Cloning and characterization of a canine UDP-glucuronosyltransferase.
UDP-glucuronosyltransferases (UGTs) are a major family of enzymes catalyzing the transfer of glucuronic acid to a range of endogenous compounds and xenobiotics facilitating their elimination in either urine or bile. Although the dog is commonly used in drug metabolism studies, relatively little is known about the expression and activity of UGTs in this species. This report describes the molecular cloning and functional characterization of the first dog UGT, UGT1A6. The cloned protein is composed of 528 amino acids with the variable region demonstrating a 67-72% identity with the variable regions of mouse, rat, and human UGT1A6. The enzyme expressed stably in V79 cells predominantly catalyzed the glucuronidation of simple, planar phenols (e.g., for 1-naphthol, K(m) = 41 microM, V(max) = 0.07 nmol/min/mg protein), a class of compounds extensively glucuronidated by human UGT1A6. Based on sequence homology and common catalytic activity, this dog UGT1A protein appears to be the canine orthologue of human UGT1A6.


Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial.
We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0·16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0·10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27·0% (95% CI 23·0-30·9) in the whole-breast irradiation group versus 23·3% (19·9-26·8) in the APBI group (p=0·12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10·7% (95% CI 8·0-13·4) in the whole-breast irradiation group versus 6·9% (4·8-9·0) in the APBI group (difference -3·8%, 95% CI -7·2 to 0·4; p=0·020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9·7% (95% CI 7·1-12·3) in the whole-breast irradiation group versus 12·0% (9·4-14·7) in the APBI group (difference 2·4%; 95% CI -1·4 to 6·1; p=0·28). The cumulative incidence of grade 2-3 breast pain was 11·9% (95% CI 9·0-14·7) after whole-breast irradiation versus 8·4% (6·1-10·6) after APBI (difference -3·5%; 95% CI -7·1 to 0·1; p=0·074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0·62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0·12). No treatment-related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated. 5-year toxicity profiles and cosmetic results were similar in patients treated with breast-conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation. German Cancer Aid.


[Experiment of wet FGD process with waste marble].
The wet FGD process with waste marble was studied experimentally, and the mass transfer reaction mechanism was analyzed. Main parameters including liquid/gas ratio, pH value of the absorbent slurry and inlet SO2 concentration, etc. affecting SO2 removal efficiency were studied for the process. The results show that the suitable operating conditions were recommended as follows: pH0 = 5.5-6.5, L/G = 3L/m3, a = 2%; the sulfur dioxide removal efficiency can reach more than 60% when the inlet SO2 concentration was 1000 ml/m3. In addition, the industrial application potential for this process was discussed.


The cloudy crystal ball of cost-effectiveness studies.
Despite the use of identical clinical trial data (Anastrazole, Tamoxifen, Alone or in Combination for the adjuvant treatment of postmenopausal women with localised hormone receptor-positive breast cancer data), not dependent on differences between countries, the outcome of 11 published cost-effectiveness analyses varied more than 20-fold. The observed wide variation in predicted life-years gained (a parameter derived from clinical trial data) demonstrates that authors used substantially different methods for handling the same data. We therefore consider it to be of utmost importance to strive for standardization of and better guidance for disease-specific modeling in economic evaluations.


On two-channel filter banks with directional vanishing moments.
The contourlet transform was proposed to address the limited directional resolution of the separable wavelet transform. One way to guarantee good approximation behavior is to let the directional filters in the contourlet filter bank have sharp frequency response. This requires filters with large support size. We seek to isolate the key filter property that ensures good approximation. In this direction, we propose filters with directional vanishing moments (DVM). These filters, we show, annihilate information along a given direction. We study two-channel filter banks with DVM filters. We provide conditions under which the design of DVM filter banks is possible. A complete characterization of the product filter is, thus, obtained. We propose a design framework that avoids 2-D factorization using the mapping technique. The filters designed, when used in the contourlet transform, exhibit nonlinear approximation comparable to the conventional filters while being shorter and, therefore, providing better visual quality with less ringing artifacts. Furthermore, experiments show that the proposed filters outperform the conventional ones in image approximation and denoising.


DNA damage uncouples the mitogenic response to IGF-I in MCF-7 malignant breast cancer cells by switching the roles of PI3 kinase and p21WAF1/Cip1.
In addition to its mitogenic and survival actions, recent evidence indicates that IGF-I can enhance DNA repair, implying IGF activity may limit the efficacy of many therapeutic strategies that rely on induction of DNA damage. Although the individual pathways by which DNA damage and IGF-I act are well understood, the cross-talk between these signaling events is not well defined. We examined the effects of DNA damage on the IGF-I response of MCF-7 breast cancer cells. Cells were exposed to the UV mimetic, 4-NQO, or the gamma-irradiation mimetic and chemotherapeutic drug, bleomycin; cellular proliferation was assessed by cell counting, tritiated thymidine incorporation and FACS cell cycle analysis. Although IGF-I acutely suppressed the p53 response to both agents, it subsequently enhanced the chronic increase in p53 and p21(WAF1/Cip1), resulting in cell cycle arrest; however, no apoptosis was observed. Use of specific inhibitors demonstrated that PI3 kinase was utilized with p38 MAPK to induce the p53 response to DNA damage, but was also utilized by IGF-I to diminish the acute p53 response. In addition, p21WAF1/Cip1 was increased by IGF-I, which has previously been shown to contribute to the mitogenic response. Here we demonstrate that with DNA damage IGF-I can also enhance the chronic p53-dependent increase in p21WAF1/Cip1, culminating in growth arrest. Overall, we have shown that PI3 kinase and p21WAF1/Cip1 play dual roles in mediating the mitogenic response to IGF-I, but these are both switched by cellular DNA damage to mediate a growth arrest.


Observing atomic collapse resonances in artificial nuclei on graphene.
Relativistic quantum mechanics predicts that when the charge of a superheavy atomic nucleus surpasses a certain threshold, the resulting strong Coulomb field causes an unusual atomic collapse state; this state exhibits an electron wave function component that falls toward the nucleus, as well as a positron component that escapes to infinity. In graphene, where charge carriers behave as massless relativistic particles, it has been predicted that highly charged impurities should exhibit resonances corresponding to these atomic collapse states. We have observed the formation of such resonances around artificial nuclei (clusters of charged calcium dimers) fabricated on gated graphene devices via atomic manipulation with a scanning tunneling microscope. The energy and spatial dependence of the atomic collapse state measured with scanning tunneling microscopy revealed unexpected behavior when occupied by electrons.


Mediator antagonists in the treatment of allergic disease.
New approaches to allergic inflammation include specific cytokine antagonists and monoclonal antibodies against IgE, against chemokines, and against adhesion molecules. Currently available therapies, such as leukotriene antagonists, may soon be approved for allergic rhinitis. New generation antihistamines such as desloratadine have wide-ranging anti-allergic, anti-inflammatory profiles, including suppression of cytokine, chemokine, and adhesion molecule expression. Recent desloratadine studies have demonstrated that this highly potent H1 receptor antagonist consistently provides relief of nasal congestion and may provide benefits similar to montelukast in mild asthma patients. New generation intra-nasal corticosteroids such as fluticasone and mometasone provide high corticosteroid potency while being minimally bioavailable when administered as intranasal preparations. Future advances in allergy therapy also include improved T-cell selective formats of immunotherapy. The range of therapies for allergic rhinitis is likely to substantially increase in the coming years.


Oxidative stress and airway inflammation after allergen challenge evaluated by exhaled breath condensate analysis.
Allergen exposure may increase airway oxidative stress, which causes lipid membrane peroxidation and an increased formation of 8-isoprostane. The aim of the study was to investigate oxidative stress induced by allergen challenge in mild asthmatics, by measuring 8-isoprostane in exhaled breath condensate (EBC), and to examine their relationship with mediators derived from arachidonic acid. Methods 8-isoprostane, cysteinyl leukotrienes (cys-LTs) and prostaglandin E2 (PGE(2) ) concentrations in EBC were measured at baseline and after allergen challenge in 12 patients with mild allergic asthma sensitized to cat allergen. At 24 h after allergen challenge, compared with baseline values, EBC 8-isoprostane increased [48.64 pg/mL (44.14-53.61) vs. 21.56 pg/mL (19.92, 23.35), P<0.001], cys-LTs increased [27.37 pg/mL (24.09-31.10) vs. 13.28 pg/mL (11.32, 15.57), P<0.001] and PGE(2) decreased [18.69 pg/mL (12.26, 28.50) vs. 39.95 pg/mL (34.37, 46.43), P<0.001]. The trend of increasing 8-isoprostane after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.85, P<0.001) whereas the trend of decreasing PGE(2) after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.52, P=0.001). The increase in EBC 8-isoprostane observed after allergen challenge indicates that allergen exposure increases airway oxidative stress in allergic asthma. The strict correlation between cys-LTs and 8-isoprostane underlines the relationship between allergic inflammation and oxidative stress. A shift of arachidonic acid metabolism towards lipoxygenase pathway is induced by the allergen challenge. Airway oxidative stress occurs after allergen challenge even in patients with mild intermittent allergic asthma.


Water oxidation at a tetraruthenate core stabilized by polyoxometalate ligands: experimental and computational evidence to trace the competent intermediates.
Converging UV-vis, EPR, rRaman, and DFT calculations highlight the evolution of [Ru(4)(H(2)O)(4)(mu-O)(4)(mu-OH)(2)(gamma-SiW(10)O(36))(2)](10-), 1, to high-valent intermediates. In analogy with the natural enzyme, five different oxidation states, generated from 1, have been found to power the catalytic cycle for water oxidation. A high electrophilic tetraruthenium(V)-hydroxo species is envisaged as the competent intermediate, undergoing nucleophilic attack by an external water molecule as a key step in the formation of a new O-O bond under catalytic conditions.


