title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Better environmental decision making - recent progress and future trends. | Recent trends in risk-based decision making are reviewed in relation to novel developments in comparative risk analysis, strategic risk analysis, weight of evidence frameworks, and participative decision making. Delivery of these innovations must take account of organisational capabilities in risk management and the institutional culture that implements decision on risk. We stress the importance of managing risk knowledge within organisations, and emphasise the use of core criteria for effective risk-based decisions by reference to decision process, implementation and the security of strategic added value. | 18,774,589 |
Diffusion-weighted magnetic resonance imaging in the early detection of response to chemoradiation in cervical cancer. | To investigate diffusion-weighted magnetic resonance imaging (DWI) as an early and reproducible response indicator in women receiving concurrent radiotherapy and chemotherapy (chemoradiation) for advanced cervical cancer. Twenty women with advanced cervical cancer were included in a prospective cohort study. DWI was carried out prior to chemoradiation, repeated after 2 weeks of therapy and at the conclusion of therapy using a 1.5 T MRI scanner. The apparent diffusion coefficient (ADC) was calculated from the diffusion data at each assessment. This was correlated with final tumour response as determined by change in tumour size using MRI and conventional clinical response. Twelve women also underwent 2 separate pre-treatment DWI examinations to test for reproducibility of the ADC measurements. ADC values after 2 weeks of therapy showed a significant correlation with eventual MR response (p=0.048, rho=0.448, Spearman's correlation) and clinical response (p=0.009, rho=0.568) as did the change in ADC after 2 weeks of therapy (p=0.01, rho=0.56 for MR response, p=0.03, rho=0.48 for clinical response). Reproducibility of ADC measurements was confirmed with a mean difference in ADC of -0.003 between consecutive pre-therapy MRI assessments and 95% confidence intervals of -0.12 and 0.11. DWI has potential to provide a surrogate biomarker of treatment response in advanced cervical cancers. The use of ADC offers an early and reproducible indication of tumour response which may ultimately allow the development of individualised regimens. | 18,774,597 |
Effect of bleaching on the elution of monomers from modern dental composite materials. | The aim of this study was to evaluate the effect of bleaching on the elution of monomers from two modern composite materials. Two different resin composites (a nanohybrid the Filtek Supreme XT and an ormocer the Ceram X) were bleached with two products (hydrogen peroxide 38% for 45 min and carbamide peroxide 15% for 56 h). Four groups (n=10, diameter: 4.5 mm, thickness: 2 mm) of each material were fabricated, two for each bleaching product. One group was used as unbleached control and the other one was bleached. Then the samples were stored in 1 ml of 75 vol% ethanol at room temperature, and the storage medium was renewed after 24 h, 7 days, and 28 days. From the storage medium that was removed samples were prepared and analysed with LC-MS/MS. None of the bleaching products had an effect on the amount of Bis-GMA and TEGDMA released from Ceram X. The amount of Bisphenol A released from the bleached samples of Ceram X was significantly lower compared to the control samples. Bleaching reduced significantly the amount of Bis-GMA released from Filtek Supreme XT. The amount of TEGDMA released from Filtek Supreme XT was not affected by bleaching. The bleaching agents tested in the present study reduced the amount of some of the monomers released from the two composite materials. Bleaching of modern composite materials does not increase the release of monomers. | 18,774,601 |
Intermediate-scale 2D experimental investigation of in situ chemical oxidation using potassium permanganate for remediation of complex DNAPL source zones. | In situ chemical oxidation is a technology that has been applied to speed up remediation of a contaminant source zone by inducing increased mass transfer from DNAPL sources into the aqueous phase for subsequent destruction. The DNAPL source zone can consist of one or more individual sources that may be present as an interconnected pool of high saturation, as a region of disconnected ganglia at residual saturation, or as combinations of these two morphologies. Potassium permanganate (KMnO(4)) is a commonly employed oxidant that has been shown to rapidly destroy DNAPL compounds like PCE and TCE following second-order kinetics in an aqueous system. During the oxidation of a target DNAPL compound, or naturally occurring reduced species in the subsurface, manganese oxide (MnO(2)) solids are produced. Research has shown that these manganese oxide solids may result in permeability reductions in the porous media thus reducing the ability for oxidant to be transported to individual DNAPL sources. It can also occur at the DNAPL-water interface, decreasing contact of the oxidant with the DNAPL. Additionally, MnO(2) formation at the DNAPL-water interface, and/or flow-bypassing as a result of permeability reductions around the source, may alter the mass transfer from the DNAPL into the aqueous phase, potentially diminishing the magnitude of any DNAPL mass depletion rate increase induced by oxidation. An experiment was performed in a two-dimensional (2D) sand-filled tank that included several discrete DNAPL source zones. Spatial and temporal monitoring of aqueous PCE, chloride, and permanganate concentrations was used to relate changes in mass depletion of, and mass flux, from DNAPL residual and pool source zones to chemical oxidation performance and MnO(2) formation. During the experiment, permeability changes were monitored throughout the 2D tank and these were related to MnO(2) deposition as measured through post-oxidation soil coring. Under the conditions of this experiment, MnO(2) formation was found to reduce permeability in and around DNAPL source zones resulting in changes to the overall flow pattern, with the effects depending on source zone configuration. A pool with little or no residual around it, in a relatively homogeneous flow field, appeared to benefit from resulting MnO(2) pore-blocking that substantially reduced mass transfer from the pool even though there was relatively little PCE mass removed from the pool. In contrast, a pool with residual around it (in a more typical heterogeneous flow field) appeared to undergo increased mass transfer as MnO(2) reduced permeability, altering the water flow and increasing the mixing at the DNAPL-water interface. Further, the magnitude of increased PCE mass depletion during oxidation appeared to depend on the PCE source configuration (pool versus ganglia) and decreased as MnO(2) was formed and deposited at the DNAPL-water interface. Overall, the oxidation of PCE mass appeared to be rate-limited by the mass transfer from the DNAPL to aqueous phase. | 18,774,622 |
The study of operating variables in soil washing with EDTA. | This study discusses the operating variables for removal of metals from soils using EDTA, including the type of EDTA, reaction time, solution pH, dose, temperature, agitation, ultrasound and number of extractions. For As, Cd, Cu, Pb and Zn, the removal efficiency order was: H(4)-EDTA > Na(2)EDTA > (NH(4))(2)EDTA. At low EDTA concentrations the removal increased progressively with increasing dose while above 0.4 mmol/g only small increases in extraction efficiency were observed. EDTA induced a two-step process including a rapid desorption within the first hour, and a gradual release in the following hours. The extraction efficiency of metals decreased with increasing pH in the range of 2-10. Consecutive extractions using low concentrations were more effective than a single extraction with concentrated EDTA if the same dose of EDTA was used. | 18,774,633 |
Isolation and characterization of human anti-VEGF165 monoclonal antibody with anti-tumor efficacy from transgenic mice expressing human immunoglobulin loci. | The purpose of this study was to prepare a fully human anti-VEGF (vascular endothelial growth factor) monoclonal antibody with anti-tumor activity from five-feature mice which express human immunoglobin loci. Four hybridomas secreting mAb stably were isolated successfully. Some characters such as isotypes, cross-reactivity, inhibition on the binding of hVEGF to VEGFR-2, dissociation constants and the idiotypic characteristic were determined. Proliferation of T24 and Ls-174-T cell line and nude mice bearing human colorectal cancer were used to evaluate therapeutic effects and safety of this mAb. Pharmacokinetics data shows the half life of this mAb was about 5 days after a single intravenous injection. These results suggest the fully human anti-VEGF mAb maybe safe and efficient for cancer treatment. | 18,774,636 |
The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. | HER2 overexpression is observed in 5-25% of gastric cancers. Lapatinib is a dual inhibitor of the epidermal growth factor receptor and HER2 tyrosine kinase. We examined the antitumor effect of lapatinib in gastric cancer cell lines. Lapatinib induced selective and potent growth inhibition in two HER2-amplified gastric cancer cell lines (SNU-216 and NCI-N87). Lapatinib inhibited the phosphorylation of HER2, EGFR and downstream signaling proteins, resulting in G1 arrest in both cell lines with down-regulation of cMyc and induction of p27kip1. Lapatinib also induced apoptosis in NCI-N87 which has high HER2 amplification ratio. Lapatinib combined with 5-fluorouracil, cisplatin, oxaliplatin or paclitaxel showed an additive or synergistic effect. These results provide a rationale for the future clinical trials of lapatinib combined with cytotoxic drugs in the treatment of HER2-positive gastric cancer. | 18,774,637 |
