PENELOPE, MCNP6, FLUKA, NASIC and PHITS). Comparison of the participants' simulation results for both micro and nanodosimetric quantities using different MC codes was the first step of the exercise. The deviation between results is due to different cross-sections but also different tracking methods and particle transport cut-off energies. The second step of the exercise will involve using identical cross-section datasets to account only for the other variations in the first step, thus enabling the determination of the uncertainty contribution due to different cross-sections. This paper presents a comparison of the MC simulation results obtained in the first part of the exercise. For the microdosimetric simulations, particularly in the configuration where the electron source is contained within the micrometric target, the choice of MC code has a small influence on the results. For the nanodosimetric results, on the other hand, the mean ionisation cluster size distribution (ICSD) was sensitive to the physical models used in the MC codes. The ICSD was therefore chosen to study the influence of different cross-section data on the uncertainty of simulation results.


Information processing from the motor cortices to the subthalamic nucleus and globus pallidus and their somatotopic organizations revealed electrophysiologically in monkeys.
To understand how the information derived from different motor cortical areas representing different body parts is organized in the basal ganglia, we examined the neuronal responses in the subthalamic nucleus (STN), and the external (GPe) and internal (GPi) segments of the globus pallidus (input, relay and output nuclei, respectively) to stimulation of the orofacial, forelimb and hindlimb regions of the primary motor cortex (MI) and supplementary motor area (SMA) in macaque monkeys under the awake state. Most STN and GPe/GPi neurons responded exclusively to stimulation of either the MI or SMA, and one-fourth to one-third of neurons responded to both. STN neurons responding to the hindlimb, forelimb and orofacial regions of the MI were located along the medial-lateral axis in the posterolateral STN, while neurons responding to the orofacial region of the SMA were located more medially than the others in the anteromedial STN. GPe/GPi neurons responding to the hindlimb, forelimb and orofacial regions of the MI were found along the dorsal-ventral axis in the posterolateral GPe/GPi, and neurons responding to the corresponding regions of the SMA were similarly but less clearly distributed in more anteromedial regions. Moreover, neurons responding to the distal and proximal forelimb MI regions were found along the lateral-medial axis in the STN and the ventral-dorsal axis in the GPe/GPi. Most STN and GPe/GPi neurons showed kinaesthetic responses with similar somatotopic maps. These observations suggest that the somatotopically organized inputs from the MI and SMA are well preserved in the STN and GPe/GPi with partial convergence.


Material characterization of in vivo and in vitro porcine brain using shear wave elasticity.
Realistic computer simulation of closed head trauma requires accurate mechanical properties of brain tissue, ideally in vivo. A substantive deficiency of most existing experimental brain data is that properties were identified through in vitro mechanical testing. This study develops a novel application of shear wave elasticity imaging to assess porcine brain tissue shear modulus in vivo. Shear wave elasticity imaging is a quantitative ultrasound technique that has been used here to examine changes in brain tissue shear modulus as a function of several experimental and physiologic parameters. Animal studies were performed using two different ultrasound transducers to explore the differences in physical response between closed skull and open skull arrangements. In vivo intracranial pressure in four animals was varied over a relevant physiologic range (2-40 mmHg) and was correlated with shear wave speed and stiffness estimates in brain tissue. We found that stiffness does not vary with modulation of intracranial pressure. Additional in vitro porcine specimens (n = 14) were used to investigate variation in brain tissue stiffness with temperature, confinement, spatial location and transducer orientation. We observed a statistically significant decrease in stiffness with increased temperature (23%) and an increase in stiffness with decreasing external confinement (22-37%). This study determined the feasibility of using shear wave elasticity imaging to characterize porcine brain tissue both in vitro and in vivo. Our results underline the importance of temperature- and skull-derived boundary conditions to brain stiffness and suggest that physiologic ranges of intracranial pressure do not significantly affect in situ brain tissue properties. Shear wave elasticity imaging allowed for brain material properties to be experimentally characterized in a physiologic setting and provides a stronger basis for assessing brain injury in computational models.


Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia.
The metabolic adaptation to fasting in infants with hyperinsulinism was examined to see whether a characteristic abnormality could be found that would aid in the diagnosis of this disorder. Seven infants under 1 year of age with hyperinsulinism were studied; 7 control infants of similar age and 12 children with ketotic hypoglycemia served as contrast groups. At the time of hypoglycemia, four of the seven infants with hyperinsulinism did not have elevated levels of insulin. However, levels of beta-hydroxybutyrate were significantly lower in the infants with hyperinsulinism than in the control and ketotic hypoglycemic groups. Levels of free fatty acids were also lower in the infants with hyperinsulinism. Expected levels and normal limits for beta-hydroxybutyrate, insulin, and free fatty acids when plasma glucose is below 40 mg/100 ml were estimated by combining the control and ketotic hypoglycemic groups. Using these values as standards, the diagnosis of hyperinsulinism can be made by evaluation of the response to fasting hypoglycemia. The application of this approach is illustrated by three case examples.