Do higher salaries lower physician migration?
It is believed that low wages are an important reason why doctors and nurses in developing countries migrate, and this has led to a call for higher wages for health professionals in developing countries. In this paper, we provide some of the first estimates of the impact of raising health workers' salaries on migration. Using aggregate panel data on the stock of foreign doctors in 16 Organization for Economic Cooperation and Development countries, we explore the effect of a wage increase programme in Ghana on physician migration. We find evidence that 6 years after the implementation of this programme, the foreign stock of Ghanaian doctors abroad had fallen by approximately 10% relative to the estimated counterfactual. This result should be interpreted with caution, however, given the sensitivity of the results to changes in model specification.


Low frequency pressure waves of possible autonomic origin in severely head-injured children.
Useful information (both clinical and pathophysiological) which may be extracted from intracranial pressure (ICP) recordings include: (1) the mean level of ICP (and CPP), (2) cerebrovascular autoregulation status, (3) the intracranial pulse pressure (the pulse wave index, ICPpp/ICPm) or the pressure-volume compensatory reserve index (RAP) and (4) the presence of any abnormal ICP waveform. This paper describes a slow frequency ICP waveform in children with TBI and postulates the pathophysiological basis and whether it contains clinically useful detail. Children admitted to the Regional Head Injury Service in Edinburgh with TBI have continuously monitored ICP, MAP, CPP, and other physiological data (stored at a 1-min resolution). Slow frequency waveforms were noted, prompting a review of the stored monitoring from all cases over a 10 year period. Episodic slow pressure waves were detected in 11 of 122 severely head-injured (HI) children. The waveforms were detected in children of all ages (1.6-15 years) in the ICP signal, which were in phase with similar fluctuations in the MAP, CPP, and HR signals. Their mean periodicity was 1 per 7 min (range 1 per 5-10 min), with a mean ICP pulse wave amplitude of 5.45 mmHg (range 4-7.5), and mean MAP pulse wave amplitude (pulse pressure) of 10.4 mmHg (range 4-15 mmHg). The duration was variable (range approx 2 h to 4.5 days). They were detected in the preterminal phase after serious HI, as well as in those children who made an independent recovery (GOS 4/5). The waves were not related to the mean levels of ICP, CPP, MAP, temperature or the state of cerebrovascular autoregulation. We postulate that these previously unreported slow waveforms may reflect the very low frequency (VLF) and ultra low frequency (ULF; < or = 1 per 5 min) components of heart rate and arterial blood pressure variability.


The contribution of cortical thickness and surface area to gray matter asymmetries in the healthy human brain.
Human cortical gray matter (GM) is structurally asymmetrical and this asymmetry has been discussed to be partly responsible for functional lateralization of human cognition and behavior. Past studies on brain asymmetry have shown mixed results so far, with some studies focusing on the global shapes of the brain's surface, such as gyrification patterns, while others focused on regional brain volumes. In this study, we investigated cortical GM asymmetries in a large sample of right-handed healthy volunteers (n = 101), using a surface-based method which allows to analyze brain cortical thickness and surface area separately. As a result, substantially different patterns of symmetry emerged between cortical thickness and surface area measures. In general, asymmetry is more prominent in the measure of surface compared to that of thickness. Such a detailed investigation of structural asymmetries in the normal brain contributes largely to our knowledge of normal brain development and also offers insights into the neurodevelopmental basis of psychiatric disorders, such as schizophrenia.


Synopsis of the genus Pharaonus (Coleoptera: Scarabaeidae: Rutelinae), with descriptions of new taxa.
An overview of the genus Pharaonus Blanchard, 1851 is presented. Pharaonus farsensis new species and P. adelphus new species are described from Iran, P. lederi turcmenius Ohaus, 1941 is recognized as new synonym of P. lederi (Reitter, 1888), and the subgenus Tamerlanius new subgenus is proposed for the two central-Asian species. New distribution records and systematic notes are presented: P. caucasicus (Reitter, 1888) is removed from the fauna of Iran and P. varicoloreus (Burmeister, 1844) from that of Israel; P. fasciculatus (Burmeister, 1844) is reported for the first time from Israel, P. semenowi (Reitter, 1888) from Tajikistan. All known species are illustrated and a key to species is presented.


Mild preoperative renal dysfunction as a predictor of long-term clinical outcome after coronary bypass surgery.
Renal dysfunction is a prognostic marker in patients with cardiovascular disease. However, no long-term follow-up studies on the influence of mild renal dysfunction on mortality in patients undergoing coronary bypass grafting have been reported. Therefore, we aimed to identify the significance of preoperative (mild) renal dysfunction as a long-term predictor of clinical outcome after coronary bypass surgery. In 358 patients who underwent isolated saphenous vein aorta-coronary artery bypass grafting, estimated glomerular filtration rates were calculated with the Cockroft-Gault equation (GFRc). Patients were categorized into 2 groups (group 1, GFRc >71.1 mL x min (-1) x 1.73 m (-2) ; group 2, GFRc <71.1 mL x min (-1) x 1.73 m (-2) ). Multivariate Cox proportional hazard analyses were performed to determine the independent prognostic value of GFRc. During a median follow-up of 18.2 years, 233 patients (65.1%) died. Patients who died had lower GFRc and were older. Multivariate analysis demonstrated that total mortality in patients with lower GFRc was significantly increased (lower GFRc group vs normal GFRc group: hazard ratio, 1.44; P = .019). Lower GFRc was also an independent predictor of cardiac mortality (hazard ratio, 1.51; P = .032). No significant differences were observed between groups in the occurrence of myocardial infarction and the need for reintervention. Our study demonstrates that after long-term follow-up, preoperative mild renal dysfunction is an independent predictor of long-term (cardiac) mortality in patients who undergo coronary artery bypass grafting.


A human nuclear protein with sequence homology to a family of early S phase proteins is required for entry into S phase and for cell division.
Molecular cloning and characterisation of a human nuclear protein designated BM28 is reported. On the amino acid level this 892 amino acid protein, migrating on SDS-gels as a 125 kDa polypeptide, shares areas of significant similarity with a recently defined family of early S phase proteins. The members of this family, the Saccharomyces cerevisiae Mcm2p, Mcm3p, Cdc46p/Mcm5p, the Schizosaccharomyces pombe Cdc21p and the mouse protein P1 are considered to be involved in the onset of DNA replication. The highest similarity was found with Mcm2p (42% identity over the whole length and higher than 75% over a conservative region of 215 amino acid residues), suggesting that BM28 could represent the human homologue of the S. cerevisiae MCM2. Using antibodies raised against the recombinant BM28 the corresponding antigen was found to be localised in the nuclei of various mammalian cells. Microinjection of anti-BM28 antibody into synchronised mouse NIH3T3 or human HeLa cells presents evidence for the involvement of the protein in cell cycle progression. When injected in G1 phase the anti-BM28 antibody inhibits the onset of subsequent DNA synthesis as tested by the incorporation of bromodeoxyuridine. Microinjection during the S phase had no effect on DNA synthesis, but inhibits cell division. The data suggest that the nuclear protein BM28 is required for two events of the cell cycle, for the onset of DNA replication and for cell division.


Prognostic value of S-phase fraction in lymph-node-negative breast cancer by image and flow cytometric analysis.
Cellular DNA content and proliferation rates have been suggested as prognostic factors in breast carcinomas. A series of 271 lymph-node negative breast carcinoma patients without adjuvant therapy was reviewed (mean follow-up, 108 mo). Tumor cells from the same paraffin-embedded block tissue (Hedley's method) were analyzed by image analysis (IA) in Feulgen-stained smears and by flow cytometric analysis (FC). Clinicopathologic features, ploidy, S-phase fraction, and percentage of tumor cells with more than 5n DNA content (in diploid tumors, by IA) were related to outcome. The results of IA and FC were compared in 115 cases. Tumor size, histologic grade, desmoplasia and S-phase fraction were significant predictors of survival in multivariate analysis (Cox proportionate regression) (P < or = 0.03). Ploidy by the two methods showed agreement in 100 carcinomas (87%). Of the 15 discordant cases, FC detected 6 multiploid and 4 aneuploid-peridiploid. In contrast, IA detected more tetraploid carcinomas. Tumor size, histologic grade, desmoplasia, and S-phase fraction were independent predictors of long-term prognosis in our patients. Ploidy and percentage of tumor cells with more than 5n DNA content were not prognostic indicators. FC detected aneuploidy more frequently than did IA.


Rapid estimation of microbial populations in fish samples by using terminal restriction fragment length polymorphism analysis of 16S rDNA.
A rapid system using terminal restriction fragment length polymorphism (T-RFLP) analysis targeting 16S rDNA is described for microbial population analysis in edible fish samples. The defined terminal restriction fragment database was constructed by collecting 102 strains of bacteria representing 53 genera that are associated with fish. Digestion of these 102 strains with two restriction enzymes, HhaI and MspI, formed 54 pattern groups with discrimination to the genus level. This T-RFLP system produced results comparable to those from a culture-based method in six natural fish samples with a qualitative correspondence of 71.4 to 92.3%. Using the T-RFLP system allowed an estimation of the microbial population within 7 h. Rapid assay of the microbial population is advantageous for food manufacturers and testing laboratories; moreover, the strategy presented here allows adaptation to specific testing applications.


Interaction of 2-hydroxy-substituted Nile red fluorescent probe with organic nitrogen compounds.
The fluorescent properties of 2-hydroxy Nile red dye (HONR) proved to be highly sensitive to the basicity of hydrogen bond acceptors. Fluorescence quantum yields and fluorescence decay profiles were measured as the function of the concentration of organic nitrogen compounds in solvents of various polarities. The detailed mechanism and the kinetics of the fluorescence quenching were revealed with the combined analysis of the steady-state and time-resolved spectroscopic data. The relative contribution of the competing reaction steps was found to be very sensitive to the basicity of the additive and to solvent polarity. The most profound change appeared in the unimolecular deactivation pathways of the excited hydrogen-bonded HONR, whereas the formation rate of this species varied to a lesser extent. The dissociation into excited HONR and ground-state base was able to compete with the energy dissipation only when 2,4,6-trimethylpyridine was used as hydrogen bond acceptor in toluene. The bimolecular quenching of the excited hydrogen-bonded complex played significant role in apolar solvents. Proton displacement along the hydrogen bond in the excited complex led to excited ion pairs in polar media.