Switch of transforming growth factor beta function from tumor suppression to stimulation in adenomatous polyposis coli (APC) knocked-down human colon carcinoma cells. | TGFbeta exerts a potent tumor-suppressive effect in the human colon carcinoma CBS and Moser cells. However, TGFbeta can also function as a tumor promoter. The mechanisms underlying the tumor promoting effect of TGFbeta are not understood. Both the CBS and Moser cells were found to express mutant (truncated) APC. Expression of this form of APC did not interfere with the tumor-suppressive function of TGFbeta. However, when APC expression was knocked down in these cells, TGFbeta function switched from that of tumor suppression to that of tumor promotion. TGFbeta stimulated cellular invasion and anchorage-independent growth in APC knocked-down cells. Knocking down APC expression abrogated the ability of TGFbeta to induce the expression of the tumor suppressor E-cadherin and the cyclin dependent kinase inhibitor p21/Waf1. TGFbeta now stimulated the constitutive TCF transcriptional activation activity associated with the beta-catenin/Wnt pathway in the APC knocked-down cells. Thus, the level of APC expression determined the type of TGFbeta function in these human colon carcinoma cells. | 18,774,639 |
Further study of Codiostomum struthionis (Horst, 1885) Railliet and Henry, 1911 (Nematoda, Strongylidae) parasite of ostriches (Struthio camelus Linnaeus, 1758) (Aves, Struthioniformes). | Codiostomum struthionis is a nematode parasite of the ostrich caecum. Little is known about its pathology, being considered by many authors as a non-pathogenic parasite. Infections by C. struthionis are sometimes overlooked because its eggs are indistinguishable from another ostrich nematode, Libyostrongylus spp. Fecal cultures and infective larvae identification are necessary for proper identification. The aim of this study is to provide improved morphological characterization of adults and infective larvae of C. struthionis. Ten caeca of adult ostriches were collected and washed in 0.09% saline solution. Male and female nematodes were collected and quantified separately. Nematodes were fixed in A.F.A. for optical microscopy or fixed in Karnovsky solution for scanning electron microscopy. To obtain infective larvae, fecal samples were collected at sites of high concentration of parasites in the caeca and fecal cultured. The resultant larvae were identified and measured with light microscope at 400x. Nine of the 10 slaughtered ostriches were parasitized by C. struthionis. All nematodes were found in the distal third of the caeca. A total of 566 parasites were recovered (234 males and 332 females). All the cultured larvae had characteristics of C. struthionis (rounded cephalic region with a flat extremity, an acute larvae tail termination and a long and filamentous sheath tail). All the adult parasites were characterized as C. struthionis. Through the analysis of the infective larvae it was determined that the morphology of the larvae tail was the best trait to use in the distinction of this species (live bird diagnosis). | 18,774,651 |
Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. | As we gain a better understanding of the factors affecting cancer etiology, we can design improved treatment strategies. Over the past three to four decades, there have been numerous successful efforts in recognizing important cellular proteins essential in cancer growth and therefore these proteins have been targeted for cancer treatment. However, studies have shown that targeting one or two proteins in the complex cancer cascade may not be sufficient in controlling and/or inhibiting cancer growth. Therefore, there is a need to examine features which are potentially involved in multiple facets of cancer development. In this review we discuss the targeting of the elevated copper (both in serum and tumor) and oxidative stress levels in cancer with the aid of a copper chelator d-penicillamine (d-pen) for potential cancer treatment. Numerous studies in the literature have reported that both the serum and tumor copper levels are elevated in a variety of malignancies, including both solid tumor and blood cancer. Further, the elevated copper levels have been shown to be directly correlated to cancer progression. Enhanced levels of intrinsic oxidative stress has been shown in variety of tumors, possibly due to the combination of factors such as elevated active metabolism, mitochondrial mutation, cytokines, and inflammation. The cancer cells under sustained ROS stress tend to heavily utilize adaptation mechanisms and may exhaust cellular ROS-buffering capacity. Therefore, the elevated copper levels and increased oxidative stress in cancer cells provide for a prospect of selective cancer treatment. | 18,774,652 |
The relation of salivary cortisol to patterns of performance on a word list learning task in healthy older adults. | A pattern of performance on a word list learning task known as a reduced primacy effect has been shown to be characteristic of Alzheimer's disease (AD) and can distinguish AD from depression. Deficits in memory and hippocampal atrophy seen in AD have been associated with hypercortisolism. The present study evaluated whether the reduced primacy effect is associated with elevated salivary cortisol in a sample of 40 healthy older community-dwelling adults participating in a study of memory and stress. We found that primacy, but not recency, was associated with higher salivary cortisol levels. In addition, participants who showed a reduced primacy had higher salivary cortisol levels than those with a normal serial position curve. Results suggest that there may be value to examining both serial position curves and changes to cortisol patterns over time as potential predictors of cognitive decline in healthy older adults. | 18,774,653 |
Upgrading the Gleason score in extended prostate biopsy: implications for treatment choice. | To determine the incidence of overestimation of Gleason score (GS) in extended prostate biopsy, and consequently circumventing unnecessary aggressive treatment. This is a retrospective study of 464 patients who underwent prostate biopsy and radical prostatectomy between January 2001 and November 2007. The GS from biopsy and radical prostatectomy were compared. The incidence of overestimation of GS in biopsies and tumor volume were studied. Multivariate analysis was applied to find parameters that predict upgrading the GS in prostate biopsy. The exact agreement of GS between prostate biopsy and radical prostatectomy occurred in 56.9% of cases. In 29.1% cases it was underestimated, and it was overestimated in 14%. One hundred and six (22.8%) patients received a diagnosis of high GS (8, 9, or 10) in a prostate biopsy. In 29.2% of cases, the definitive Gleason Score was 7 or lower. In cases in which GS was overestimated in the biopsy, tumors were significantly smaller. In multivariate analysis, the total percentage of tumor was the only independent factor in overestimation of GS. Tumors occupying less than 33% of cores had a 5.6-fold greater chance of being overestimated. In the extended biopsy era and after the International Society of Urological Pathology consensus on GS, almost one third of tumors considered to have high GS at the biopsy may be intermediate-risk cancers. In that condition, tumors are smaller in biopsy. This should be remembered by professionals involved with prostate cancer to avoid overtreatment and undesirable side effects. | 18,774,658 |
Modification of the side chain of micromolide, an anti-tuberculosis natural product. | This paper describes a series of modifications of the side chain of micromolide, an anti-tuberculosis natural product. Most of the synthesized compounds showed significantly decreased activities, which suggests that the long aliphatic side chain of micromolide and its double bond are essential to its activity. | 18,774,716 |
Three-dimensional motion of the scapula and shoulder during activities of daily living. | The purpose of this study was to describe 3-dimensional scapular motion during the activities of daily living (ADL) and the full range of arm motion, and to suggest a standardized method for evaluating scapular mobility. Eight healthy subjects between the ages of 25-40, with no prior history of shoulder pathology or surgery for the past 12 months, were recruited for this study. Touching 8 predetermined landmarks on the head and the trunk was used to simulate ADL. Touching the contralateral ear and contralateral shoulder resulted in the maximum scapular protraction 46 degrees (8 degrees) and 48 degrees (8 degrees), respectively, and the maximum degrees of the scapular anterior tilt, -11 degrees (4 degrees) and -11 degrees (5 degrees), respectively. Asking patients to reach to the back of the neck, and the contralateral shoulder, the clinician can evaluate the overall scapular mobility in all directions. A protocol controlling the performance variability during ADL tasks was suggested to improve the clinical evaluation of the shoulder joint complex. Findings of this study can guide clinicians to identify specific tasks which may relate to particular shoulder girdle dysfunction. | 18,774,735 |
Severe skin necrosis after breast reconstruction with a transverse rectus abdominis musculocutaneous flap in methylenetetrahydrofolate reductase deficiency. | We report a case of unexpected severe skin necrosis after autologous transverse rectus abdominis musculocutaneous flap breast reconstruction in a patient with homozygosis for the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene. This genetic deficiency is hypothesised as the cause of this exceptional skin necrosis. A 46-year-old woman underwent a radical mastectomy and immediate rectus abdominis musculocutaneous flap breast reconstruction. At the end of surgery, the blood supply to the flap and the abdominal wall was excellent. On the 5th postoperative day, the patient developed an extensive abdominal skin necrosis and a partial flap necrosis on the reconstructed breast. The rectus abdominis musculocutaneous flap breast reconstruction can be proposed to patients without any haemostatic defect in order to avoid life-threatening complications and unaesthetic results. This procedure requires careful patient selection, detailed preoperative planning, and complete laboratory investigations: However, mutation of the 5,10- methylenetetrahydrofolate reductase gene is too exceptional to form part of the routine preoperative investigation and can be looked for in these cases of extensive necrosis. | 18,774,766 |