Functional studies of Peyer's patches: evidence for their participation in intestinal immune responses.
The pattern of responsiveness of lymphocytes from Peyer's patches, spleen, mesenteric, and inguinal nodes of guinea pigs was compared after oral and parenteral immunization. After oral immunization with BCG, Peyer's patch lymphocytes showed the best in vitro proliferative responses to PPD (tuberculin). Responsiveness to Clostridia, normal constituents of the intestinal microflora, also was significant in Peyer's patches, and low or absent in the other lymphoid tissues examined. In animals immunized parenterally with heat-killed Mycobacterium tuberculosis, lymphocytes from the spleen reacted best to PPD and those from Peyer's patches least. Selective elimination of B or T cells from PPD-reactive Peter's patch lymphocyte populations showed that the T-cell-rich fraction remained responsive to PPD, the B cell-rich fraction became unresponsive; but both fractions reacted to Clostridia. We conclude from this experiment that a functional T cell population is present in these organs. Peyer's patches in the guinea pig are immunocompetent lymphoid organs which seem to be primarily engaged in immune responses to antigens presented from the intestinal lumen.


Repair of Anomalous Left Coronary Artery From the Right Pulmonary Artery: A Series of Nine Cases.
Repair of anomalous left coronary artery from the right pulmonary artery presents a particular technical challenge to the congenital cardiac surgeon. There is disagreement in the literature over the optimal technique for this defect, with some authors advocating for unroofing of the periaortic segment of coronary artery, while others prefer direct aortic reimplantation of the artery. We performed a retrospective study examining outcomes of patients who were repaired for this anomaly at our institution. In-hospital and outpatient follow-up data were analyzed. Nine patients were identified. Most patients had poor left ventricular function at the time of surgery. All patients in our series were repaired using the direct coronary transfer technique. To date there were no mortalities among the study participants. At last follow-up, all patients with available echocardiograms had normal ventricular function. One patient required reoperation for anastomotic stenosis. We demonstrate that using the technique of direct coronary transfer to the aorta, we have achieved excellent results with repair of this defect.


Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients.
To determine the frequency of KCNQ2 mutations in patients with neonatal epileptic encephalopathy (NEE), and to expand the phenotypic spectrum of KCNQ2 epileptic encephalopathy. Eighty-four patients with unexplained NEE were screened for KCNQ2 mutations using classic Sanger sequencing. Clinical data of 6 additional patients with KCNQ2 mutations detected by gene panel were collected. Detailed phenotyping was performed with particular attention to seizure frequency, cognitive outcome, and video-EEG. In the cohort, we identified 9 different heterozygous de novo KCNQ2 missense mutations in 11 of 84 patients (13%). Two of 6 missense mutations detected by gene panel were recurrent and present in patients of the cohort. Seizures at onset typically consisted of tonic posturing often associated with focal clonic jerking, and were accompanied by apnea with desaturation. One patient diagnosed by gene panel had seizure onset at the age of 5 months. Based on seizure frequency at onset and cognitive outcome, we delineated 3 clinical subgroups, expanding the spectrum of KCNQ2 encephalopathy to patients with moderate intellectual disability and/or infrequent seizures at onset. Recurrent mutations lead to relatively homogenous phenotypes. One patient responded favorably to retigabine; 5 patients had a good response to carbamazepine. In 6 patients, seizures with bradycardia were recorded. One patient died of probable sudden unexpected death in epilepsy. KCNQ2 mutations cause approximately 13% of unexplained NEE. Patients present with a wide spectrum of severity and, although rare, infantile epilepsy onset is possible.


[The absorption of homologous alkyl sulphonates of tridihexethyl (author's transl)].
The pharmaceutical-technological measure of varied salt formation acts on the in vivo diffusion processes of quaternary tridihexethyl (gastro-intestinal absorption, transperitoneal diffusion) in principle in the same manner as it acts on the in vitro diffusion processes (membrane diffusion): Due to the formation of corresponding ion pairs, lipophilic counterions of opposite sign facilitate the passage through membranes. In contrast, the direct pharmacodynamic activity (spasmolysis at the isolated jejunum of the rat) is not changed by varying the counterions of opposite sign.