Regulation of GTP cyclohydrolase I gene expression and tetrahydrobiopterin content in cultured sympathetic neurons by leukemia inhibitory factor and ciliary neurotrophic factor.
Cultures of neonatal rat superior cervical ganglia (SCG) were used to test the hypothesis that the cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) control GTP cyclohydrolase I (GTPCH) gene expression and 5,6,7,8-tetrahydrobiopterin (BH4) content as traits of the noradrenergic phenotype. Treatment for 7 days with 1 ng/ml of LIF was found to produce the characteristic switch in the SCG neurotransmitter phenotype reported by others, as evidenced by a 60% decline in tyrosine hydroxylase. (TH) activity and a 75% increase in choline acetyltransferase activity. This LIF treatment paradigm decreased BH4 levels in a concentration-dependent manner, with a maximal decline of 60% observed at 1 ng/ml. Analysis of the time course of this response indicated that LIF decreased BH4 levels by 60% following 3-7 days of treatment. Treatment of cultures with CNTF (2 ng/ml) resulted in a decline in BH4 levels that was of equal magnitude and followed the same time course as that produced by LIF. The LIF-dependent decline in BH4 levels resulted from a reduction in GTPCH enzyme activity, which decreased by 75% following 7 days of treatment. Nuclease protection assays of RNA extracted from cells treated for 7 days with 2 ng/ml of LIF or CNTF detected a 78-96% reduction in GTPCH mRNA content relative to beta-actin mRNA content. Concomitant decreases in TH and GTPCH gene expression in response to LIF or CNTF demonstrate a coordinated regulation of gene expression for this BH4-dependent enzyme and the rate-limiting enzyme in the synthesis of its essential cofactor, BH4. Moreover, these results indicate that GTPCH gene expression in SCG neurons should be regarded as a trait of the noradrenergic phenotype.


Delaware Longitudinal Study of Fraction Learning: Implications for Helping Children With Mathematics Difficulties.
The goal of the present article is to synthesize findings to date from the Delaware Longitudinal Study of Fraction Learning. The study followed a large cohort of children ( N = 536) between Grades 3 and 6. The findings showed that many students, especially those with diagnosed learning disabilities, made minimal growth in fraction knowledge and that some showed only a basic grasp of the meaning of a fraction even after several years of instruction. Children with low growth in fraction knowledge during the intermediate grades were much more likely to fail to meet state standards on a broad mathematics measure at the end of Grade 6. Although a range of general and mathematics-specific competencies predicted fraction outcomes, the ability to estimate numerical magnitudes on a number line was a uniquely important marker of fraction success. Many children with mathematics difficulties have deep-seated problems related to whole number magnitude representations that are complicated by the introduction of fractions into the curriculum. Implications for helping students with mathematics difficulties are discussed.


Management of critically ill children with traumatic brain injury.
The management of critically ill children with traumatic brain injury (TBI) requires a precise assessment of the brain lesions but also of potentially associated extra-cranial injuries. Children with severe TBI should be treated in a pediatric trauma center, if possible. Initial assessment relies mainly upon clinical examination, trans-cranial Doppler ultrasonography and body CT scan. Neurosurgical operations are rarely necessary in these patients, except in the case of a compressive subdural or epidural hematoma. On the other hand, one of the major goals of resuscitation in these children is aimed at protecting against secondary brain insults (SBI). SBI are mainly because of systemic hypotension, hypoxia, hypercarbia, anemia and hyperglycemia. Cerebral perfusion pressure (CPP = mean arterial blood pressure - intracranial pressure: ICP) should be monitored and optimized as soon as possible, taking into account age-related differences in optimal CPP goals. Different general maneuvers must be applied in these patients early during their treatment (control of fever, avoidance of jugular venous outflow obstruction, maintenance of adequate arterial oxygenation, normocarbia, sedation-analgesia and normovolemia). In the case of increased ICP and/or decreased CPP, first-tier ICP-specific treatments may be implemented, including cerebrospinal fluid drainage, if possible, osmotic therapy and moderate hyperventilation. In the case of refractory intracranial hypertension, second-tier therapy (profound hyperventilation with P(a)CO(2) < 35 mmHg, high-dose barbiturates, moderate hypothermia, decompressive craniectomy) may be introduced, after a new cerebral CT scan.


Effect of nitroprusside on regional myocardial blood flow in coronary artery disease. Results in 25 patients and comparison with nitroglycerin.
The effect of nitroprusside on regional myocardial specific blood flow (RMBF) was evaluated in 25 patients with the xenon-133 washout technique. Six patients were normal (group 1), six patients had coronary artery disease without collateral vessels (group 2), and thirteen patients had coronary artery disease with collateral vessels (group 3). In group 1, RMBF was unchanged following nitroprusside. RMBF decreased significantly in both group 2 and group 3, including seven patients in group 3 with high-grade collateral vessels. The results were compared to the effect of nitroglycerin in 31 patients previously studied using the same technique. Mean arterial pressure and pressure-rate product were comparably reduced by both drugs. In contrast to the findings with nitroprusside, after sublingual nitroglycerin RMBF decreased markedly in normals and increased in patients with coronary artery disease and high-grade collaterals. The data suggest that nitroprusside may primarily affect resistance vessels within the coronary circulation, as opposed to the effect of nitroglycerin on conductance vessels. Thus, nitroprusside could result in redistribution of blood flow away from ischemic areas and potentially increase ischemic injury in some patients with coronary artery disease.


Evaluation of Practical Interpretation Hurdles in 68Ga-PSMA PET/CT in 55 Patients: Physiological Tracer Distribution and Incidental Tracer Uptake.
To investigate the physiologic Ga-PSMA distribution and evaluate focal or diffuse radiotracer uptake in nonprostate cancer malignancies and in incidental findings. Ga-PSMA PET/CT scans in 55 men performed for prostate cancer (49) or renal cell carcinoma (6) staging were analyzed retrospectively. Two radiologists evaluated the datasets in 2 reading sessions. First, physiological Ga-PSMA uptake was evaluated. Second, scans were analyzed for incidental uptake. SUVmax and SUVmean were recorded. Other imaging modalities, histopathology, or clinical follow-up served as standard of reference. Homogenous Ga-PSMA uptake of the lacrimal glands (SUVmax, 15.7 ± 7.2), parotid glands (SUVmax, 24.4 ± 8.1), submandibular glands (SUVmax, 26.7 ± 7.1), vocal cords (SUVmax, 8.4 ± 3), Waldeyer ring (SUVmax, 10.4 ± 4.3), liver (SUVmax, 8.2 ± 2.5), spleen (SUVmax, 10.9 ± 3.9), kidneys (SUVmax, 66.4 ± 25.4), and pars descendens duodeni (SUVmax, 17.6 ± 8.9) was observed in all patients. In 65% and 36%, respectively, homogenous Ga-PSMA uptake of the colon descendens (SUVmax, 10.6 ± 9.2) and the rectum (SUVmax, 3.7 ± 1.1) was found. Approximately 22% exhibited a Ga-PSMA uptake of the thyroid (SUVmax, 4.5 ± 1.2), and 21% exhibited a Ga-PSMA uptake of the knee's synovia (SUVmax, 2.9 ± 0.2). Furthermore, Ga-PSMA uptake was found in 1 patient because of fibrous dysplasia of the right os ilium (SUVmax, 7.7). Physiologic distribution of Ga-PSMA comprises uptake in lacrimal and salivary glands, vocal cords, Waldeyer ring, liver, spleen, and kidneys as well as various parts of the intestine. Moreover, nonspecific tracer uptake is regularly found in the thyroid and the synovia of the knee. Incidental Ga-PSMA uptake can occasionally reveal nonprostate cancer-associated remodeling processes, such as fibrous dysplasia.


Amblyopia.
Amblyopia, a decrease in visual acuity, is a major public health problem with a prevalence of 1 to 4 percent in the United States. It is thought to develop early in life during the critical period of visual development. Early recognition of amblyogenic risk factors such as strabismus, refractive errors, and anatomic obstructions can facilitate early treatment and increase the chance for recovery of visual acuity. Multiple medical organizations endorse screening for visual abnormalities in children and young adults, yet only 20 percent of school-age children have routine vision screening examinations. Any child with a visual acuity in either eye of 20/40 or worse at age three to five years or 20/30 or worse at age six years or older, or a two-line difference in acuity between eyes, should be referred to an ophthalmologist for further evaluation and definitive therapy. Treatment is started at the time of diagnosis and depends on the etiology. Treatment options for children with strabismus include patching and atropine drops. Children with refractive errors should be prescribed corrective lenses. Corneal lesions, cataracts, and ptosis require surgery. The success of therapy is highly dependent on treatment compliance. Patients and their parents should be educated about the need for regular follow-up and the risk of permanent vision loss.


Mechanisms of cell death induced by histone deacetylase inhibitors in androgen receptor-positive prostate cancer cells.
Histone deacetylase inhibitors (HDACI) are potential therapeutic agents that inhibit tumor cell growth and survival. Although there are several publications regarding the effects of HDACIs on prostate cancer cell growth, their mechanism(s) of action remains undefined. We treated several human prostate cancer cell lines with the HDACI trichostatin A and found that trichostatin A induced cell death in androgen receptor (AR)-positive cell lines to higher extent compared with AR-negative cell lines. We then discovered that trichostatin A and other HDACIs suppressed AR gene expression in prostate cancer cell lines as well as in AR-positive breast carcinoma cells and in mouse prostate. Trichostatin A also induced caspase activation, but trichostatin A-induced AR suppression and cell death were caspase independent. In addition, we found that doxorubicin inhibited AR expression, and p21 protein completely disappeared after simultaneous treatment with trichostatin A and doxorubicin. This effect may be attributed to the induction of protease activity under simultaneous treatment with these two agents. Further, simultaneous treatment with trichostatin A and doxorubicin increased cell death in AR-positive cells even after culturing in steroid-free conditions. The protease/proteasome inhibitor MG132 protected AR and p21 from the effects of trichostatin A and doxorubicin and inhibited trichostatin A-induced cell death in AR-positive prostate cells. Taken together, our data suggest that the main mechanism of trichostatin A-induced cell death in AR-positive prostate cancer is inhibition of AR gene expression. The synergistic effect of simultaneous treatment with trichostatin A and doxorubicin is mediated via inhibition of AR expression, induction of protease activity, increased expression of p53, and proteolysis of p21.