Core protein phosphorylation facilitates the repair of photodamaged photosystem II at high light. | Phosphorylation of photosystem II (PSII) reaction center protein D1 has been hypothesised to function as a signal for the migration of photodamaged PSII core complex from grana membranes to stroma lamellae for concerted degradation and replacement of the photodamaged D1 protein. Here, by using the mutants with impaired capacity (stn8) or complete lack (stn7 stn8) in phosphorylation of PSII core proteins, the role of phosphorylation in PSII photodamage and repair was investigated. We show that the lack of PSII core protein phosphorylation disturbs the disassembly of PSII supercomplexes at high light, which is a prerequisite for efficient migration of damaged PSII complexes from grana to stroma lamellae for repair. This results in accumulation of photodamaged PSII complexes, which in turn results, upon prolonged exposure to high light (HL), in general oxidative damage of photosynthetic proteins in the thylakoid membrane. | 18,774,768 |
Ion chemistry of 1H-1,2,3-triazole. 2. Photoelectron spectrum of the iminodiazomethyl anion and collision induced dissociation of the 1,2,3-triazolide ion. | The 363.8 nm photoelectron spectrum of the iminodiazomethyl anion has been measured. The anion is synthesized through the reaction of the hydroxide ion (HO-) with 1 H-1,2,3-triazole in helium buffer gas in a flowing afterglow ion source. The observed spectrum exhibits well-resolved vibronic structure of the iminodiazomethyl radical. Electronic structure calculations have been performed at the B3LYP/6-311++G(d,p) level of theory to study the molecular structure of the ion. Equilibrium geometries of four possible conformers of the iminodiazomethyl anion have been obtained from the calculations. Spectral simulations have been performed on the basis of the calculated geometries and normal modes of these conformationally isomeric ions and the corresponding radicals. The spectral analysis suggests that the ions of two conformations are primarily formed in the aforementioned reaction. The relative abundance of the two conformers substantially deviates from the thermal equilibrium populations, and it reflects the potential energy surfaces relevant to conformational isomerization processes. The electron affinities of the ( ZE)- and ( EE)-iminodiazomethyl radicals have been determined to be 2.484 +/- 0.007 and 2.460 +/- 0.007 eV, respectively. The energetics of the iminodiazomethyl anion is compared with that of the most stable structural isomer, the 1,2,3-triazolide ion. Collision-induced dissociation of the 1,2,3-triazolide ion has also been studied in flowing afterglow-selected ion flow tube experiments. Facile fragmentation generating a product ion of m/ z 40 has been observed. DFT calculations suggest that fragmentation of the 1,2,3-triazolide ion to the cyanomethyl anion and N2 is exothermic. The stability of the ion is discussed in comparison with other azolide ions with different numbers of N atoms in the five-membered ring. | 18,774,783 |
Vibrational anharmonicity and harmonic force fields for dichloromethane from quantum-chemical calculations. | Anharmonic and related constants have been calculated for CH2Cl2, CD2Cl2, and CHDCl2 by using the program Gaussian03 and B3LYP and MP2 models. Bases used were 6-311++G** and cc-pVTZ. The size of grid used in the B3LYP/6-311++G** model had a noticeable effect on resulting data. Features of the MP2/6-311++G** calculations suggested a deleterious effect of the absence of f functions in this basis set. The need for the replacement of second-order terms in the perturbation theory formulas for the vibrational anharmonic constants x ij in the presence of Fermi resonance was explored, and minor resonances were found associated with the cubic constants varphi 122 and varphi 299 (d 0 isotopomer), phi122 and phi849 (d2), and phi278 (d1). Computed xij values for nuCH and nuCD motions agree quite well with earlier experimental data. Observed anharmonic frequencies, nu obsd, were corrected to "observed" harmonic frequencies, omega obsd, by using computed differences Delta = omegaQC-nuQC. These differences Delta are larger for the antisymmetric nuasCH2 mode than for symmetric nusCH2 motion. This fact made it necessary to use differing scale factors for the two kinds of CH stretching force constants in a subsequent scaling of the harmonic force field to nuobsd. Force field scaling was also carried out by refining to omega obsd. In both approaches, the B3LYP models required differing scale factors for symmetric and antisymmetric CCl stretching force constants, indicating a failure to compute an accurate C-Cl stretch-stretch interaction force constant. The MP2/cc-pVTZ force field was preferred. Both scaled and unscaled harmonic force fields were used to calculate centrifugal distortion constants (CDCs) and contributions to the vibrational dependence of the rotational constants (alphas). Variations in the CDCs can, in part, be explained by the magnitudes of the frequencies used in the scaling process. | 18,774,789 |
Influence of ligand polarizability on the reversible binding of O2 by trans-[Rh(X)(XNC)(PPh3)2] (X = Cl, Br, SC6F5, C2Ph; XNC = xylyl isocyanide). Structures and a kinetic study. | The complexes trans-[Rh(X)(XNC)(PPh 3) 2] (X = Cl, 1; Br, 2; SC 6F 5, 3; C 2Ph, 4; XNC = xylyl isocyanide) combine reversibly with molecular oxygen to give [Rh(X)(O 2)(XNC)(PPh 3) 2] of which [Rh(SC 6F 5)(O 2)(XNC)(PPh 3) 2] ( 7) and [Rh(C 2Ph)(O 2)(XNC)(PPh 3) 2] ( 8) are sufficiently stable to be isolated in crystalline form. Complexes 2, 3, 4, and 7 have been structurally characterized. Kinetic data for the dissociation of O 2 from the dioxygen adducts of 1- 4 were obtained using (31)P NMR to monitor changes in the concentration of [Rh(X)(O 2)(XNC)(PPh 3) 2] (X = Cl, Br, SC 6F 5, C 2Ph) resulting from the bubbling of argon through the respective warmed solutions (solvent chlorobenzene). From data recorded at temperatures in the range 30-70 degrees C, activation parameters were obtained as follows: Delta H (++) (kJ mol (-1)): 31.7 +/- 1.6 (X = Cl), 52.1 +/- 4.3 (X = Br), 66.0 +/- 5.8 (X = SC 6F 5), 101.3 +/- 1.8 (X = C 2Ph); Delta S (++) (J K (-1) mol (-1)): -170.3 +/- 5.0 (X = Cl), -120 +/- 13.6 (X = Br), -89 +/- 18.2 (X = SC 6F 5), -6.4 +/- 5.4 (X = C 2Ph). The values of Delta H (++) and Delta S (++) are closely correlated (R (2) = 0.9997), consistent with a common dissociation pathway along which the rate-determining step occurs at a different position for each X. Relative magnitudes of Delta H (++) are interpreted in terms of differing polarizabilities of ligands X. | 18,774,795 |
Magnetic field affects enzymatic ATP synthesis. | The rate of ATP synthesis by creatine kinase extracted from V. xanthia venom was shown to depend on the magnetic field. The yield of ATP produced by enzymes with 24Mg2+ and 26Mg2+ ions in catalytic sites increases by 7-8% at 55 mT and then decreases at 80 mT. For enzyme with 25Mg2+ ion in a catalytic site, the ATP yield increases by 50% and 70% in the fields 55 and 80 mT, respectively. In the Earth field the rate of ATP synthesis by enzyme, in which Mg2+ ion has magnetic nucleus 25Mg, is 2.5 times higher than that by enzymes, in which Mg2+ ion has nonmagnetic, spinless nuclei 24Mg or 26Mg. Both magnetic field effect and magnetic isotope effect demonstrate that the ATP synthesis is an ion-radical process, affected by Zeeman interaction and hyperfine coupling in the intermediate ion-radical pair. | 18,774,801 |
Fluorescent signaling based on sulfoxide profluorophores: application to the visual detection of the explosive TATP. | The first visual fluorescence-based assay for the peroxide explosive triacetone triperoxide (TATP) is described. The assay is based on a conceptually new fluorescence signaling mechanism, in which nonemissive pyrenyl sulfoxide profluorophores are oxidized to visibly emissive pyrenyl sulfones. Although not without limitations, these first-generation fluorescent probes can provide a visual response to ca. 100 nmol of TATP. In addition, the success of this assay suggests the potential for broader application of aryl sulfoxides in fluorescent chemosensing. | 18,774,810 |
Low coordinate, monomeric molybdenum and tungsten(III) complexes: structure, reactivity and calculational studies of (silox)3Mo and (silox)3ML (M = Mo, W; L = PMe3, CO; silox = (t)Bu3SiO). | Treatment of (silox)3MCl (M = Mo, 1-Cl; W, 2-Cl; silox = (t)Bu3SiO) with PMe3 and Na/Hg led to formation of monomeric, d(3) phosphine adducts, (silox)3MPMe3 (M = Mo, 1-PMe3; W, 2-PMe3) via (silox)3ClMPMe3 (M = Mo, 1-ClPMe3; W, 2-ClPMe3). Structural studies show 1-PMe3 and 2-PMe3 to be highly distorted; calculations on full chemical models corroborate experimentally determined S = 1/2 ground states and their structural features. The compounds contain a bent M-P bond that is characteristic of significant sigma/pi-mixing. PMe3 may be thermally removed from 1-PMe3 in vacuo to produce (4)A2' (silox) 3Mo (1), which was derivatized with CO, NO, and 1/4 P4 to form (silox)3Mo (1-CO), (silox)3MoNO (1-NO), and (silox)3MoP (1-P), respectively. Calculations revealed (silox)3W (2') to have an S = 1/2 ground state, which may render it too reactive to be isolated. Treatment of 2-PMe3 with CO, NO, and 1/4 P4 formed (silox)3WCO (2-CO), (silox)3WNO (2-NO), and (silox)3WP (2-P), respectively. 2-CO and 2-NO are more conveniently prepared from Na/Hg reductions of 2-Cl in the presence of CO and NO, respectively. Calculations reveal subtle effects of nd(z2)/(n+1)s mixing in differentiating the chemistry of Mo and W and in rationalizing the generation of mononuclear species. | 18,774,815 |
An expeditious synthesis of C(3)-N(1') heterodimeric indolines. | This paper describes the efficient and relatively simple synthesis of C(3)-N(1') heterodimeric indolines from the addition of indole nucleophiles to readily available bromopyrroloindolines. | 18,774,822 |