Effect of cyclooxygenase-2 (COX-2) inhibitors on prostate cancer cell proliferation.
The tricyclic cyclooxygenase-2 (COX-2) inhibitors celecoxib and rofecoxib exhibit different magnitudes of antiproliferative activity against the human prostate cancer cell lines LNCaP and PC-3. We investigated the correlation between the COX-2 inhibitory potencies, antiproliferative activities and the nature of the central ring system of novel tricyclic COX-2 inhibitors belonging to the diarylcycloalkyl and diarylheterocyclic classes possessing a central 3-membered cyclopropyl (1 and 2), a 5-membered isoxazoline (3), an isoxazole (4) or 2-(5H) furanone (5), and a 6-membered pyran-2-one (6a-c) ring system. Novel tricyclics were synthesized and evaluated in vitro for their COX-1/COX-2 inhibitory activities and their abilities to inhibit cell proliferation in prostate (AT3B-1, PC-3 and LNCaP) and breast (MCF-7) cancer cell lines. A molecular modeling study was carried out to characterize the electronic nature of the central ring systems of the novel tricyclic COX-2 inhibitors. The isoxazoline (3), which exhibited excellent COX-2 inhibitory potency and selectivity, showed growth inhibition in all the cell lines tested with IC50 values of 349 microM (AT3B-1), 378 microM (PC-3), 100 microM (LNCaP) and 200 microM (MCF-7), respectively. The rofecoxib analog (5) and 6-membered pyran-2-ones (6a-c) showed weak inhibition (MCF-7, AT3-B-1 and PC-3) inspite of possessing good COX-2 inhibitory potencies and selectivities. This study demonstrates that the antiproliferative activity profiles exhibited by the novel tricyclic COX-2 inhibitors is dependent on the electronic nature of the central ring system and is independent of their COX-2 inhibitory potencies and selectivities. Accordingly, the 2,3-dimethyl-5-(4-methylsulfonylphenyl)-4-phenyl-4-isoxazoline (3), which possesses an electron rich central 5-membered isoxazole ring, could serve as a lead compound to develop novel drugs to treat prostate cancer.


Donor-derived Strongyloides stercoralis infection in solid organ transplant recipients in the United States, 2009-2013.
Infection with Strongyloides stercoralis is typically asymptomatic in immunocompetent hosts, despite chronic infection. In contrast, immunocompromised hosts such as solid organ transplant recipients are at risk for hyperinfection syndrome and/or disseminated disease, frequently resulting in fatal outcomes. Infection in these recipients may result from reactivation of latent infection or infection through transmission from an infected donor. We describe the Centers for Disease Control and Prevention's experience with seven clusters of donor-derived infection from 2009 to 2013. Six of the seven (86%) donors were born in Latin America; donor screening was not performed prior to organ transplantation in any of these investigations. Eleven of the 20 (55%) organ recipients were symptomatic, two of whom died from complications of strongyloidiasis. We also describe the New York Organ Donor Network (NYODN) experience with targeted donor screening from 2010 to 2013. Of the 233 consented potential donors tested, 10 tested positive for Strongyloides antibody; and 18 organs were transplanted. The majority (86%) of the donors were born in Central or South America. Fourteen recipients received prophylaxis after transplantation; no recipients developed strongyloidiasis. The NYODN experience provides evidence that when targeted donor screening is performed prior to transplantation, donor-derived infection can be averted in recipients.


The applicability of the Beck Depression Inventory and Hamilton Depression Scale in the automatic recognition of depression based on speech signal processing.
Depression is a growing problem worldwide, impacting on an increasing number of patients, and also affecting health systems and the global economy. The most common diagnostical rating scales of depression are self-reported or clinician-administered, which differ in the symptoms that they are sampling. Speech is a promising biomarker in the diagnostical assessment of depression, due to non-invasiveness and cost and time efficiency. In our study, we try to achieve a more accurate, sensitive model for determining depression based on speech processing. Regression and classification models were also developed using a machine learning method. During the research, we had access to a large speech database that includes speech samples from depressed and healthy subjects. The database contains the Beck Depression Inventory (BDI) score of each subject and the Hamilton Rating Scale for Depression (HAMD) score of 20% of the subjects. This fact provided an opportunity to compare the usefulness of BDI and HAMD for training models of automatic recognition of depression based on speech signal processing. We found that the estimated values of the acoustic model trained on BDI scores are closer to HAMD assessment than to the BDI scores, and the partial application of HAMD scores instead of BDI scores in training improves the accuracy of automatic recognition of depression.


Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor.
The aryl hydrocarbon receptor (AhR) mediates the toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. In a process termed transformation, ligand binding converts the AhR into its high affinity DNA binding form that represents a dimer of the AhR and Arnt, a closely related nuclear protein. During transformation, protein chaperone Hsp90 is thought to be replaced by Arnt in overlapping binding sites in the basic helix loop helix and PASB domains of the AhR. Here, analysis of AhR variants containing a modified PASB domain and AhR PASA-PASB fragments of various lengths revealed (i) an inhibitory effect on transformation concomitant with Hsp90 binding in the PASB domain, (ii) an ability of the PASA-PASB fragment of the AhR to reproduce key steps in the transformation process, and (iii) a ligand-dependent conformational change in the PASA domain consistent with increased PASA exposure during AhR transformation. Based on these results, we propose a new mechanism of AhR transformation through initiation of Arnt dimerization and Hsp90 displacement in AhR PASA/B domains. This study provides insights into mechanisms of AhR transformation, dimerization of PAS domain proteins, and Hsp90 dissociation in activation of its client proteins.