Effect of metal ions and calcium on purified PON1 and PON3 from rat liver.
The effect of several metal ions and calcium on purified paraoxonases (PON1 and PON3) from rat liver was studied. PON1 and PON3 were also inhibited by EDTA and both enzyme activities were restored by the addition of free calcium. The reactivation by calcium was a time-dependent effect for PON1; however, this was not the case for PON3. We also studied the response of PON1 and PON3 to several inhibitors: Co, Cu, Mn, Hg and p-hydroxymercurybenzoate (pOHMB), and determined the type of inhibition and the inhibition constants. Among all the compounds tested, mercurials (Hg and pOHMB) were the most potent inhibitors of PON1. For PON3 mercurials and copper showed the highest inhibitory potency. Purified PON3 also showed different inhibition patterns as compared to PON1. A comparison of PON1 and PON3 shows qualitative and quantitative differences in the sensitivity against the inhibitors tested, showing major differences in the case of cobalt, copper and pOHMB, which may be related to structural differences of both PONs. These results increase our knowledge of the biochemical properties of PON1 and PON3 and may help in the understanding of their physiological role as a potential detoxification mechanism against environmental metal ions.


Iron and calcium bioavailability of fortified foods and dietary supplements.
Bioavailability is a key consideration when developing strategies for preventing mineral deficiencies through improved dietary supply. Factors that affect the bioavailability of iron and calcium, forms used for fortification and supplementation, and methods used to assess bioavailability are described. Illustrations of the impact of introducing iron-fortified foods in developing and industrialized countries are given, and the alternative approach of supplementation with iron and calcium is discussed.


Association of cigarette smoking, alcohol consumption and physical activity with lower urinary tract symptoms in older American men: findings from the third National Health And Nutrition Examination Survey.
To examine the association of cigarette smoking, alcohol consumption and physical activity with lower urinary tract symptoms (LUTS) in older men. The study included 2797 men participating in the Third National Health and Nutrition Examination Survey (NHANES III), who were aged > or = 60 years. During an interview, LUTS, smoking history, alcohol consumption and physical activity were assessed. Cases comprised men with at least three of the symptoms of nocturia, hesitancy, weak stream and incomplete emptying. Men who had had prostate surgery unrelated to cancer were not included as cases. Controls were men with no symptoms or surgery. We adjusted for age and race in logistic regression models and used sampling weights to account for selection probability. Current cigarette smokers had no higher odds of LUTS than 'never' smokers, but former heavy smokers (> or = 50 pack-years) had a higher odds of LUTS than never smokers (odds ratio 2.01; 95% confidence interval 1.04-3.89). Men who drank alcohol daily had a lower chance of LUTS than non-drinkers (0.59; 0.37-0.95; P trend, 0.07). All levels of moderate and vigorous activity were statistically significantly inversely associated with LUTS (P trend, 0.06), whereas men who reported no leisure-time physical activity had a greater odds of LUTS (2.06; 1.26-3.39). Moderate alcohol consumption and physical activity may be protective against LUTS. Current cigarette smoking was not consistently associated with the condition. The possible association in former smokers warrants further investigation.


Adenosine mediates tubuloglomerular feedback response: an element of metabolic control of kidney function.
Numerous studies have shown during the past 10 years that adenosine is present in the normoxic kidney and accumulates when ATP hydrolysis prevails over ATP synthesis. Local generation of adenosine by the macula densa cells and its release into the interstitium of the juxtaglomerular apparatus (JGA) is considered to be the link between the enhanced NaCl concentration in the tubular fluid and the subsequent responses including preglomerular vasoconstriction and reduction of renin release by the juxtaglomerular cells. Micropuncture and microperfusion experiments using specific adenosine agonists and antagonists support the concept that adenosine functions as a mediator in the signal transmission of the JGA.


A single polycystic kidney disease 2-like 1 channel opening acts as a spike generator in cerebrospinal fluid-contacting neurons of adult mouse brainstem.
Cerebrospinal fluid contacting neurons (CSF-cNs) are found around the central canal of all vertebrates. They present a typical morphology, with a single dendrite that projects into the cavity and ends in the CSF with a protuberance. These anatomical features have led to the suggestion that CSF-cNs might have sensory functions, either by sensing CSF movement or composition, but the physiological mechanisms for any such role are unknown. This hypothesis was recently supported by the demonstration that in several vertebrate species medullo-spinal CSF-cNs selectively express Polycystic Kidney Disease 2-Like 1 proteins (PKD2L1). PKD2L1 are members of the 'transient receptor potential (TRP)' superfamily, form non-selective cationic channels of high conductance, are regulated by various stimuli including protons and are therefore suggested to act as sensory receptors. Using patch-clamp whole-cell recordings of CSF-cNs in brainstem slices obtained from wild type and mutant PKD2L1 mice, we demonstrate that spontaneously active unitary currents in CSF-cNs are due to PKD2L1 channels that are capable, with a single opening, of triggering action potentials. Thus PKD2L1 might contribute to the setting of CSF-cN spiking activity. We also reveal that CSF-cNs have the capacity of discriminating between alkalinization and acidification following activation of specific conductances (PKD2L1 vs. ASIC) generating specific responses. Altogether, this study reinforces the idea that CSF-cNs represent sensory neurons intrinsic to the central nervous system and suggests a role for PKD2L1 channels as spike generators.


[Synergistic cytotoxic effects of chemotherapy in colon tumor cells by simultaneous inhibition of de novo and salvage energy metabolism pathways].
The success of chemotherapy of colon tumours is currently limited. We have therefore used the human colon tumour cell line HT-29 to evaluate the cytotoxic effects of various drug combinations. Trimidox (3,4,5-trihydroxybenzamidoxime), a recently patented inhibitor of ribonucleotide reductase was combined with cytosinearabinoside (Ara-C) or 2',2'-difluorodeoxycytidine (DFDC) in order to inhibit both pyrimidine de novo and salvage pathways. Synergistic cytotoxic effects were observed. When HT-29 cells were sequentially treated with trimidox (20 microM for 24 h) and Ara-C (2 microM for 2 h), colony numbers decreased to 71% of the value calculated for additive cytotoxicity. When cells were simultaneously treated with trimidox (10 microM and 15 microM) and DFDC (0.2 nM), synergistic inhibition of colony formation was likewise noted (colony numbers decreased to values as low as 73% or 71% of the values calculated for additive cytotoxicity). On the other hand, we combined tiazofurin, an inhibitor of the guanylate de novo pathway, with allopurinol, which inhibits the guanylate salvage pathway by increasing intracellular hypoxanthine concentrations, leading to inhibition of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Synergistic cytotoxic effects were observed under these conditions too. When cells were treated with 10 microM tiazofurin and 400 microM or 800 microM allopurinol the number of colonies decreased to 69% and 27%, respectively, of the values calculated for additive effects. Our data suggest these drug combinations to be promising options in the treatment of human colon cancer.


Effect of the reactant mixing sequence on the chymotrypsin inhibition assay.
In assaying chymotrypsin inhibition by the soybean Bowman-Birk inhibitor, two sequences of mixing the reactants were tried: adding the substrate last (s-last test) or adding the enzyme last (e-last test). The inhibition values obtained from the s-last test were either equal to or lower than those from the e-last test, depending on the pre-mix pH and pre-incubation time, while the values from the e-last test were independent of these conditions. The differences between the two tests were largest at a pre-mix pH of 4.0 or 8.5 and zero near pH 7.0. Abruptly changing the pre-mix pH from 4.0 to 7.0 brought the values of the two tests closer. These observations suggest a reversible, yet limited, hydrolysis of the inhibitor by the very enzyme it inhibits and indicate the greater reliability of the e-last test over the s-last test, paralleling a similar previous finding on the trypsin inhibition assay.


Drug-eluting stents in the treatment of intermediate lesions: pooled analysis from four randomized trials.
To address the safety and efficacy of drug-eluting stents (DES) in the treatment of intermediate lesions, we performed a pooled analysis of four randomized DES versus bare-metal stent (BMS) trials and assessed outcomes among patients with intermediate lesions. Before the introduction of DES, intermediate coronary lesions were commonly managed based on physiologic or anatomic assessment of lesion severity. The DES may challenge this paradigm. The study population involved 167 of 2,478 randomized patients (6.7%) with intermediate lesions (diameter stenosis <50% [mean 44%] by quantitative coronary angiography) from the Sirolimus-coated Bx Velocity Balloon Expandable Stent in the Treatment of Patients with De Novo Coronary Artery Lesions (SIRIUS), TAXUS-IV, and the First and Second First Use to Underscore Restenosis Reduction with Everolimus (FUTURE-I and -II) trials. End points examined included early (in-hospital and 30-day) and late (1-year) major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis, and follow-up angiographic restenosis. Patients with intermediate lesions randomized to DES versus BMS had low rates of 30-day MACE (1.1% vs. 4.0% respectively; p = 0.22). At one-year follow-up, patients treated with DES versus BMS had similar rates of cardiac death (0% vs. 2.7%, respectively; p = 0.11) and MI (3.4% vs. 5.4%; p = 0.49) but markedly lower rates of TVR (3.4% vs. 20.3%; p = 0.0004), MACE (5.6% vs. 25.4%; p = 0.0003), and binary angiographic restenosis (1.8% vs. 34.0%; p < 0.0001). No patient in either group developed stent thrombosis. Compared with BMS, treatment of intermediate lesions with DES appears safe and results in a marked reduction in clinical and angiographic restenosis. The efficacy of DES may require a reevaluation of current treatment paradigms for intermediate lesions.