Cantilever tip near-field surface-enhanced Raman imaging of tris(bipyridine)ruthenium(II) on silver nanoparticles-coated substrates. | The near-field surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF) images of tris(bipyridine)ruthenium(II) adsorbed on a silver nanoparticles-coated substrate were obtained with a scanning near-field optical microscope (SNOM, or near-field scanning optical microscopy, NSOM) using a cantilever tip. In comparison with the most widely used fiber tip for SNOM, the cantilever tip has higher optical throughput and better thermal stability, making it more suitable for detecting the extremely low Raman signal in the near-field spectroscopic investigations. Our preliminary results show that the near-field SERS with the higher spatial resolution can provide richer fingerprint information than the far-field SERS. A comparison of the two types of images shows that there are more SERS than SEF hot spots, and the two types of hot spots do not overlap. More surprisingly, the near-field SERS spectra differ from the far-field SERS spectra obtained on the same sample in the band frequency and relative intensities of some major Raman bands, and some IR-active bands were observed with the near-field mode. These results are explained mainly by the electric field gradient effect and heterogeneous polarization character that operate only in the near-field SERS. | 18,774,828 |
Synthesis and surface self-assembly of [3]rotaxane-porphyrin conjugates: toward the development of a supramolecular surface tweezer for C60. | Surface immobilization of pristine C60 by supramolecular interactions is an attractive way to introduce C60 on surfaces since the pi-electron network and the electronic properties of C60 remain intact. Several hosts have been developed for surface complexation of C60. With few exceptions, the hosts reported to date are "electronically inert", limiting the potential applications of pristine C60-based devices. In this study, we present the synthesis and self-assembly of a potential tweezer-like host for C60 having a light-harvesting moiety and an electron-donating unit. More precisely, an azide-containing [3]rotaxane scaffold having ferrocene moieties as blocking group and thioctic acid as anchoring group for a gold surface has been synthesized. This [3]rotaxane has been self-assembled on gold in its protonated (NH2+) (1p) and neutral (NH) (1n) forms and characterized using electrochemistry, XPS, and contact angle measurements. The SAMs were functionalized with free-base and zinc porphyrin using copper-catalyzed 1,3-dipolar cycloaddition in optimized conditions. In combination with C60, this new host is expected to form a triad that could potentially be used as active building block in the preparation of nanostructured electrodes for photoelectrochemical application. | 18,774,831 |
In-situ heating study on the structural change of surfactant-templated germanium oxide mesostructure. | Mesostructured germanium oxide has been well-synthesized by using a surfactant-templated approach under basic hydrothermal conditions. The cationic surfactant cetyltrimethylammonium bromide (CTAB) has formed nanotubes with uniform diameter of about 3.2 nm. Blanket-like morphology of the as-prepared sample has been observed with transmission electron microscopy (TEM). High-resolution TEM image reveals that the nanotubes are connected with inorganic germanium oxide and have self-assembled into periodic mesostructure. In-situ heating X-ray diffraction (XRD) patterns confirm that the germanium oxide is in amorphous phase in the temperature range from room temperature (RT) to 700 degrees C. In-situ heating small-angle X-ray scattering (SAXS) presents the mesostructural change with temperature. The local atomic structures around germanium atom have been obtained with in-situ heating X-ray adsorption fine structure (XAFS) techniques. The stability of this mesostructure has been determined to be correlated with the cationic surfactant CTAB. The structural evolution from the GeO 2/NaOH aqueous solution, the as-prepared sample to the sample heated at 700 degrees C, has been described, and the formation mechanism of mesostructured germanium oxide has been discussed. | 18,774,850 |
Total synthesis of hyacinthacine A1, a glycosidase inhibitor. | A practical and enantioselective total synthesis of hyacinthacine A1 is achieved involving syn allylic epoxide opening with retention using Pd catalysis and "domino" hydrogenation (five steps in one pot) sequences. | 18,774,860 |
11-Hydroxymonocerin from the plant endophytic fungus Exserohilum rostratum. | A new analogue of monocerin, 11-hydroxymonocerin (2), along with monocerin (1) and 12-hydroxymonocerin (3) were isolated from cultures of Exserohilum rostratum, a fungal strain endophytic in Stemona sp. The structure of 2 was determined by analysis of NMR and MS data and by comparison of spectroscopic data to those of 1. Monocerin (1) and 11-hydroxymonocerin (2) displayed activity against Plasmodium falciparum (K1, multidrug-resistant strain) with IC50 values of 0.68 and 7.70 microM, respectively. None of the compounds were cytotoxic against any of the tumor cell lines tested. | 18,774,863 |
Sources and types of discrepancies between electronic medical records and actual outpatient medication use. | Accuracy and transportability of the recorded outpatient medication list are important in the continuum of patient care. Classifying discrepancies between the electronic medical record (EMR) and actual drug use by the root cause of discrepancy (either system generated or patient generated) would guide quality improvement initiatives. To quantify and categorize the number and type of medication discrepancies that exist between the medication lists recorded in EMRs and the comprehensive medication histories obtained through telephone interviews conducted by a team of nurses providing advice to health plan members at the Palo Alto Medical Foundation in Palo Alto, California. The study was conducted as a retrospective comparison of EMR medication lists with information obtained by patient interview. Interview data were obtained by a review of telephone calls made to a nurse advice line by health plan members seeking information about sinusitis, urinary tract infection, acute conjunctivitis, pharyngitis, emergency contraception, or mastitis. As part of the advice protocol, a medication reconciliation process was conducted between July 1 and December 31, 2006. Changes to the medication list made during the telephone visit were extracted, categorized, and evaluated by the study's principal investigator. Data extraction included the number and type of identified medication discrepancies, patient age, gender, and condition that prompted the telephone contact. A modified version of the Medication Discrepancy Tool (MDT) was used to categorize medication discrepancies as either system generated (e.g., failure of the provider to update a medication list) or patient generated (e.g., failure of the patient to report use of an over-the-counter product). A total of 233 discrepancies were identified from 85 medication reconciliation phone visits, averaging 2.7 per medication list. The most common type of discrepancy was a medication recorded in the EMR but no longer being used by the patient (n=164, 70.4%), followed by omission from the EMR of a medication being taken by the patient (n=36, 15.5%). 79.8% (n=186) of the discrepancies were attributed to system-generated factors, whereas 20.2% (n=47) were patient generated. Approximately half (n=118, 50.6%) of the discrepancies fell into 4 broad American Hospital Formulary System therapeutic classifications: anti-infective agents (14.2%), anti-inflammatory agents (14.2%), analgesics (12.4%), and vitamins (9.9%). The most common patient-generated discrepancy was omission of a multivitamin (n=13, 27.7%), and the most common system-generated prescription drug discrepancy was expired entry for the intranasal corticosteroid mometasone furoate (n=12, 6.5%). Discrepancies in the outpatient setting were common and predominantly system generated. The most common discrepancy was the presence in the EMR of a medication no longer being taken by the patient. Adding foreseeable end dates to prescription drug orders at computerized order entry might be considered in an effort to improve the accuracy of the outpatient medication list. Reliable systems to involve patients in routinely reconciling EMRs with actual medication use may also warrant examination. The MDT methodology served as a useful qualitative guide for evaluating discrepancies and developing targeted means for resolution. | 18,774,872 |
Economic and clinical impact of multiple myeloma to managed care. | Because of the development of novel agents such as immunomodulators, proteasome inhibitors, and bisphosphonates, the standards of care for the multiple myeloma (MM) patient have changed. The costs associated with current and emerging therapies, as well as supportive care, are significant and pose a tremendous financial burden to both patients and managed care. To review the economic impact of MM and to weigh the advantages and disadvantages of current treatments in bringing value for prolonged life versus the cost of treatment. This chapter will also discuss the need for thorough data review and pharmacoeconomic analyses to determine the most cost-effective therapies. Although MM accounts for only a small percentage of all cancer types, the costs associated with treating and managing it are among the highest. Recent developments in diagnosing, treating, and managing myeloma have led to novel treatment strategies. Immunomodulators, proteasome inhibitors, and bisphosphonates are improving response rates and preserving quality of life. However, these agents are not replacing older treatment modalities, but being used in addition to them. Intensive chemotherapy, stem cell transplantation, and supportive care are all important components in achieving treatment goals. Costs associated with stem cell transplants and complications of the disease add to the economic burden of myeloma. Additional costs for routine diagnostics to measure the progression of the disease or response to treatment need to be considered. Complications (e.g., lytic bone disease, infection, anemia, and renal failure) also add to morbidity and mortality, thus increasing the burden to the patient and the health care system as a whole. Financial and time constraints of caregivers must also be considered, as well as the added administrative burdens to health care providers. New standards of care in the treatment and management of myeloma are likely to lead to significant increases in costs. Although costs are not the only elements to be considered, they are crucial in the management of this already costly disease. All aspects of myeloma treatment and supportive care must be evaluated and analyzed. Cost of pharmaceuticals alone must not be a driving factor in treatment decisions. Economic analyses can be used to demonstrate that the least expensive alternative is not always the most economical, and that it may not produce an optimal outcome for both the health plan and the patient. Although cost containment is clearly an important objective, quality of care is the first priority, and managed care organizations have the challenge of making balanced cost and benefit assessments. | 18,774,882 |