Studies of amino-acid sequence in dihydrofolate reductase from a human methotrexate-resistant cell line KB/6b. Structural and kinetic comparison with mouse L1210 enzyme.
The partial amino acid sequence of dihydrofolate reductase (DHFR, EC 184.108.40.206) from human KB/6b cells has been determined by using 3.5 mg of protein. Peptides covering the entire polypeptide chain were recovered from preparative peptide maps generated by the combination of paper chromatography and electrophoresis at pH 4.4 Peptide maps from mouse L1210 DHFR were also generated for comparison. Amino acid sequence of 75% of the 186 amino acid residues in the polypeptide chain of human KB/6b DHFR was obtained from Edman degradations and the remaining sequence was deduced from the amino acid compositions, from electrophoretic mobilities of related peptides and from the sequence homologies with other known mammalian DHFR sequences. A comparison of the proposed human DHFR sequence with the previously known sequences of mouse enzyme [Stone, et al. (1979) J. Biol. Chem. 245, 480-488] indicates that 18 differences are located in the established sequence of 139 residues and that 5 additional differences are in the tentative sequence of the remaining 47 amino acids. Kinetic properties of human KB/6b and mouse L1210 DHFR, which were determined in parallel experiments, are also compared. The possible structural-functional relationships between human and mouse DHFR are discussed.


The short-rooted phenotype of the brevis radix mutant partly reflects root abscisic acid hypersensitivity.
To gain further insight into abscisic acid (ABA) signaling and its role in growth regulation, we have screened for Arabidopsis (Arabidopsis thaliana) mutants hypersensitive to ABA-mediated root growth inhibition. As a result, we have identified a loss-of-function allele of BREVIS RADIX (BRX) in the Columbia background, named brx-2, which shows enhanced response to ABA-mediated inhibition of root growth. BRX encodes a key regulator of cell proliferation and elongation in the root, which has been implicated in the brassinosteroid (BR) pathway as well as in the regulation of auxin-responsive gene expression. Mutants affected in BR signaling that are not impaired in root growth, such as bes1-D, bzr1-D, and bsu1-D, also showed enhanced sensitivity to ABA-mediated inhibition of root growth. Triple loss-of-function mutants affected in PP2Cs, which act as negative regulators of ABA signaling, showed impaired root growth in the absence of exogenous ABA, indicating that disturbed regulation of ABA sensitivity impairs root growth. In agreement with this result, diminishing ABA sensitivity of brx-2 by crossing it with a 35S:HAB1 ABA-insensitive line allowed significantly higher recovery of root growth after brassinolide treatment. Finally, transcriptomic analysis revealed that ABA treatment negatively affects auxin signaling in wild-type and brx-2 roots and that ABA response is globally altered in brx-2. Taken together, our results reveal an interaction between BRs, auxin, and ABA in the control of root growth and indicate that altered sensitivity to ABA is partly responsible for the brx short-root phenotype.


The Antidepressant Activity of a Taurine-Containing Derivative of 4-Phenylpyrrolidone-2 in a Model of Chronic Unpredictable Mild Stress.
This study investigates the therapeutic potential of a new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner's chronic unpredictable mild stress model of male Wistar rats was used as a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group with saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light-dark box, were used to assess the animals' conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to the intact animals. These results suggest that Compound I has reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.


Variability in assessing treatment response: metastatic colorectal cancer as a paradigm.
The cutoff values currently used to categorize tumor response to therapy are neither biologically based nor tailored for measurement reproducibility with contemporary imaging modalities. Sources and magnitudes of discordance in response assessment in metastatic colorectal cancer (mCRC) are unknown. A subset of patients' CT images of chest, abdomen, and pelvis were randomly chosen from a multicenter clinical trial evaluating insulin-like growth factor receptor type 1-targeted therapy in mCRC. Using Response Evaluation Criteria in Solid Tumors (RECIST), three radiologists selected target lesions and measured "uni" (maximal diameter), "bi" (product of maximal diameter and maximal perpendicular diameter), and "vol" (volume) on baseline and 6-week posttherapy scans in the following ways: (i) each radiologist independently selected and measured target lesions and (ii) one radiologist's target lesions were blindly remeasured by the others. Variability in relative change of tumor measurements was analyzed using linear mixed effects models. Three radiologists independently selected 138, 101, and 146 metastatic target lesions in the liver, lungs, lymph nodes, and other organs (e.g., peritoneal cavity) in 29 patients. Of 198 target lesions total, 33% were selected by all three, 28% by two, and 39% by one radiologist. With independent selection, the variability in relative change of tumor measurements was 11% (uni), 19% (bi), and 22% (vol), respectively. When measuring the same lesions, the corresponding numbers were 8%, 14%, and 12%. The relatively low variability in change of mCRC measurements suggests that response criteria could be modified to allow more accurate and sensitive CT assessment of anticancer therapy efficacy.