Hyperhomocysteinemia: an additional risk factor in white coat hypertension.
The association between homocysteine and sustained hypertension (HT) has been studied. The aim of this study was to assess homocysteine levels in white coat hypertension (WCH) as an indicator of increased risk in the development of cardiovascular diseases. WCH was defined as clinical hypertension and a daytime ambulatory blood pressure of < 135/85 mmHg. Plasma levels of homocysteine were determined in patients with WCH, hypertension, and normotension (NT). The study group included 100 subjects, 33 with WCH (16 males, 17 females) aged 49.1 +/- 1.9; 35 sustained hypertensives (17 males,18 females) aged 48.5 +/- 1.7 and 32 normotensive control subjects (15 males, 17 females) aged 48.8 +/- 2.2. The subjects were matched for age, gender, and body mass index. Patients with a smoking habit, dyslipidemia, or diabetes mellitus were not included in the study. Homocysteine levels were analyzed by ELISA. Plasma homocysteine levels were significantly higher in the WCH group compared to the controls (12.32 +/- 1.07 versus 5.35 +/- 1.38 micromol/L; P < 0.001) and the WCH group had significantly lower homocysteine values than the hypertensives (19.03 +/- 0.76 micromol/L P < 0.001). Total cholesterol and tri-glycerides were not different among the groups. There were no statistically significant differences in urinary albumin excretion (UAE) or creatinine clearance between the three groups. Hypertensive retinopathy was observed in the WCH group, but was less severe and less frequent compared to HTs. LVMI was greater in the WCH group compared to the NTs, but significantly less than HTs. The data demonstrate that WCH is associated with high levels of homocysteine. The increase in homocysteine level in WCH is not as high as in SHT. Since an elevated plasma homocysteine level is a strong risk factor for coronary artery disease and there was target organ damage in our WCH group, we conclude that WCH should not be considered to be an innocent trait.


Voluntary drinking and hydration in non-acclimatized girls exercising in the heat.
The intent of this study was to assess the influence of drink flavor and composition on voluntary drinking and hydration status in girls exercising intermittently in the heat (35 +/- 1 degrees C, 45-50% relative humidity). Twelve physically active, nonacclimatized girls (9-12 years) performed three 3 h identical sessions, each consisting of four 20 min cycling bouts at 50% (VO(2max)), separated by 25 min of rest. One of the three beverages (chilled to 8-10 degrees C) was assigned to each session: unflavored water (W), grape-flavored water (FW) and grape-flavored water plus 6% carbohydrate and 18 mmol l(-1) NaCl (CNa). Drinking was ad libitum. Body weight (BW), drink intake (DI), heart rate, rectal and skin temperatures, and perceptions of thirst and stomach fullness were monitored periodically. Total DI was 759, 940, 1,045 g in W, FW and CNa, respectively (P < 0.05 for CNa-W and FW-W). BW changes were -0.15, 0.16, and 0.45% in W, FW and CNa, respectively, but only the difference between CNa and W was significant (P < 0.05). Other physiological and perceptual variables were not different between trials. In conclusion, beverage flavoring regardless if its combination with carbohydrate and NaCl, mildly enhanced voluntary drinking in young non-acclimatized girls. In contrast to previous research in young boys, euhydration was maintained in the girls by an adequate intake of unflavored water.


Self-assembly of nanoparticles onto the surfaces of polystyrene spheres with a tunable composition and loading.
Functional colloidal materials were prepared by design through the self-assembly of nanoparticles (NPs) on the surfaces of polystyrene (PS) spheres with control over NP surface coverage, NP-to-NP spacing, and NP composition. The ability to control and fine tune the coating was extended to the first demonstration of the co-assembly of NPs of dissimilar composition onto the same PS sphere, forming a multi-component coating. A broad range of NP decorated PS (PS@NPs) spheres were prepared with uniform coatings attributed to electrostatic and hydrogen bonding interactions between stabilizing groups on the NPs and the functionalized surfaces of the PS spheres. This versatile two-step method provides more fine control than methods previously demonstrated in the literature. These decorated PS spheres are of interest for a number of applications, such as catalytic reactions where the PS spheres provide a support for the dispersion, stabilization, and recovery of NP catalysts. The catalytic properties of these PS@NPs spheres were assessed by studying the catalytic degradation of azo dyes, an environmental contaminant detrimental to eye health. The PS@NPs spheres were used in multiple, sequential catalytic reactions while largely retaining the NP coating.


[Sydenham's chorea: report of a case treated with carbamazepine with excellent clinical response].
Sydenham's chorea is the most common cause of acquired chorea in childhood. This disorder is secondary to an autoimmune response against basal ganglia in the brain, induced by prior streptococcal infection. Chorea is a major criterion for the diagnosis of rheumatic fever and can also be the presenting feature of the disease. The incidence of rheumatic fever has been markedly decreased by improved socioeconomic conditions and increased antibiotic prescription. In the last two decades, however, this disease has reappeared and should be taken into account in the evaluation of children with movement disorders. Chorea is characterized by acute exacerbations that can cause substantial functional impairment and may warrant drug treatment. Carbamazepine has proven to be both efficacious and safe in the treatment of this condition. We present a case of rheumatic chorea, in which carbamazepine therapy produced excellent clinical response.


The activity of aminoglycoside antibiotics against Trypanosoma brucei.
The trypanocidal activity of four aminoglycosides was determined against Trypanosoma brucei in vitro. The drug activity in descending order, was as follows; paromomycin kanamycin>gentamycin > neomycin. Paromomycin bad the highest activity and the concentration that inhibited 50% of trypanosome growth (IC50) was 11.4microM. The effect of paromomycin on the causative agents of the East African form of sleeping sickness - T.b. rhodesiense KETRI 265, 2285, 2545, 2562 and EATRO 110,112, 1152 was subsequently assessed. Variations sensitivities between the trypanosome populations were observed and IC50 values ranging from 13.01 to 43.06 microM recorded. However, when paromomycin was administered intraperitoneally (i.p) at 500 mg/kg, it was not effective in curing mice infected with T. b. rhodesienseKETRI 2545 the most drug-sensitive isolate in vitro. Lack of in vivo activity may be because the trypanosome is an extracellular parasite. The pharmacokinetics of paromomycin in the mouse model need to be determined.


Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer.
To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC). A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m(2), 5-fluorouracil 2000 mg/m(2), folinic acid 500 mg/m(2) weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m(2) applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS). A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio=1.14; 95% confidence interval (CI) 0.94-1.37; P=0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio=1.08, P=0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P=0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P=0.006) mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.


[Nasal carriage of Staphylococcus aureus among personnel working in a teaching hospital].
We have studied prospectively the nasal carriage status of Staphylococcus aureus among all health-care workers in the Valdivia Hospital Base. A total of 522 nasal samples were evaluated. Nasal carriage rate was 34.9% for all personnel. Higher rates were seen in Pediatric wards and Central Kitchen Service. Isolated strains were resistant to penicillin (98.3%). However, sensitivity to other antimicrobial agents was high. According to the antimicrobial susceptibility pattern, we identified 12 different groups of strains or antibiotypes. Three of the multiple resistant antibiotypes (resistant to 4 or 5 antimicrobial agents) were isolated from pediatric wards.


Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy.
The results of recent clinical trials for the management of limited-stage Hodgkin lymphoma have led to considerable debate, especially regarding the role of radiation therapy. This review highlights those recent trials and provides perspectives regarding their interpretation from a radiation oncologist and a hematologist. The trial protocol is available at http://www.nejm.org/doi/suppl/10.1056/NEJMoa1111961/suppl_file/nejmoa1111961_protocol.pdf.


Necessity of monitoring after negative head CT in acute head injury.
The main objective of this study was to evaluate the incidence of delayed complications in acute head injury (HI) patients with an initial normal head computed tomography (CT). This retrospective study included 3023 consecutive patients who underwent head CT due to an acute HI at the Emergency Department (ED) of Tampere University Hospital (August 2010-July 2012). Regardless of clinical injury severity, the patients with a normal head CT were selected (n=2444, 80.9%). The medical records of these patients were reviewed to identify the individuals with a serious clinically significant complication related to the primary HI. The time window considered was the following 72h after the primary head CT. A repeated head CT in the hospital ward, death, or return to the ED were indicative of a possible complication. The majority (n=1811, 74.1%) of the patients with a negative head CT were discharged home and 1.1% (n=27) of these patients returned to ED within 72h post-CT. A repeated head CT was performed on 12 (44.4%) of the returned patients and none of the scans revealed an acute lesion. Of the 632 (25.9%) CT-negative patients admitted to the hospital ward from the ED, a head CT was repeated in 46 (7.3%) patients within 72h as part of routine practice. In the repeated CT sample, only one (0.2%) patient had a traumatic intracranial lesion. This lesion did not need neurosurgical intervention. The overall complication rate was 0.04%. In the present study, which includes head injuries of all severity, the probability of delayed life-threatening complications was negligible when the primary CT scan revealed no acute traumatic lesions.


Spatial and temporal influence of onsite wastewater treatment systems, centralized effluent discharge, and tides on aquatic hazards of nutrients, indicator bacteria, and pharmaceuticals in a coastal bayou.
In the rapidly urbanizing watersheds and estuaries flowing to the Gulf of Mexico in Texas, USA, instream flows are increasingly influenced by point source and nonpoint source discharges. Spatial and temporal tidal influences on water quality, especially for contaminants of emerging concern (CECs), is poorly understood in estuaries and coastal systems. We selected Dickinson Bayou, an urban estuary in Galveston County, Texas, for study because it has historically impaired water quality, receives point source discharge from one major wastewater treatment plant (WWTP), while also being influenced by high densities of onsite sewage facilities upstream in the watershed. We explored the occurrence and potential hazards of aquatic contaminants, including nutrients, indicator bacteria for pathogens, and CECs, in relation to this point source discharge, across seasons and at high and low tides. Aquatic contaminants and associated hazards varied significantly in relation to the WWTP discharge, and were influenced by onsite systems. In fact, spatiotemporal water quality varied by class of contaminants (e.g., nutrients, indicator bacteria, CECs), which indicates that traditional surface water monitoring activities should account for such environmental complexity. This study provides a diagnostic approach for future studies of emerging water quality challenges across gradients of rapidly urbanizing coastal bays and estuaries.