High prevalence of prolonged norovirus shedding and illness among hospitalized patients: a model for in vivo molecular evolution. | During a 2-year survey in an academic hospital, 8 (8.4%) of all norovirus (NoV)-positive patients showed prolonged norovirus illness and shedding (duration, 21-182 days). All patients had underlying illnesses, resulting in some level of immunodeficiency in 5. Four patients were admitted to the hospital with gastroenteritis, 2 acquired norovirus while hospitalized, and 2 were outpatients. Genotypes GII.4 and GIIb-GII.3 were found. Reinfection occurred in 3 patients. Full capsid sequences were determined from strains detected in sequentially collected stool specimens to study evolution. The greatest number of amino acid mutations in a given patient was 11; they were detected in NoV isolates recovered over a 119-day period and were mapped to positions at or near putative antigenic sites. In the patient with most severe immune dysfunction, only 5 amino acids mutated over 182 days, suggesting immune-driven selection. The severe impact on patients and hospitals and the potential role of prolonged shedders as a reservoir for viral antigenic variants lead us to stress the importance of confinement of outbreaks of NoV infection that occur in hospitals. | 18,774,885 |
Prescription medication borrowing and sharing among women of reproductive age. | The purpose of this study was to describe the patterns of prescription medication borrowing and sharing among adults, particularly women of reproductive age. Data were collected from the 2001-2006 HealthStyles surveys, an annual mail survey conducted in the United States concerning trends in health behavior. The total responses received were 26,566 of 36,420 surveys mailed (response rate 73%). Of these total responses, there were 7,456 women of reproductive age (18-44 years). Survey questions included whether participants had ever shared or borrowed a prescription medication, how often participants shared or borrowed medications in the past year, and types of medications shared or borrowed. Data were weighted by matching sex, age, income, race, and household size variables to annual U.S. census data. Associations between demographic factors and borrowing and sharing were studied. Overall, 28.8% of women and 26.5% of men reported ever borrowing or sharing prescription medications. Women of reproductive age were more likely to report prescription medication borrowing or sharing (36.5%) than women of nonreproductive age (>or=45 years) (19.5%) (rate ratio [RR] 1.87, 95% confidence interval [CI] 1.77-1.99). Of reproductive-aged women who borrowed or shared prescription medication, the most common medications borrowed or shared were allergy medications (43.8%) and pain medications (42.6%). Prescription medication borrowing and sharing is a common behavior among adults and is more common among reproductive-aged women than among women in other age groups. | 18,774,892 |
Improving reversal median computation using commuting reversals and cycle information. | In the past decade, genome rearrangements have attracted increasing attention from both biologists and computer scientists as a new type of data for phylogenetic analysis. Methods for reconstructing phylogeny from genome rearrangements include distance-based methods, MCMC methods, and direct optimization methods. The latter, pioneered by Sankoff and extended with the software suites GRAPPA and MGR, is the most accurate approach, but is very limited due to the difficulty of its scoring procedure--it must solve multiple instances of the reversal median problem to compute the score of a given tree. The reversal median problem is known to be NP-hard and all existing solvers are extremely slow when the genomes are distant. In this paper, we present a new reversal median heuristic for unichromosomal genomes. The new method works by applying sets of reversals in a batch where all such reversals both commute and do not break the cycle of any other. Our testing using simulated datasets shows that this method is much faster than the leading solver for difficult datasets with only a slight accuracy penalty, yet retains better accuracy than other heuristics with comparable speed, and provides the additional option of searching for multiple medians. This method dramatically increases the speed of current direct optimization methods and enables us to extend the range of their applicability to organellar and small nuclear genomes with more than 50 reversals along each edge. | 18,774,904 |
Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. | Sulfhydryl chemistry plays a vital role in normal biology and in defense of cells against oxidants, free radicals, and electrophiles. Modification of critical cysteine residues is an important mechanism of signal transduction, and perturbation of thiol-disulfide homeostasis is an important consequence of many diseases. A prevalent form of cysteine modification is reversible formation of protein mixed disulfides (protein-SSG) with glutathione (GSH). The abundance of GSH in cells and the ready conversion of sulfenic acids and S-nitroso derivatives to S-glutathione mixed disulfides suggests that reversible S-glutathionylation may be a common feature of redox signal transduction and regulation of the activities of redox sensitive thiol-proteins. The glutaredoxin enzyme has served as a focal point and important tool for evolution of this regulatory mechanism, because it is a specific and efficient catalyst of protein-SSG deglutathionylation. However, mechanisms of control of intracellular Grx activity in response to various stimuli are not well understood, and delineation of specific mechanisms and enzyme(s) involved in formation of protein-SSG intermediates requires further attention. A large number of proteins have been identified as potentially regulated by reversible S-glutathionylation, but only a few studies have documented glutathionylation-dependent changes in activity of specific proteins in a physiological context. Oxidative stress is a hallmark of many diseases which may interrupt or divert normal redox signaling and perturb protein-thiol homeostasis. Examples involving changes in S-glutathionylation of specific proteins are discussed in the context of diabetes, cardiovascular and lung diseases, cancer, and neurodegenerative diseases. | 18,774,901 |
Plasmid DNA as a safe gene delivery vehicle for treatment of chronic inflammatory disease. | The development of plasmid DNA (pDNA) vectors for safe and efficacious gene transfer therapy for chronic inflammatory diseases is a natural sequel to biological therapies which, whilst effective, are relatively expensive, require frequent administration and are not suitable for all patients. To outline the methods of non-viral gene therapy using pDNA and detail research on potential targets in the treatment of chronic inflammatory diseases, with particular emphasis on multiple sclerosis, rheumatoid arthritis and osteoarthritis. A comprehensive online journal search was used to examine current approaches in pDNA transfer and practical applications in chronic inflammatory diseases; conditions with similar disease processes were also considered. Significant progress has been made in increasing the efficiency and efficacy of non-viral gene transfer. For modulation of inflammatory targets, the conversion of biological therapy to gene therapy using pDNA is achievable. | 18,774,919 |
Ad-MDA-7; INGN 241: a review of preclinical and clinical experience. | The melanoma differentiation-associated gene-7 (MDA-7) was isolated while screening for upregulated genes in terminally differentiated melanoma cell lines. Preclinical studies attempted to test the theory that oncogenesis arises from a cellular differentiation process culminating in dysregulation of the cell cycle and ultimately malignancy. The MDA-7 gene (gene symbol IL-24) has been classified as part of the IL-10 family of cytokines demonstrating significant anticancer potential. Preclinical studies have shown that MDA-7/IL-24 is effective in inducing cancer cell death by several pathways in various tumor models. A Phase I clinical trial studying intratumoral injections of solid tumors showed evidence of clinical activity with limited toxicity. This small trial suggested therapeutic potential. Results are reviewed. Future opportunities involve combination with different gene delivery systems with systemic potential. | 18,774,929 |
Metal cofactors play a dual role in Mycobacterium tuberculosis inorganic pyrophosphatase. | Inorganic pyrophosphatase from Mycobacterium tuberculosis (Mt-PPase) is one of the possible targets for the rational design of anti-tuberculosis agents. In this paper, functional properties of this enzyme are characterized in the presence of the most effective activators--Mg2+ and Mn2+. Dissociation constants of Mt-PPase complexed with Mg2+ or Mn2+ are essentially similar to those of Escherichia coli PPase. Stability of a hexameric form of Mt-PPase has been characterized as a function of pH both for the metal-free enzyme and for Mg2+- or Mn2+-enzyme. Hexameric metal-free Mt-PPase has been shown to dissociate, forming monomers at pH below 4 or trimers at pH from 8 to 10. Mg2+ or Mn2+ shift the hexamer-trimer equilibrium found for the apo-Mt-PPase at pH 8-10 toward the hexameric form by stabilizing intertrimeric contacts. The pK(a) values have been determined for groups that control the observed hexamer-monomer (pK(a) 5.4), hexamer-trimer (pK(a) 7.5), and trimer-monomer (pK(a) 9.8) transitions. Our results demonstrate that due to the non-conservative amino acid residues His21 and His86 in the active site of Mt-PPase, substrate specificity of this enzyme, in contrast to other typical PPases, does not depend on the nature of the metal cofactor. | 18,774,936 |