Xylitol for preventing acute otitis media in children up to 12 years of age.
Acute otitis media (AOM) is the most common bacterial infection among young children in the United States with limitations and concerns over its treatment with antibiotics and surgery. Therefore, effective preventative measures are attractive. A potential preventative measure is xylitol, a natural sugar substitute that reduces the risk for dental decay. Xylitol can reduce the adherence of Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) to nasopharyngeal cells in vitro. To assess the efficacy and safety of xylitol to prevent AOM in children up to 12 years old. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to August Week 1, 2011), EMBASE (1974 to August 2011), CINAHL (1982 to August 2011), Health and Psychosocial Instruments (1985 to August 2011), Healthstar (OVID) (1966 to August 2011) and International Pharmaceutical Abstracts (2000 to August 2011). Randomised controlled trials (RCTs) or quasi-RCTs of children aged 12 years or younger where xylitol supplementation was compared to placebo or no treatment to prevent AOM. Two review authors independently selected trials from search results, assessed and rated study quality and extracted relevant data for inclusion in the review. We contacted trial authors to request missing data. We noted data on any adverse events of xylitol. We extracted data on relevant outcomes and estimated the effect size by calculating risk ratio (RR), risk difference (RD) and associated 95% confidence intervals (CI). We identified four studies of adequate methodological quality that met our eligibility criteria. In three RCTs with a total of 1826 healthy Finnish children attending day care, there was a reduced risk of occurrence of AOM in the xylitol group (in any form) compared to the control group (RR 0.75; 95% CI 0.65 to 0.88). The fourth RCT included 1277 Finnish day care children with a respiratory infection and found no effect of xylitol on reducing the occurrence of AOM (RR 1.13; 95% CI 0.83 to 1.53). Xylitol chewing gum was superior to xylitol syrup in preventing AOM among healthy children (RR 0.59; 95% CI 0.39 to 0.89) but not during respiratory infection (RR 0.68; 95% CI 0.43 to 1.07). There was no difference between xylitol lozenges and xylitol syrups in preventing AOM among healthy children (RR 0.77; 95% CI 0.53 to 1.11) or among children during respiratory infection (RR 0.74; 95% CI 0.47 to 1.14). Similarly, no difference was noted between xylitol chewing gum and xylitol lozenges in preventing AOM among healthy children (RR 0.73; 95% CI 0.47 to 1.13) or among children during respiratory infection (RR 0.92; 95% CI 0.59 to 1.46). Among the reasons for drop-outs, there were no significant differences in abdominal discomfort and rash between the xylitol and the control groups. There is fair evidence that the prophylactic administration of xylitol among healthy children attending day care centres reduces the occurrence of AOM by 25%. This meta-analysis is limited since the data arise from a small number of studies, mainly from the same research group.


Separating homogeneous and inhomogeneous line widths of heavy- and light-hole excitons in weakly disordered semiconductor quantum wells.
Optical two-dimensional Fourier-transform spectroscopy is used to study the heavy- and light-hole excitonic resonances in weakly disordered GaAs quantum wells. Homogeneous and inhomogeneous broadening contribute differently to the two-dimensional resonance line shapes, allowing separation of homogeneous and inhomogeneous line widths. The heavy-hole exciton exhibits more inhomogeneous than homogeneous broadening, whereas the light-hole exciton shows the reverse. This situation occurs because of the interplay between the length scale of the disorder and the exciton Bohr radius, which affects the exciton localization and scattering. Utilizing this separation of line widths, excitation-density-dependent measurements reveal that many-body interactions alter the homogeneous dephasing, while disorder-induced dephasing is unchanged.


[Basophil activation test in the diagnosis of allergy to medicines].
In this paper we study the reliability of the basophil activation test (BAT) in the "in-vitro" diagnosis of allergy to betalactams and to metamizol, and the sensitivity and specificity of the technique are analyzed. To this end, we studied 58 patients allergic to betalactam antibiotics with a positive cutaneous test facing any derivative of penicillin and 30 healthy controls who tolerated betalactams, and 26 patients allergic to metamizol with an immediate reaction and 30 healthy controls who tolerated the medicine. Sensitivity to BAT in allergy to betalactams was 52.8%, and specificity was 92.6%. For metamizol, sensitivity was 42.3% and specificity was 100%. The positive predictive value of BAT in allergy to betalactams was 18.9% and the negative predictive value was 98.4%. For metamizol, the positive predictive value of the technique was 100% and the negative predictive value was 99.4%. The joint use of BAT and CAP (specific IgE) makes it possible to diagnose some 65% of patients allergic to betalactams. The combined use of cutaneous tests and BAT in allergy to metamizol detects 70% of the cases. BAT is a useful, non-invasive technique in the "in-vitro" diagnosis of allergy to betalactams and metamizol.


[Blunt kidney trauma in childhood].
In a retrospective analysis of 42 paediatric blunt renal injuries the indications for conservative and surgical treatment were evaluated. The type of injury (contusion, laceration, fragmentation, pedicle injury), associated injuries, the diagnostic procedures, the therapy and its results were analysed. All 18 contusions were treated conservatively. For the 24 severe injuries there was a surgery rate of 66% (16/24), a renal loss rate of 16% (4/24); the other organs could be saved by the operation. With primarily conservative treatment we had to operate in one case only due to recurrent haematuria; the renal loss rate was 0%. The following criteria are defined as indications for surgical treatment: (1) deteriorating vital signs, (2) pedicle injury, (3) large devitalized renal segments, (4) large extravasations of contrast medium ("Page kidney").