Is hip muscle strength the key to walking as a bilateral amputee, whatever the level of the amputations?
Little data have been reported on the factors that are important in bilateral amputee walking ability especially the role of hip strength. Observational, case-control study where participants were evaluated at a single point in time. The aim of this study was to investigate the factors involved in bilateral amputee walking ability by assessment of walking speed, perceived exertion, exercise intensity, physiological cost index (PCI) and hip muscle strength. For a group of 10 bilateral amputees, with different levels of amputation, and a non-pathological reference group, walking ability was assessed using the two-minute walk test. Hip muscle strength was assessed using isokinetic strength tests. Bilateral amputees were found to have slower walking speeds and increased PCI of walking which were correlated to higher levels of amputation. Peak hip torques were reduced in the amputees, which was only significant for concentric extension torque (p = 0.029), and approaching significance for concentric flexion (p = 0.061) and abduction (p = 0.057). Bilateral amputee peak hip strength suggested a positive trend with increasing walking ability. Bilateral amputee walking ability was reduced and mainly related to level of amputation. The role of hip strength in bilateral amputee walking ability requires further investigation.


A quality study of 35 mm, miniaturization of full-size radiographic film.
Twenty-one radiologists with 6 months--25 years experience judged the quality and the possibilities for the routine use of miniaturized full-size radiographic films for long time archiving. Twenty-eight examinations on full-size radiographs were photographed on 35 mm. film. After mounting in transparent jackets, the miniaturized films were read with enlarging equipment and diagnoses and quality noted. Comparison was later made with the originals. The consensus was that the quality of the miniaturized film was good enough to permit their use for long-term archiving purposes and subsequent comparison with future full-size radiographs. The use of reading equipment was not considered tedious.


Armstrong Lecture: Opening the envelope: the continuing legacy of Maj. Gen. Harry G. Armstrong, USAF, MC (Ret.).
From 1929-1957, Harry Armstrong, M.D., rose from first lieutenant in the U.S. Army to the rank of major general in the U.S. Air Force. He founded the aeromedical research laboratory at Wright Field, Dayton, OH, founded the Central Medical Establishment, England, became command flight surgeon, U.S. 8th Air Force, England, and founded the Department of Space Medicine (1947), Randolph Field, TX, and served as Surgeon General, USAF (1949-54). Armstrong worked throughout his career on the most advanced aeromedical problems and personally directed breakthrough programs for which he received the highest national and international awards. Applying Armstrong-like projections, one can forecast faster, larger aircraft for the coming decades as well as 21st century habitations on the moon and Mars.


Is nasotracheal intubation safe in surgery for mandibular cancer?
A retrospective study of problems of postoperative airway maintenance after surgery for mandibular cancers was conducted. Twenty-seven patients treated in an intensive care unit after mandibular resection and primary reconstruction were included. The mean duration of nasotracheal intubation in 22 patients was 33.7 hours. Reintubation because of breathing difficulties was required in four cases. In one of these cases, failed intubation led to an emergency cricothyroidostomy. Failure to perform reintubation resulted in the death of one patient. One patient was tracheostomized after 5 days of nasotracheal intubation. Prolonged nasotracheal intubation after major surgery for oral malignant neoplasms may be an alternative to tracheostomy, provided that adequate monitoring is available after extubation. The safe duration of endotracheal intubation is difficult to determine. Primary reconstruction does not eliminate the need for an artificial airway after tumor surgery.


Validation of the modified Graeb score in aneurysmal subarachnoid hemorrhage.
Intraventricular hemorrhage (IVH) in patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) is a known negative predictor. Scoring systems like Fisher, Le Roux, and original Graeb score (oGS) are established to quantify the volume of IVH. The aim of this study was to evaluate the validity of the recently introduced modified Graeb score (mGS) in patients with aSAH. A retrospective analysis of the validity of the oGS and mGS in 257 aSAH patients was performed to assess and compare the predictive value of hospital mortality, development of CHC, and early functional outcome. In univariate analysis, an increase in either the oGS or mGS was associated with a higher risk for hospital mortality, development of CHC, and poor early functional outcome. The correlation of the oGS and mGS was excellent using Pearson's product-moment (r = 0.918; p < 0.001). The predictive value of the oGS was superior to the predictive value of the mGS using receiver operating characteristics and corresponding area under the curve value as there was no statistical significant differences between the scores. Our study confirms the validity of the recently introduced mGS to quantify the volume of IVH and extends its value in aSAH. However, the mGS offers no additional predictive value for hospital mortality, development of CHC, and poor early functional outcome in patients with aSAH patients compared to the less complex oGS.


Microscopic mapping of subnanometric motion.
The sensitivity of a microscope-based holographic system designed for mapping the motion of components of a living cell is calibrated by means of a simple procedure. Bubbles of air are allowed to drift with known velocity in a nearly horizontal, glycerine-filled capillary observed through the microscope. The ultrafine motion of the bubbles is captured interferometrically by subtractive superposition of a pair of holograms recorded a few milliseconds apart. Stationary portions of the field of view are rendered dimly in images reconstructed from the interferogram, while the brightness of moving portions varies monotonically with their displacement. Displacements as small as 1.1 nm were betrayed in the images. Analysis of the experimental conditions suggests that bubble displacements as small as 0.7 nm will become detectable once minor improvements are made in the apparatus.


Stringlike structure formed in thin films of a lamella-forming diblock copolymer.
Thin films of a lamella-forming polystyrene-block-poly(2-vinylpyridine) diblock copolymer, PS-P2VP, were annealed by a tetrahydrofuran (THF) vapor treatment. The thin films immediately developed a multilayered lamellar structure, similar to those known for conventional heat treatment. However, in the case of the vapor treatment, the steps moved over a significantly larger distance than the case of the heat treatment. This process strikingly developed stringlike objects (strings) that appeared near the steps. The strings were found to be cylindrical domains of poly(2-vinylpyridine) blocks (P2VP) partitioned from P2VP lamella during the step motion and sandwiched by the polystyrene phase that results in perforating the P2VP lamella. The string formation seemed to be associated with the motion of the step, which was considerably faster in the vapor treatment process than in the heat treatment process.


An unusual phospholipase A₂ from puff adder Bitis arietans venom--a novel blocker of nicotinic acetylcholine receptors.
The venoms of snakes from Viperidae family mainly influence the function of various blood components. However, the published data indicate that these venoms contain also neuroactive components, the most studied being neurotoxic phospholipases A₂ (PLA₂s). Earlier we have shown (Gorbacheva et al., 2008) that several Viperidae venoms blocked nicotinic acetylcholine receptors (nAChRs) and voltage-gated Ca²+ channels in isolated identified neurons of the fresh-water snail Lymnaea stagnalis. In this paper, we report on isolation from puff adder Bitis arietans venom and characterization of a novel protein bitanarin that reversibly blocks nAChRs. To isolate the protein, the venom of B. arietans was fractionated by gel-filtration, ion-exchange and reversed phase chromatography and fractions obtained were screened for capability to block nAChRs. The isolated protein competed with [¹²⁵I]iodinated α-bungarotoxin for binding to human α7 and Torpedo californica nAChRs, as well as to acetylcholine-binding protein from L. stagnalis, the IC₅₀ being 20 ± 1.5, 4.3 ± 0.2, and 10.6 ± 0.6 μM, respectively. It also blocked reversibly acetylcholine-elicited current in isolated L. stagnalis neurons with IC₅₀ of 11.4 μM. Mass-spectrometry analysis determined the molecular mass of 27.4 kDa and the presence of 28 cysteine residues forming 14 disulphide bonds. Edman degradation of the protein and tryptic fragments showed its similarity to PLA₂s from snake venoms. Indeed, the protein possessed high PLA₂ activity, which was 1.95 mmol/min/μmol. Bitanarin is the first described PLA₂ that contains 14 disulphide bonds and the first nAChR blocker possessing PLA₂ activity.


Procalcitonin ratio indicates successful surgical treatment of abdominal sepsis.
On-demand relaparotomy has been associated with a slightly decreased mortality compared to planned relaparotomy in the surgical treatment of secondary peritonitis. On-demand relaparotomy must be performed without delay to detect progressing sepsis early, before the onset of multiorgan failure. The aim of the study was to evaluate procalcitonin (PCT) as a parameter for early detection of progressing sepsis after operative treatment of the infective source. In 104 consecutive patients with secondary peritonitis, PCT serum levels were monitored on postoperative days 1 and 2 after initial operative elimination of the septic focus. The PCT ratio between postoperative days 1 and 2 was calculated and correlated to the success of the initial intervention. The latter was considered inadequate if relaparotomies were necessary to eliminate the intraabdominal infection. Using classification and regression tree analysis, a cutoff could be calculated at 1.03 for the PCT ratio of postoperative day 1 to day 2. Lesser values indicated unsuccessful elimination of the septic source, whereas values above 1.03 represented successful operative treatment of the septic focus. Unsuccessful treatment of the septic process could be detected with a specificity of 63% and a sensitivity of 95%. The PCT ratio appears to be a valuable aid in deciding if further relaparotomies are necessary after initial operative treatment of an intraabdominal septic focus.


The inverse problem of depth dose curve estimation.
The inverse problem of the depth dose curve is formulated and a proposition for its solution is presented. The solution is based on the approximation of the observation equation with a numerical quadrature operator and the regularization of this inverse problem with a smoothness side constraint. The problem formulation is applicable for both the electron and the photon depth dose curve estimation. Moreover, the method is equivalent for, for example, all energies, field sizes and source-to-phantom distances. Simulations show that the estimation error is smaller with the proposed method than with direct linear interpolation. The main result of the paper, however, is the formulation of the problem that allows feasible extensions and modifications for different measurement situations.