Cardiac autonomic function and baroreflex changes following 4 weeks of resistance versus aerobic training in individuals with pre-hypertension. | Cardiac autonomic modulation and baroreflex sensitivity (BRS) are altered in individuals with hypertension. Aerobic exercise (AE) training has been shown to improve both measures, yet little is known about the effects of resistance exercise (RE). The purpose of this study was to examine the heart rate variability (HRV) and BRS following 4 weeks of resistance or aerobic training in a population with borderline high blood pressure (BP). Twenty-nine mild hypertensives were recruited and randomly assigned to 4 weeks of RE or AE training. Before and after training, resting measures of HRV frequencies and BRS were obtained. There was a significant decrease in resting systolic BP for both exercise training modes (RE 136 +/- 3.0 pre- to 132 +/- 3.4 post-training vs. AE 142 +/- 4.0 pre- to 137 +/- 3.6 mmHg post-training, P = 0.019). Diastolic BP decreased significantly following both exercise training modes (RE 78 +/- 1.31 pre to 74 +/- 1.1 post vs. AE 80 +/- 1.7 pre to 77 +/- 1.6 mmHg post, P = 0.002). A significant time by training mode interaction for low frequency : high frequency (HF) ratio (P = 0.017) with AE decreasing the ratio (275.21 +/- 67.28 to 161.26 +/- 61.49) and RE increasing this ratio (143.73 +/- 65.00 to 227.83 +/- 59.41). Natural log-transformed (ln) HRV values showed a time-by-training mode interaction for ln HF (P = 0.05) as ln HF increased (4.7 +/- 0.38 to 5.4 +/- 0.35 ms(2)) following AE and decreased (5.98 +/- 0.37 to 5.76 +/- 0.42 ms(2)) following RE. BRS increased following aerobic training and decreased after resistance training (6.74 +/- 1.2 to 7.94 +/- 1.3 and 10.44 +/- 1.2 to 9.1 +/- 1.2 ms mmHg(-1) respectively, P = 0.021). Aerobic exercise improved the autonomic nervous system (increasing vagal tone, reducing sympathovagal balance while increasing BRS) while RE showed no improvements in cardiac autonomic tone and decreased BRS. | 18,774,947 |
An enhanced level of motor cortical excitability during the control of human standing. | The study examined the role of the motor cortex in the control of human standing. Subjects (n = 15) stood quietly with or without body support. The supported standing condition enabled subjects to stand with a reduced amount of postural sway. Peripheral electrical stimulation, transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (TES) was applied to elicit a soleus (SOL) H-reflex, or motor-evoked potentials (MEPs) in the SOL and the tibialis anterior (TA). Trials were grouped based on the standing condition (i.e. supported vs. normal) as well as sway direction (i.e. forward and backward) while subjects were standing normally. During normal when compared to supported standing, the SOL H-reflex was depressed (-11 +/- 4%), while the TMS-evoked MEPs from the SOL and TA were facilitated (35 +/- 11% for the SOL, 51 +/- 15% for the TA). TES-evoked SOL and TA MEPs were, however, not different between the normal and supported standing conditions. The data based on sway direction indicated that the SOL H-reflex, as well as the SOL TMS- and TES-evoked MEPs were all greater during forward when compared to backward sway. In contrast, the TMS- and TES-evoked MEPs from the TA were smaller when swaying forward as compared to backward. The results indicated the presence of an enhanced cortical excitability because of the need to control for postural sway during normal standing. The increased cortical excitability was, however, unlikely to be involved in an on-going control of postural sway, suggesting that postural sway is controlled at the spinal and/or subcortical levels. | 18,774,948 |
Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone. | Niemann-Pick C disease (NPC) is an autosomal recessive neurodegenerative disorder caused by the abnormal function of NPC1 or NPC2 proteins, leading to an accumulation of unesterified cholesterol and glycosphingolipids (GSLs) in the lysosomes. The mechanisms underlying the pathophysiology in NPC disease are not clear. Oxidative damage is implicated in the pathophysiology of different neurological disorders and the effect of GSL accumulation on the intracellular redox state has been documented. Therefore, we determined whether the intracellular redox state might contribute to the NPC disease pathophysiology. Because the treatment of NPC mice with allopregnanolone (ALLO) increases their lifespan and delays the onset of neurological impairment, we analysed the effect of ALLO on the oxidative damage in human NPC fibroblasts. Concentrations of reactive oxygen species (ROS) and lipid peroxidation were higher in fibroblasts from NPC patients than in fibroblasts from normal subjects. Fibroblasts from NPC patients were more susceptible to cell death through apoptosis after an acute oxidative insult. This process is mediated by activation of the NF-kappaB signalling pathway. Knockdown of NPC1 mRNA both in normal fibroblasts and in human SH-SY5Y neuroblastoma cells caused increased ROS concentrations. ALLO treatment of fibroblasts from NPC patients or NPC1 knockdown cells reduced the levels of ROS and lipid peroxidation and prevented peroxide-induced apoptosis and NF-kB activation. Thus, these findings suggest that oxidative stress might contribute to the NPC disease and ALLO might be beneficial in the treatment of the disease, at least in part, due to its ability to restore the intracellular redox state. | 18,774,957 |
ABCB19/PGP19 stabilises PIN1 in membrane microdomains in Arabidopsis. | Auxin transport is mediated at the cellular level by three independent mechanisms that are characterised by the PIN-formed (PIN), P-glycoprotein (ABCB/PGP) and AUX/LAX transport proteins. The PIN and ABCB transport proteins, best represented by PIN1 and ABCB19 (PGP19), have been shown to coordinately regulate auxin efflux. When PIN1 and ABCB19 coincide on the plasma membrane, their interaction enhances the rate and specificity of auxin efflux and the dynamic cycling of PIN1 is reduced. However, ABCB19 function is not regulated by the dynamic cellular trafficking mechanisms that regulate PIN1 in apical tissues, as localisation of ABCB19 on the plasma membrane was not inhibited by short-term treatments with latrunculin B, oryzalin, brefeldin A (BFA) or wortmannin--all of which have been shown to alter PIN1 and/or PIN2 plasma membrane localisation. When taken up by endocytosis, the styryl dye FM4-64 labels diffuse rather than punctuate intracellular bodies in abcb19 (pgp19), and some aggregations of PIN1 induced by short-term BFA treatment did not disperse after BFA washout in abcb19. Although the subcellular localisations of ABCB19 and PIN1 in the reciprocal mutant backgrounds were like those in wild type, PIN1 plasma membrane localisation in abcb19 roots was more easily perturbed by the detergent Triton X-100, but not other non-ionic detergents. ABCB19 is stably associated with sterol/sphingolipid-enriched membrane fractions containing BIG/TIR3 and partitions into Triton X-100 detergent-resistant membrane (DRM) fractions. In the wild type, PIN1 was also present in DRMs, but was less abundant in abcb19 DRMs. These observations suggested a rationale for the observed lack of auxin transport activity when PIN1 is expressed in a non-plant heterologous system. PIN1 was therefore expressed in Schizosaccharomyces pombe, which has plant-like sterol-enriched microdomains, and catalysed auxin transport in these cells. These data suggest that ABCB19 stabilises PIN1 localisation at the plasma membrane in discrete cellular subdomains where PIN1 and ABCB19 expression overlaps. | 18,774,968 |
Insulin allergy desensitization with simultaneous intravenous insulin and continuous subcutaneous insulin infusion. | Persistent 'IgE-mediated' insulin allergy (type 1 allergy) (1), unresponsive to changes in insulin type or the use of antihistamines, necessitates desensitization. A number of case reports (2-7) and recent reviews (8, 9) have demonstrated that desensitization can be achieved with continuous subcutaneous insulin infusion (CSII), but in type 1 diabetes mellitus, the need to slowly increase insulin dose from sub-therapeutic levels competes with the need for glycaemic control and suppression of ketogenesis. Tolerance to intravenous (IV) insulin despite persistent life-threatening allergic reactions to subcutaneous human insulin (bolus or CSII) has been recently described (10). We present the cases of two unrelated 9-yr-old boys with persistent generalized urticarial reactions to subcutaneous injections of all available insulin types, despite treatment with oral antihistamines. After failed rapid desensitization to insulin delivered by either subcutaneous injection or CSII, the concurrent use of IV insulin allowed desensitization to CSII over 5-6 d. | 18,775,000 |
Early onset of type I diabetes mellitus, Hashimoto's thyroiditis and celiac disease in a 7-yr-old boy with Down's syndrome. | Patients with Down's syndrome are at higher risk for developing autoimmune diseases than those of the general population. Autoimmune diseases like Hashimoto's thyroiditis, Graves' disease, diabetes mellitus type I, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo and hypoparathyroidism are recognized associations with Down's syndrome. We describe the case of a very young boy with Down's syndrome who was diagnosed with diabetes mellitus type I, Hashimoto's thyroiditis and celiac disease before 8 yr of age. Unspecific symptoms like weight loss, unstable blood sugar with high amplitudes, behavioural problems and dry skin were suspicious for other endocrine disorders or celiac disease in our case. The boy was showing the typical human leukocyte antigen profile for these autoimmune diseases. The prevalence of these autoimmune diseases is higher in Down's syndrome than in general population. Therefore, we advice to follow children with Down's syndrome who develop more than two autoimmune diseases very carefully. | 18,775,001 |