Potential for increased photosynthetic performance and crop productivity in response to climate change: role of CBFs and gibberellic acid.
We propose that targeting the enhanced photosynthetic performance associated with the cold acclimation of winter cultivars of rye (Secale cereale L.), wheat (Triticum aestivum L.), and Brassica napus L. may provide a novel approach to improve crop productivity under abiotic as well as biotic stress conditions. In support of this hypothesis, we provide the physiological, biochemical, and molecular evidence that the dwarf phenotype induced by cold acclimation is coupled to significant enhancement in photosynthetic performance, resistance to photoinhibition, and a decreased dependence on photoprotection through non-photochemical quenching which result in enhanced biomass production and ultimately increased seed yield. These system-wide changes at the levels of phenotype, physiology, and biochemistry appear to be governed by the family of C-repeat/dehydration-responsive family of transcription factors (CBF/DREB1). We relate this phenomenon to the semi-dwarf, gibberellic acid insensitive (GAI), cereal varieties developed during the "green revolution" of the early 1960s and 1970s. We suggest that genetic manipulation of the family of C-repeat/dehydration-responsive element binding transcription factors (CBF/DREB1) may provide a novel approach for the maintenance and perhaps even the enhancement of plant productivity under conditions of sub-optimal growth conditions predicted for our future climate.


Natural remedies medicine derived from flaxseed (secoisolariciresinol diglucoside, lignans, and α-linolenic acid) improve network targeting efficiency of diabetic heart conditions based on computational chemistry techniques and pharmacophore modeling.
Cytokine storms lead to cardiovascular diseases (CVDs). Natural herbal compounds are considered the primary source of active agents with the potential to prevent or treat inflammatory-related pathologies such as CVD and diabetes. Flaxseed contains phytochemicals, including secoisolariciresinol diglucoside (SDG), α-linolenic acid (ALA), and lignans, termed "SAL." Hence, we evaluated the effect of the SAL on the H9c2 cardiac cells in hyperlipidemic and hyperglycemic conditions. Here, candidate hub genes, TNF-α, IL6, SIRT1, NRF1, NPPA, and FGF7, were selected as effective genes in diabetic cardiovascular pathogenesis based on in-silico analysis and chemoinformatic. Myocardial infarction (MI) was induced using H9c2 cardiac cells in hyperlipidemic and hyperglycemic conditions. Real-time qPCR was conducted to assess the expression level of hub genes. This study indicated that SAL compounds bound to the Il-6, SIRT1, and TNF-α active sites as druggable candidate proteins based on the chemoinformatics analysis. This study displayed that the TNF-α, IL6, SIRT1, NRF1, NPPA, and FGF7 network dysfunction in MI models were ameliorated by SAL consumption. Furthermore, SAL compounds improved the function and myogenesis of H9c2 cells in hyperlipidemic and hyperglycemic conditions. Our data suggested that phytochemicals obtained from flaxseed might have proposed potential complementary treatment or preventive strategies for MI. PRACTICAL APPLICATIONS: Phytochemicals obtained from flaxseed (SAL) could reverse diabetic heart dysfunction hallmarks and provide new potential treatment approaches in cardiovascular therapy. SAL could be considered complementary and alternative medicines for treating various disorders/diseases singly or synchronizing with prescription drugs.


Features involved in the diagnostic delay of cluster headache.
Cluster headache (CH) is a comparatively rare, very severe primary headache. Although circumscript and recognisable criteria are available, the diagnosis is often missed or delayed. Besides, while adequate and evidence based treatment is available in diagnosed cases, CH seems to be poorly managed. The authors performed a nationwide survey among CH patients, and looked for factors involved in the diagnostic delay. The authors performed a nationwide mailing to all Dutch general practitioners (about 5800), and neurologists (about 560) and invited them to refer patients in whom the diagnosis CH was made or considered. Patients could also apply via the Dutch Headache Patients Society. A variety of clinical characteristics were assessed by means of questionnaires. Specifically, patients were asked about the time between their first episode and the diagnosis. The IHS criteria for CH were met by 1429 of 2001 responders, and 1163 of these filled in an extended questionnaire. The male to female ratio was 3.7:1. Mean age at onset was 32 (SD 14) years. Seventy three per cent had episodic CH, 21% had chronic CH, and in 6% the periodicity was undetermined. The time between the first episode and the diagnosis ranged from 1 week to 48 years (median 3 years): 34% had consulted a dentist and 33% an ENT specialist before the diagnosis was established. Among factors that increased the diagnostic delay were the presence of photophobia or phonophobia, nausea, an episodic attack pattern and a low age at onset (p<0.01). Sex or presence of restlessness during episodes did not influence the diagnostic delay. CH remains unrecognised or misdiagnosed in many cases for many years. Photophobia or phonophobia and nausea were in part responsible for this delay, and should be recognised as part of the clinical spectrum of CH. Many patients were first seen by a dentist or ENT specialist for their CH episodes, so more attention should be paid to educate first line physicians to recognise CH, to improve the diagnostic process and so to expose patients to earlier and better treatment of CH.