Effects of azocyclotin on gene transcription and steroid metabolome of hypothalamic-pituitary-gonad axis, and their consequences on reproduction in zebrafish (Danio rerio).
The widely used organotins have the potential to disrupt the endocrine system, but little is known of underlying mechanisms of azocyclotin toxicity in fish. The objective of the present study was to investigate the impact of azocyclotin on reproduction in zebrafish. Adult zebrafish were exposed to 0.09 and 0.45μg/L azocyclotin for 21days, and effects on steroid hormones and mRNA expression of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. Mass spectrometry methodology was developed to profile steroids within the metabolome of the gonads. They were disrupted as a result of azocyclotin exposure. Alterations in the expression of key genes associated with reproductive endocrine pathways in the pituitary (lhβ), gonad (cyp19a1a, cyp17a1 and 17β-hsd3), and liver (vtg1, vtg2, cyp1a1, comt, ugt1a and gstp1) were correlated with significant reductions in estrogen in both sexes and increased testosterone in females. Azocyclotin-induced down-regulation of cyp19a1a in males suggested a reduction in the rate of estrogen biosynthesis, while up-regulation of hepatic cyp1a1 and comt in both sexes suggested an increase in estrogen biotransformation and clearance. Azocyclotin also induced change in the expression of 17β-hsd3, suggesting increased bioavailability of 11-ketotestosterone (11-KT) in the blood. Furthermore, the down-regulation of lhβ expression in the brains of azocyclotin-exposed fish was associated with inhibition of oocyte maturation in females and retarded spermatogenesis in males. As a histological finding, retarded development of the ovaries was found to be an important cause for decreased fecundity, with down-regulation of vtg suspected to be a likely underlying mechanism. Additionally, relatively high concentrations of azocyclotin in the gonads may have directly caused toxicity, thereby impairing gametogenesis and reproduction. Embryonic or larval abnormalities occurred in the F1 generation along with accumulated burdens of azocyclotin in F1 eggs, following parental exposure. Overall, our results indicate that exposure to azocyclotin can impair reproduction in fish, and induce toxicity related abnormalities in non-exposed offspring.


[Surgical treatment for lung cancer in the elderly].
The prevalence of lung cancer in the elder increases gradually recently, and lung cancer has become the main cause of cancer-related death. The aim of this study is to analyse the operative indication, complication, perioperative management and surgical measures, results and specificity for lung cancer in the elderly patients. One hundred and thirty-seven elderly patients with lung can-cer, aged from 70 to 83 years old with mean age of 74 were analysed. Of the 137 cases, 13 patients were in the stage I, 76 in stage II, 48 in stage III. Surgical procedures included pneumonectomy for 4 patients, lobectomy for 122 patients, segmentectomy and wedge resection for 7 patients, sleeve lobectomy for 19 patients, bronchoplastic procedure and pulmonary artery reconstruction for 2 patients. Video-assisted thoracic surgery was performed in 13 cases for segmentectomy and wedge excision There was no operative death. The resection rate was 97.1%, and postoperative complication rate was 29.9%. The follow-up rate was 88.3% . The 1-, 2-, 3-year survival rate was 62%, 35%, 28% respectively. Elderly patients with lung cancer can obtain good therapeutic results and prognosis undergoing surgical therapy, but the operative indications will be limited. Exquisite surgical technique and application of respirator after operation may expand the operative indications.


[Alcohol and the digestive tract].
Alcohol leads to acute and chronic defects at the alimentary tract. Immediate and indirect effects are often not to be deliminated easily in the individual case. In the oesophagus above all disturbances of motility, reduction of the tonus, gastroesophageal reflux, oesophagotitides, Barrett's syndrome and carcinoma of the oesophagus develop. The Mallory-Weiss- and the Boerhaavesyndrome are to be regarded more as indirect associated sequelae. As to the stomach haemorrhagic gastrotitides and haemorrhages from erosions of the mucous membrane, as to the intestine changes of the motility, diarrhoea and malabsorptions.


Chronic pain and depression among geriatric psychiatry inpatients.
We examined whether chronic pain among depressed geriatric inpatients was associated with several clinical variables-comorbid psychiatric and medical diagnoses, length of hospitalization, suicidal ideation, and sleep duration. Medical charts of inpatients admitted to a geriatric psychiatry unit over 2 years were examined retrospectively; 148 patients with a depressive disorder were identified. Admission pain assessments were used to classify whether patients had chronic pain. Other variables of interest were collected from charts. 62% of patients reported chronic pain. In multivariate regression analysis, depressed older adults with chronic pain were more likely to report suicidal ideation, be diagnosed with personality disorder, have higher medical burden, and experience decreased total sleep time compared to depressed older adults without chronic pain. Chronic pain--common in depressed older adults--may influence clinical features of depression and should be assessed as a possible suicide risk factor. Prospective studies should examine causal relationships and determine the effects of adequate pain treatment on depression course and suicide risk in older adults.


Are Asian coronary arteries smaller than Caucasian? A study on angiographic coronary artery size estimation during life.
Asian immigrants to the UK have a higher mortality from coronary artery disease (CAD) than native Caucasians. There is a clinical impression that Asians have smaller coronary arteries than Caucasians. In the present study, consecutive series of 72 male Caucasian and 70 male Asian patients undergoing diagnostic coronary angiography were recruited. Measurements of proximal disease-free segments of the three major coronary arteries were made using the catheter tip as the calibrating object. Electronic callipers were used for all measurements. Total coronary artery diameter was derived by adding the diameters of right, left anterior descending and circumflex arteries. Asians had significantly smaller total vessel diameter compared to Caucasians. They also had smaller body surface areas. This observation has important therapeutic implications regarding coronary intervention in this ethnic group already suffering excess mortality from CAD.


Silymarin extraction from milk thistle using hot water.
Hot water is attracting attention as an extraction solvent in the recovery of compounds from plant material as the search for milder and "greener" solvents intensifies. The use of hot water as an extraction solvent for milk thistle at temperatures above 100 degrees C was explored. The maximum extraction yield of each of the silymarin compounds and taxifolin did not increase with temperature, most likely because significant compound degradation occurred. However, the time required for the yields of the compounds to reach their maxima was reduced from 200 to 55 min when the extraction temperature was increased from 100 to 140 degrees C. Severe degradation of unprotected (plant matrix not present) silymarin compounds was observed and first-order degradation kinetics were obtained at 140 degrees C.


[Ca2+, phospholipid-dependent protein kinase (C-kinase) in the rat placental chorion].
C-kinase is one of the enzymes which phosphorylate cellular proteins, and is reported to be involved in transmission of the extracellular signals regarding hormones, etc. to inside the cell. This enzyme is widely distributed in many tissues and organs and several C-kinase-mediated cellular responses were reported. However, in the placenta, the presence of C-kinase has not been reported. In this paper we reported for the first time the purification of C-kinase from rat placental chorion and investigated the physiological functions of C-kinase. The results were as follows: A considerable amount of C-kinase was detected in the membrane fraction of rat placenta. C-kinase specifically phosphorylated several membrane proteins, and the phosphorylation pattern was different from those of mid pregnancy and late pregnancy. The C-kinase activity in late pregnancy was 6 times higher than that of mid pregnancy. Hemin and Polylysine inhibited partially-purified membrane-bound C-kinase. Substrate specificity C-kinase from rat placenta was similar to those from other organs.


Hepatocyte growth factor treatment improves alveolarization in a newborn murine model of bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) is thought to be one form of developmental arrest of the lung. Hepatocyte growth factor (HGF) participates in normal lung growth and in lung regeneration. The purpose of this study is to investigate whether HGF can improve alveolarization and attenuates functional abnormalities of a murine model of BPD induced by hyperoxia. Three-day-old CD-1 mice were exposed to 90% of oxygen or room air (control group) for 7 days. These animals were then kept in room air for the next 7 days. Recombinant human (rh) HGF (100 microg/g b.w., divided 3 times, rhHGF group) or vehicle (vehicle group) was administered intraperitoneally during hyperoxia. On day 17, the pulmonary function test and bronchial hyperresponsiveness (BHR) were examined. Mean linear intercepts (MLI) were measured as parameters of alveolarization. Cell renewal (on day 10) and vascularization of the lung were also evaluated. Exposure to hyperoxia induced increased airway resistance and BHR. These animals showed a severely simplified alveolar structure, increased MLI, decreased cell renewal (16.1 +/- 2.4 vs. 29.6 +/- 2.4%, p < 0.05), and decreased vascularization (15.1 +/- 0.3 vs. 18.4 +/- 1.5 vessels/hpf, p < 0.05, vehicle vs. control group, respectively). rhHGF treatment during exposure to hyperoxia significantly reduced all of these changes (27.9 +/- 1.7%, 18.2 +/- 0.5 vessels/hpf for cell renewal and vascularization, respectively; all values are p < 0.05 against vehicle animals). HGF partially protects against the inhibition of alveolarization and improves functional abnormality in the hyperoxia-induced neonatal mice model of BPD.


Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response.
Viral infection causes stress to the endoplasmic reticulum (ER). The response to endoplasmic reticulum stress, known as the unfolded protein response (UPR), is designed to eliminate misfolded proteins and allow the cell to recover. The role of hepatitis C virus (HCV) non-structural protein NS4B, a component of the HCV replicons that induce UPR, is incompletely understood. We demonstrate that HCV NS4B could induce activating transcription factor (ATF6) and inositol-requiring enzyme 1 (IRE1), to favor the HCV subreplicon and HCV viral replication. HCV NS4B activated the IRE1 pathway, as indicated by splicing of X box-binding protein (Xbp-1) mRNA. However, transcriptional activation of the XBP-1 target gene, EDEM (ER degradation-enhancing alpha-mannosidase-like protein, a protein degradation factor), was inhibited. These results imply that NS4B might induce UPR through ATF6 and IRE1-XBP1 pathways, but might also modify the outcome to benefit HCV or HCV subreplicon replication.


Blocking of cell-mediated immunity to Moloney murine sarcoma virus-transformed cells by lactate dehydrogenase virus-antibody complex.
The enhancement of Moloney murine sarcoma virus (M-MuSV) tumor growth in BALB/c mice previously infected with lactate dehydrogenase virus (LDV) was shown to depend on the timing of the inoculations. Mice infected with LDV either 3 or 4 days prior to the M-MuSV inoculations demonstrated enhanced tumor growth, whereas mice infected simultaneously with LDV and M-MuSV or with LDV 30 days prior to M-MuSV challenge did not demonstrate M-MuSV tumor enhancement. Circulating immune complexes (CIC) were isolated from serum pools of LDV-infected mice. IgM-containing CIC were isolated only between 3 and 9 days post LDV infection. CIC containing IgG1 were isolated only between days 6 and 13, whereas IgG2--containing CIC were not detected until 18 days post LDV infection. Coincubation of isolated immune complexes (IC) with M-MuSV-sensitized cytotoxic lymphocyte-transformed and M-MuSV-transformed target cells produced a 56% reduction in M-MuSV-specific cytotoxicity, with LDV-antibody IC isolated from the sera of mice 11 days post LDV infection. CIC isolated from the sera of mice 5 days and 25 days after infection with LDV demonstrated 11 and 9% reductions in M-MuSV cytotoxicity, respectively. LDV-antibody IC composed of IgG1 antibody may act as blocking factors to M-MuSV-sensitized lymphocytes in vitro and may be responsible for the transient M-MuSV tumor enhancement observed in dually infected mice.