Balloon occlusion and hypothermic perfusion of the renal artery in laparoscopic partial nephectomy. | We describe our initial experience with renal arterial catheterization for temporary balloon occlusion of renal artery and hypothermic perfusion during laparoscopic partial nephectomy and compare the preoperative and postoperative nephron function. Fifteen patients received laparoscopic partial nephrectomy from September 2005 to December 2006. During the operations, the balloons of the arterial catheters were filled with distilled water to achieve pedicle control. Chilled Ringers lactate was continuously infused into the catheters for renal hypothermia. Postoperative Tc-99m diethylenetriamine pentaacetic acid (DTPA) renal scintigraphies were carried out to estimate differential renal function. The volumes of the renal tumors, tumor-bearing and contralateral kidneys from CT scans were measured using commercial software. Estimated creatinine clearance was calculated with Cockroft Gault formula. All procedures were successfully completed. Mean tumor size was 18.4 mL (range 2.14 to 59.0). Estimated mean intraoperative blood loss was 287 mL (range minimal to 1200). Mean estimated creatinine clearance per unit volume of functional renal parenchyma did not change statistically after the operation. Multiple regression analysis revealed that ischemic time was a significant variable which correlated with the value of lost total estimated creatinine clearance of the tumor bearing kidney. The initial experience shows that renal arterial catheterization for temporary balloon occlusion and hypothermic perfusion of the renal artery in laparoscopic partial nephectomy is safe, feasible and effective. The postoperative kidney function measured by mean estimated creatinine clearance per unit of functional renal volume was similar to the preoperative measurement. | 18,775,030 |
The effect of a pedometer-based community walking intervention "Walking for Wellbeing in the West" on physical activity levels and health outcomes: a 12-week randomized controlled trial. | Recent systematic reviews have suggested that pedometers may be effective motivational tools to promote walking. However, studies tend to be of a relatively short duration, with small clinical based samples. Further research is required to demonstrate their effectiveness in adequately powered, community based studies. Using a randomized controlled trial design, this study assessed the impact of a 12-week graduated pedometer-based walking intervention on daily step-counts, self-reported physical activity and health outcomes in a Scottish community sample not meeting current physical activity recommendations. Sixty-three women and 16 men (49.2 years +/- 8.8) were randomly assigned to either an intervention (physical activity consultation and 12-week pedometer-based walking program) or control (no action) group. Measures for step-counts, 7-day physical activity recall, affect, quality of life (n = 79), body mass, BMI, % body fat, waist and hip circumference (n = 76), systolic/diastolic blood pressure, total cholesterol and HDL cholesterol (n = 66) were taken at baseline and week 12. Analyses were performed on an intention to treat basis using 2-way mixed factorial analyses of variance for parametric data and Mann Whitney and Wilcoxon tests for non-parametric data. Significant increases were found in the intervention group for step-counts (p < .001), time spent in leisure walking (p = .02) and positive affect (p = .027). Significant decreases were found in this group for time spent in weekday (p = .003), weekend (p = .001) and total sitting (p = .001) with no corresponding changes in the control group. No significant changes in any other health outcomes were found in either group. In comparison with the control group at week 12, the intervention group reported a significantly greater number of minutes spent in leisure time (p = .008), occupational (p = .045) and total walking (p = .03), and significantly fewer minutes in time spent in weekend (p = .003) and total sitting (p = .022). A pedometer-based walking program, incorporating a physical activity consultation, is effective in promoting walking and improving positive affect over 12 weeks in community based individuals. The discussion examines possible explanations for the lack of significant changes in health outcomes. Continued follow-up of this study will examine adherence to the intervention and possible resulting effects on health outcomes. | 18,775,062 |
Effects of glatiramer acetate on fatigue and days of absence from work in first-time treated relapsing-remitting multiple sclerosis. | Treatment of multiple sclerosis patients with glatiramer acetate has been demonstrated a beneficial effect on disease activity. The objective of this prospective naturalistic study was to evaluate the impact of glatiramer acetate on fatigue and work absenteeism. 291 treatment-naïve patients with relapsing remitting multiple sclerosis were included and treated with glatiramer acetate for twelve months. Relapse rates, disability, fatigue symptoms, days of absence from work and adverse events were monitored. Fatigue was measured with the MFIS scale and with a visual analogue scale. Total MFIS scores decreased by 7.6 +/- 16.4 from 34.6 to 27.0 (p < or = 0.001). Significant reductions were observed on all three subscales of the MFIS. Fatigue symptoms, assessed using a visual analogue scale, decreased by 1.04 +/- 2.88 cm from 4.47 cm to 3.43 cm (p < or = 0.001). The proportion of patients absent from work at least once was reduced by a factor of two from 65.1% to 30.1% (p < or = 0.001). Tolerance to treatment was rated as very good or good in 78.3% of patients. Adverse effects, most frequently local injection site reactions, were reported in 15.1% of patients. Treatment with glatiramer acetate was associated with a significant improvement in fatigue symptoms and a marked reduction in absence from work. Treatment was well-tolerated. Such benefits are of relevance to overall patient well-being. | 18,775,064 |
Radiographic outcome of surgical treatment of adolescent idiopathic scoliosis in males versus females. | Studies on adolescent idiopathic scoliosis have well documented the differences between natural history of male and female patients. There are also differences in responses to nonoperative treatment, but the results of operative treatment in male patients compared with females have not been widely reported. Only few studies had compared the outcomes of operative treatment between male and female patients with different results. We retrospectively reviewed the outcome of 150 (112 girls and 38 boys) consecutive patients with diagnosis of adolescent idiopathic scoliosis who were managed surgically between May 1996 and September 2005. Next, male radiographic parameters were compared with female ones pre- and postoperatively. Then, a subgroup of 38 matched girls was compared regarding the age, curve type, curve magnitude, and the instrumentation we used. In comparing male patients with unmatched girls, the boys had greater mean age (17.3 +/- 2.3 vs. 16.3 +/- 2.9; p = 0.049), greater primary curve (71.4 +/- 21.3 degrees vs. 62.7 +/- 17.5 degrees ; p = 0.013), less flexibility (30.1 +/- 13.5% vs. 40.3 +/- 17.8%; p = 0.01), and less correction percentage (51.3 +/- 12.9% vs. 58.8 +/- 16.5%; p = 0/013). The loss of correction was comparable between the two groups. In the matched comparison, the flexibility in boys was less than girls (30.1 +/- 13.5% vs. 38.1 +/- 17.5%; p = 0.027). Also, the boys had a smaller correction percentage compared to the girls, but this finding was not statistically significant. There was similar distribution curve pattern between male and female patients with AIS. Males had more rigid primary curves compared to females but a similar degree of postoperative scoliosis correction. Male AIS patients were older at the time of surgery. These preoperative gender differences, however; did not compromise the radiological outcomes of surgical treatment and the results were comparable between the genders. | 18,775,076 |
Surgery vs. radiotherapy in localized prostate cancer. Which is best? | Surgery and radiotherapy are currently accepted alternatives for the treatment of localized prostate cancer. In the absence of relevant randomized trials no decision regarding the superiority of any of the given approaches can be made. Up to now several cohort-based approaches indicate similar outcomes for both treatments. Based on a new population based approach, Merglen and co-workers recently concluded that surgery would offer the best chance of long-term control in terms of 10-year survival for T1-T3 prostate cancer patients. Unfortunately the strength of this trial is limited by several shortcomings. Most importantly, issues of radiation dosage have not been taken into account. In addition, several relevant parameters including Gleason score and PSA are not well balanced between the arms and the assignment to arbitrary risk groups does not reflect the real biological behaviour. Thus, the data provided do not support the strong conclusion issued by the authors. Based on the data available, surgery and radiotherapy still have to be considered as equally effective. | 18,775,078 |
Rb and hematopoiesis: stem cells to anemia. | The retinoblastoma protein, Rb, was one of the first tumor suppressor genes identified as a result of the familial syndrome retinoblastoma. In the period since its identification and cloning a large number of studies have described its role in various cellular processes. The application of conditional somatic mutation with lineage and temporally controlled gene deletion strategies, thus circumventing the lethality associated with germ-line deletion of Rb, have allowed for a reanalysis of the in vivo role of Rb. In the hematopoietic system, such approaches have led to new insights into stem cell biology and the role of the microenvironment in regulating hematopoietic stem cell fate. They have also clarified the role that Rb plays during erythropoiesis and defined a novel mechanism linking mitochondrial function to terminal cell cycle withdrawal. These studies have shed light on the in vivo role of Rb in the regulation of hematopoiesis and also prompt further analysis of the role that Rb plays in both the regulation of hematopoietic stem cells and the terminal differentiation of their progeny. | 18,775,080 |