Actions of benzodiazepine and beta-carboline derivatives on gamma-aminobutyric acid-activated Cl- channels recorded from membrane patches of neonatal rat cortical neurons in culture.
Using the patch-clamp, single-channel recording technique, the authors determined conductance and kinetics of gamma-aminobutyric acid-activated Cl- channels recorded from membrane patches excised from neonatal rat cortical neurons in primary culture. The anxiolytic benzodiazepine flunitrazepam increased the channel opening frequency, but it did not change conductance or channel opening burst duration. The anxiogenic compound methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate decreased gamma-aminobutyric acid-activated Cl- channel opening frequency without changing conductance or opening duration. An increase and decrease in the number of channel bursts were elicited by flunitrazepam and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, respectively. The effects of both drugs were antagonized by ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5][1,4] -benzodiazepine-3-carboxylate (flumazenil), a benzodiazepine antagonist, which per se failed to modify Cl- channel kinetics and conductance.


A Descriptive Study of the Prevalence and Typology of Alcohol-Related Posts in an Online Social Network for Smoking Cessation.
Alcohol use and problem drinking are associated with smoking relapse and poor smoking-cessation success. User-generated content in online social networks for smoking cessation provides an opportunity to understand the challenges and treatment needs of smokers. This study used machine-learning text classification to identify the prevalence, sentiment, and social network correlates of alcohol-related content in the social network of a large online smoking-cessation program, BecomeAnEX.org. Data were analyzed from 814,258 posts (January 2012 to May 2015). Posts containing alcohol keywords were coded via supervised machine-learning text classification for information about the user's personal experience with drinking, whether the user self-identified as a problem drinker or indicated problem drinking, and negative sentiment about drinking in the context of a quit attempt (i.e., alcohol should be avoided during a quit attempt). Less than 1% of posts were related to alcohol, contributed by 13% of users. Roughly a third of alcohol posts described a personal experience with drinking; very few (3%) indicated "problem drinking." The majority (70%) of alcohol posts did not express negative sentiment about drinking alcohol during a quit attempt. Users who did express negative sentiment about drinking were more centrally located within the network compared with those who did not. Discussion of alcohol was rare, and most posts did not signal the need to quit or abstain from drinking during a quit attempt. Featuring expert information or highlighting discussions that are consistent with treatment guidelines may be important steps to ensure smokers are educated about drinking risks.


Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer.
Few studies have reported on the comprehensive BRCA1/2 mutation analyses of hereditary breast cancer (HBC) families of French Canadian descent. Here we report the investigation of 82 families with at least 3 cases of breast cancer evaluated for mutations by DNA sequencing and/or multiplex ligation-dependent probe amplification (MLPA) assay. DNA sequencing identified pathogenic mutations in 37 (45.1%) families, of which 70.2% were one of three recurring mutations (BRCA1:R1443X, BRCA2:8765delAG, and BRCA2:E1953X) frequently reported in this founder population; and variants of uncertain clinical significance in 7 (8.5%) families of which two harbored BRCA2:E3002K. MLPA analysis of the 38 DNA sequence-negative families did not reveal any large rearrangements in BRCA1/2. A phenotypic characterization of the cancer families based on pathogenic mutation status revealed that there were significantly fewer very young age at diagnosis breast cancer cases (<36 years) in mutation-negative families (5.9%, 9 of 153) than in BRCA1 (22.8%, 13 of 57; P = 0.0003) or BRCA2 (22.9%, 27 of 118; P < 1× 10E5) mutation-positive families. There were significantly more mutation-positive families (29 of 36, 80.6%) with a very young age of onset of breast cancer case than those that did not (8 of 39, 20.5%) (P < 10E6). The comprehensive mutation analysis of BRCA1/2 suggests that genomic rearrangements are unlikely to account for sequence-negative HBC families and affirms that the presence of a very young age of diagnosis of breast cancer is strongly predictive of mutation carrier status of French Canadian HBC families.


Can tumour response be assessed from a biopsy?
During a course of radiotherapy or chemotherapy the number of clonogenic cells in a tumour decreases exponentially. After one third of the treatment period more than 99% of the remaining tumour consists of doomed cells. Therefore, it would appear to be impossible to assess the therapeutic response of tumours directly from biopsy material taken during treatment. Nevertheless, attempts to study the therapeutic response during treatment have been made in order to obtain prognostic information on individuals so as to individualize treatment. A variety of approaches have been used. In carcinoma of the cervix a close correlation has been established between the results of some of these assays and local tumour control or long term survival of patients. Even without a complete understanding of the undelying mechanisms, these methods may be useful for the selection of patients for unconventional treatments like fast neutrons or other modalities which are not available to all patients.