[DNA degradation during standard alkaline of thermal denaturation].
Essential degradation 8 DNA (up to 10 per cent) with liberation of acid-soluble fragments takes place on the standard alkaline (0,01 M sodium phosphate, pH 12, 60 degrees, 15 min) or thermal (0.06 M sodium phosphate buffer, pH 6.8, 102 degrees C, 15 min) denaturation. This degradation is more or less selective: fraction of low molecular weight fragments, isolated by hydroxyapatite cromatography and eluted by 0.06 M sodium phosphate buffer, pH 6.8 is rich in adenine and thymine and contains about 2 times less 5-methylcytosine than the total wheat germ DNA. The degree of degradation of DNA on thermal denaturation is higher than on alkaline degradation. Therefore while studying reassociation of various DNA, one and the same standard method of DNA denaturation should be used. Besides, both the level of DNA degradation and the nature of the resulting products (fragments) should be taken into account.


Development of a decision support system for the introduction of alternative methods into local irritancy/corrosivity testing strategies. Creation of fundamental rules for a decision support system.
The notification procedure of the European Union (EU) for new chemicals requires the application of protocols on physicochemical and toxicological tests for the evaluation of physicochemical properties and probable toxic effects of each notified substance. A computerised database was developed from data sets and toxicological test protocols relating to substance properties responsible for skin and eye irritation/corrosion. To develop specific structure-activity relationship (SAR) models and to find rules for a decision support system (DSS) to predict local irritation/corrosion, physical property data, chemical structure data and toxicological data for approximately 1300 chemicals, each having a purity of 95% or more, were evaluated. The evaluation demonstrated that the lipid solubility and aqueous solubility of a chemical are relevant to, or - in some cases - responsible for, the observed local effects of a substance on the skins and eyes of rabbits. The octanol/water partition coefficient and the measured value of the surface tension of a saturated aqueous solution of the substance give additional information that permits the definition of detailed SAR algorithms that use measured solubility values. Data on melting points and vapour pressure can be used to assess the intensity and duration of local contact with a chemical. Considerations relating to the reactivity of a pure chemical can be based on molecular weight and the nature of the heteroatoms present. With respect to local lesions produced following contact with the skin and eyes of rabbits, the data evaluation revealed that no general "local irritation/corrosion potential" of a chemical can be defined. A variety of mechanisms are responsible for the formation of local lesions on the skin or in the eyes: serious lesions are produced by mechanisms different from those that cause moderate irritation in these organs. In order to develop a DSS that uses the information extracted from the database, chemical main groups were categorised on the basis of their empirical formulae, and rules were defined of the type IF (physicochemical property) A, THEN not (toxic) effect B, based on correlations between specific local effects and measured physicochemical values. Other rules of the type IF substructure A, THEN effect B were developed based on correlations between specific local effects and the submitted structural formulae. Reactive chemical substructures relevant to the formation of local lesions and rules for the prediction of the absence of any skin irritation potential were identified. Proposals are made relating to the development of alternatives to eye irritation testing with rabbits.


Behavioural responses to infrasonic particle acceleration in cuttlefish.
Attacks by aquatic predators generate frontal water disturbances characterised by low-frequency gradients in pressure and particle motion. Low-frequency hearing is highly developed in cephalopods. Thus, we examined behavioural responses in juvenile cuttlefish to infrasonic accelerations mimicking main aspects of the hydrodynamic signals created by predators. In the experimental set-up, animals and their surrounding water moved as a unit to minimise lateral line activation and to allow examination of the contribution by the inner ear. Behavioural responses were tested in light versus darkness and after food deprivation following a 'simulated' hunting opportunity. At low acceleration levels, colour change threshold at 3, 5 and 9 Hz was 0.028, 0.038 and 0.035 m s-2, respectively. At higher stimulus levels, jet-propulsed escape responses thresholds in daylight were 0.043, 0.065 and 0.069 m s-2 at 3, 5 and 9 Hz, respectively, and not significantly different from the corresponding darkness thresholds of 0.043, 0.071 and 0.064 m s-2 In a simulated hunting mode, escape thresholds were significantly higher at 3 Hz (0.118 m s-2) but not at 9 Hz (0.134 m s-2). Escape responses were directional, and overall followed the direction of the initial particle acceleration, with mean escape angles from 313 to 33 deg for all three experiments. Thus, in the wild, particle acceleration might cause escape responses directed away from striking predators but towards suction-feeding predators. We suggest that cuttlefish jet-propulsed escape behaviour has evolved to be elicited by the early hydrodynamic disturbances generated during predator encounters, and that the inner ear plays an essential role in the acoustic escape responses.


Synthesis and biological evaluation of sialylmimetics as rotavirus inhibitors.
Rotaviruses cause severe gastroenteritis in infants and are estimated to be responsible for over 600 000 deaths annually, primarily in developing countries. The development of potential inhibitors of this virus is therefore of great interest, particularly since the safety and efficacy of rotaviral vaccines has recently been questioned. This study describes the synthesis of a variety of compounds that can be considered as mimetics of N-acetylneuraminic acid thioglycosides and the subsequent in vitro biological evaluation of these sialylmimetics as inhibitors of rotaviral infection. Our results show that readily accessible carbohydrate-based compounds have the potential to act as inhibitors of rotaviral replication in vitro, presumably through inhibition of the rotaviral adhesion process.


Amino acid ester prodrugs of the antiviral agent 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole as potential substrates of hPEPT1 transporter.
Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) were synthesized and evaluated for their affinity for hPEPT1, an intestinal oligopeptide transporter. Assays of competitive inhibition of [(3)H]glycylsarcosine (Gly-Sar) uptake in HeLa/hPEPT1 cells by the amino acid ester prodrugs of BDCRB suggested their 2- to 4-fold higher affinity for hPEPT1 compared to BDCRB. Further, promoieties with hydrophobic side chains and l-configuration were preferred by the hPEPT1 transporter.


A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children.
In 24 epileptic children refractory to antiepileptic drugs (AEDs) with generalized tonic-clonic and other types of seizures, addition of D-alpha-tocopheryl acetate (Vitamin E 400 IU/day) to existing AEDs was accompanied by a significant reduction of seizures in 10 of 12 cases. This was significantly different from controls given placebo (0 of 12, p less than 0.05). This result did not appear to be due to the effects of changes in the plasma levels of the comedication. There were no adverse side effects. The Vitamin E levels steadily increased in the responders in the trial phase but this did not occur in two clinically noncompliant subjects or in 12 patients receiving placebo. No other clinically significant alterations in hematologic or biochemical test results were observed. No treatment-related changes in plasma concentration of concomitant AEDs were noted. These findings justify further clinical controlled trials of Vitamin E as adjunctive therapy for childhood epilepsy intractable to the usual antiepileptic therapy.


MiR-210-3p attenuates lipid accumulation and inflammation in atherosclerosis by repressing IGF2.
Previous studies have shown that miR-210-3p is involved in the development and progression of atherosclerosis, but its specific mechanisms are still unclear. This study aims to reveal the mechanism of miR-210-3p and its target genes in macrophage lipid deposition and inflammatory response, and provide new ideas for the treatment of atherosclerosis. We found miR-210-3p increased sharply in the first 12 h induced by higher doses of ox-LDL in THP-1 macrophages and then gradually decreased. MiR-210-3p mimic transfection inhibited lipid uptake and inflammatory cytokine production in ox-LDL-induced macrophages. By inhibiting IGF2/IGF2R, miR-210-3p suppressed the expression of fatty acid transcriptase CD36 and transcription factor NF-κB in ox-LDL-induced macrophages. In conclusion, miR-210-3p inhibits the expression of CD36 and NF-κB by inhibiting IGF2 / IGF2R, thereby reducing lipid accumulation and inflammatory response in ox-LDL-induced macrophages. Enhancing miR-210-3p expression may be a new strategy for the treatment of atherosclerosis.


[Changes in the microcirculatory vessels of the human stomach in ulcer disease].
At the ulcerous disease certain alterations in the microcirculatory bed of all the gastric wall layers take place in the zone of the ulcer and in the areas adjoining the ulcerous focus. In the gastric wall areas, remote from the ulcer, the alterations in the microcirculatory bed are poorly manifested. The most essential deviations from the norm are defined in the mucosal tunic and in the gastric tela submucosa according to the ulcer localization. The disorders in the microcirculatory bed at the ulcerous disease affect the microarchitectonics, the wall structure and the size of the microvessel lumens and their contents. Maximal alterations are observed in capillaries and postcapillary-venular portion of the microcirculatory bed, which are manifested as a considerable dilatation of the microvessels mentioned, deformity, presence of rather great protrusions of their wall. The resistive vessels of the microcirculatory bed, at the ulcerous disease, suffer to a less extent. The morphometric data have stated certain decrease of their diameter when comparing to the norm. The adaptive apparatuses of the bloodflow regulation at the ulcerous disease are essentially altered, increasing number of the arteriolovenular anastomoses is noted in the gastric wall as compared to the norm.


[Avoidable perinatal deaths and prenatal consultation (author's transl)].
Perinatal deaths may be avoided by the prenatal consultation. We show that women with a previous preterm delivery may have a term child if they are correctly followed, that adolescent pregnancies can have term birth with good social support and medical support. We show that uterine height (pubis-fundus) is a good measure of fetal development, giving a better prediction of term weight compared to echotomography from 28 to 36 weeks, afterwhat echo is obviously better. This means that simple clinical measures can reduce during pregnancy important causes of perinatal deaths.