Service dogs and people with physical disabilities partnerships: a systematic review.
Occupational therapists have recognized the benefits that service dogs can provide people with disabilities. There are many anecdotal publications extolling the benefits of working with service dogs, but few rigorous studies exist to provide the evidence of the usefulness of this type of assistive technology option. This systematic review evaluates the published research that supports the use of service dogs for people with mobility-related physical disabilities. Articles were identified by computerized search of PubMed, CINAHL, PsycINFO, OT Seeker, the Cochrane Database of Systematic Reviews, SportDiscus, Education Research Complete, Public Administration Abstracts, Web of Knowledge and Academic Search Premier databases with no date range specified. The keywords used in the search included disabled persons, assistance dogs or service dogs and mobility impairments. The reference lists of the research papers were checked as was the personal citation database of the lead author. Twelve studies met the inclusion criteria and whereas the findings are promising, they are inconclusive and limited because of the level of evidence, which included one Level I, six Level III, four Level IV and one Level V. All of the studies reviewed had research design quality concerns including small participant sizes, poor descriptions of the interventions, outcome measures with minimal psychometrics and lack of power calculations. Findings indicated three major themes including social/participation, functional and psychological outcomes; all of which are areas in the occupational therapy scope of practice. Occupational therapists may play a critical role in referral, assessment, assisting clients and consulting with training organizations before, during and after the service dog placement process. In order for health care professionals to have confidence in recommending this type of assistive technology, the evidence to support such decisions must be strengthened.


Simulation of a small molecule analogue of a lithium ionomer in an external electric field.
We have investigated the ion dynamics in lithium-neutralized 2-pentylheptanoic acid, a small molecule analogue of a precise poly(ethylene-co-acrylic acid) lithium ionomer. Atomistic molecular dynamics simulations were performed in an external electric field. The electric field causes alignment of the ionic aggregates along the field direction. The energetic response of the system to an imposed oscillating electric field for a wide range of frequencies was tracked by monitoring the coulombic contribution to the energy. The susceptibility found in this manner is a component of the dielectric susceptibility typically measured experimentally. A dynamic transition is found and the frequency associated with this transition varies with temperature in an Arrhenius manner. The transition is observed to be associated with rearrangements of the ionic aggregates.


Isolation, characterization, and ecology of cold-active, chemolithotrophic, sulfur-oxidizing bacteria from perennially ice-covered Lake Fryxell, Antarctica.
Novel strains of obligately chemolithoautotrophic, sulfur-oxidizing bacteria have been isolated from various depths of Lake Fryxell, Antarctica. Physiological, morphological, and phylogenetic analyses showed these strains to be related to mesophilic Thiobacillus species, such as T. thioparus. However, the psychrotolerant Antarctic isolates showed an adaptation to cold temperatures and thus should be active in the nearly freezing waters of the lake. Enumeration by most-probable-number analysis in an oxic, thiosulfate-containing medium revealed that the sulfur-oxidizing chemolithotroph population peaks precisely at the oxycline (9.5 m), although viable cells exist well into the anoxic, sulfidic waters of the lake. The sulfur-oxidizing bacteria described here likely play a key role in the biogeochemical cycling of carbon and sulfur in Lake Fryxell.


Categorisation of 'perceptual' and 'premotor' neglect patients across different tasks: is there strong evidence for a dichotomy?
The aim of the presented studies was to investigate whether classifications of neglect patients into perceptual (i.e. identifying a patient as suffering from mainly attentional/space representation deficits) and premotor (judging the main impairment to be related towards actions into contralesional space) categories is consistent across different line bisection assessment techniques that have, in the past, been designed to tease these potentially overlapping aspects of hemispatial neglect apart. Twelve patients with hemispatial neglect and three control groups were tested with the Overhead Task, adapted from Nico [Neuropsychologia 34 (1996) 471] in which patients were asked to bisect lines that were mirror reversed, the Pulley Device Technique, adapted from Bisiach et al. [Neurology 40 (1990) 1278] in which they had to perform a movement opposite to the direction of the transaction mark that bisected the line and the Landmark Test, adapted from Milner et al. [Neuropsychologia 30 (1992) 515] in which they had to manually point to the half of a centrally pre-bisected line that, to them, appeared shorter. The specific question was whether these three tasks would categorise the same set of patients in the same way?Most patients could be classified into either the premotor or perceptual category in each task, but no consistent categorisation emerged across the three techniques. Just 1 out of the 12 patients, was consistently classified across all three tasks. It seemed that despite the fact that all tasks essentially required a line bisection response, the perceptual and motor differences between the tasks were still great enough to result in inconsistent classifications. The Landmark Task classified the majority of patients into the perceptual neglect category, while the Overhead and Pulley Device Techniques tended to identify more patients as suffering from a premotor deficit (albeit not the same set of patients).