Memory impairment in young women at increased risk of depression: influence of cortisol and 5-HTT genotype. | Memory deficits are common in depressed patients and may persist after recovery. The aim of the present study was to determine whether memory impairments were present in young women at increased familial risk of depression and whether memory performance was related either to cortisol secretion or to allelic variation in the promoter region of the serotonin transporter gene (5-HTT). Young women (n=35, age range 16-21 years) with no personal history of depression but with a depressed parent (FH+) carried out the Rey Auditory Verbal Learning Test (RAVLT). They also provided samples for the measurement of waking salivary cortisol and for 5-HTT genotyping. An age-matched control group of women (n=31) with no family history of depression were similarly studied. The FH+ participants had decreased immediate recall and recognition memory compared to controls. The impairment in recall, but not recognition, correlated negatively with increased cortisol secretion in FH+ subjects. There was no significant effect of 5-HTT allelic status on either memory or waking cortisol secretion. Impairments in declarative memory are present in young women at increased genetic risk of depression and may be partly related to increased cortisol secretion. Further studies are needed to explore the neural mechanisms underlying the memory impairments and whether they predict the development of clinical illness. | 18,775,088 |
Metazoan parasites of freshwater cyprinid fish ( Leuciscus cephalus): testing biogeographical hypotheses of species diversity. | The diversity and similarity of parasite communities is a result of many determinants widely considered in parasite ecology. In this study, the metazoan parasite communities of 15 chub populations (Leuciscus cephalus) were sampled across a wide geographical range. Three hypotheses of biogeographical gradients in species diversity were tested: (1) latitudinal gradient, (2) a 'favourable centre' versus 'local oasis' model, and (3) decay of similarity with distance. We found that the localities in marginal zones of chub distribution showed lower parasite species richness and diversity. A latitudinal gradient, with increasing abundance of larvae of Diplostomum species, was observed. There was a general trend for a negative relationship between relative prevalence or abundance and the distance from the locality with maximum prevalence or abundance for the majority of parasite species. However, statistical support for a 'favourable centre' model was found only for total abundance of Monogenea and for larvae of Diplostomum species. The phylogenetic relatedness of host populations inferred an important role when the 'favourable centre' model was tested. Testing of the hypothesis of 'decay of similarity with geographical distance' showed that phylogenetic distance was more important as a determinant of similarity in parasite communities than geographical distance between host populations. | 18,775,091 |
Brain morphometry volume in autistic spectrum disorder: a magnetic resonance imaging study of adults. | Several prior reports have found that some young children with autism spectrum disorder [ASD; including autism and Asperger's syndrome and pervasive developmental disorder - not otherwise specified (PDD-NOS)] have a significant increase in head size and brain weight. However, the findings from older children and adults with ASD are inconsistent. This may reflect the relatively small sample sizes that were studied, clinical heterogeneity, or age-related brain differences. Hence, we measured head size (intracranial volume), and the bulk volume of ventricular and peripheral cerebrospinal fluid (CSF), lobar brain, and cerebellum in 114 people with ASD and 60 controls aged between 18 and 58 years. The ASD sample included 80 people with Asperger's syndrome, 28 with autism and six with PDD-NOS. There was no significant between-group difference in head and/or lobar brain matter volume. However, compared with controls, each ASD subgroup had a significantly smaller cerebellar volume, and a significantly larger volume of peripheral CSF. Within ASD adults, the bulk volume of cerebellum is reduced irrespective of diagnostic subcategory. Also the significant increase in peripheral CSF may reflect differences in cortical maturation and/or ageing. | 18,775,096 |
The composition of mineral waters sourced from Europe and North America in respect to bone health: composition of mineral water optimal for bone. | The consumption of mineral waters is increasing in industrialised countries. High intakes of Ca and other alkalising cations as well as a low acid intake are beneficial to bone. We examined which components of mineral waters are conditioning their Ca content and their alkalinising power, in order to define the optimal profile. European mineral waters were randomly selected on the Internet: 100 waters with less than 200 mg Ca/l (9.98 mEq/l) and fifty with more than 200 mg/l, all with complete data for SO4, P, Cl, Na, K, Mg and Ca, and most also for HCO3. For comparison, forty North American mineral waters were randomly chosen. The potential renal acid load (PRAL) was calculated for each mineral water. North American waters did not reveal significant results because of their low mineralisation. We performed correlations between all eight components in order to explore the properties of the mineral waters. In the European waters, twenty-six out of twenty-eight correlations showed a P value of <or= 0.01. In waters with PRAL >0 (acidifying waters), PRAL was positively correlated with SO4, Ca, K and Mg (P < 0.001). In those with PRAL < 0 (alkalinising waters), PRAL was negatively correlated with HCO3, Na, Mg, Ca, K, Cl and SO4 (P < 0.001). SO4 and HCO3 were not found together in high quantities in the same water for geochemical reasons. A high Ca content is associated with either a high SO4 or a high HCO3 content. SO4 theoretically increases Ca excretion, while HCO3 and low PRAL values are associated with positive effects on bone. Therefore, the best waters for bone health are rich in both HCO3 and Ca, and by consequence low in SO4. | 18,775,101 |
Cell cycle proteins preceded neuronal death after chronic cerebral hypoperfusion in rats. | To explore the re-expression of cell cycle related proteins and delayed neuronal death after chronic cerebral hypoperfusion in rats and to investigate the relationship between aberrant expression of cell cycle proteins and apoptotic cell death. Rat model of chronic cerebral hypoperfusion was established by permanent bilateral common carotid arteries occlusion (2VO) in the retired rats. The apoptotic cells were assessed by TUNEL method. The expression of cell cycle related proteins, i.e. CDK4 and cyclin B1, were detected by immunohistochemical staining and Western blotting. A cyclin-dependent kinases (CDKs) inhibitor, roscovitine, was intracerebroventricularly administered 1 day before 2VO insult. Spatial learning behavior was assessed by the Morris water maze 7, 14 and 21 days after the surgery. Aberrant expression of CDK4 and cyclin B1 became present 7 days after 2VO insult surgery and last for a long period. On the other hand, TUNEL positive cells appeared as early as 14 days after the surgery and peaked at day 21. Furthermore, roscovitine significantly improve behavioral deficit in the Morris water maze test 7 and 14 days after the surgery. These findings indicated that aberrant expression of CDK4 and cyclin B1 takes place in the brain after chronic cerebral hypoperfusion in retired rat, and aberrant expression of cell cycle proteins preceded neuronal death in this model. Our data also suggest that the CDK inhibitor, roscovitine, has therapeutic potential for the treatment of dementia caused by chronic cerebral hypoperfusion. | 18,775,106 |
QT interval in newborns of different ethnic origin: usefulness of neonatal ECG screening. | The cost-effectiveness of neonatal electrocardiographic (ECG) screening has been questioned. The objective of this study was to establish normal values for the QT interval in newborns of different ethnic origin. Between 2005 and 2006, ECGs were obtained during the first 48 h of life from 1305 at-term newborns at the Hospital del Mar in Barcelona, Spain. The mean corrected QT interval (QTc) was 417.79+/-28.47 ms. A QTc longer than 440 ms was observed in 240 newborns (18.33%). The frequency of a pathologic QTc in Spanish newborns was 17.9%, compared with 27.7% in those of Maghreb or Near Eastern origin (P=.016), and 28.2% in those of Indian or Pakistani origin (P=.033). The QTc may vary for genetic reasons. A routine neonatal ECG is advisable only in ethnic groups in which the QTc is lengthened, to help counter the greater risk of sudden death in these infants. | 18,775,242 |
Four years of surveillance of recent HIV infections at country level, France, mid 2003 - 2006: experience and perspectives. | New systems of surveillance to better monitor the dynamics of HIV are needed. A national surveillance of new HIV diagnoses which included the collection of dried serum spots (DSS) to identify recent infections (<6 months) using an EIA-RI assay was implemented in 2003 in France. The collection of DSS is based on the voluntary participation by both patients and microbiologists. Multivariate analysis was used to identify factors associated with recent infection (RI). Between July 2003 and December 2006, 14,155 cases newly diagnosed for HIV were reported. A minority of patients refused the collection of DSS (3.3%) and the rate of participation of laboratories was 80%. The test was performed for 10,855 newly diagnosed HIV cases, the overall proportion of RI was 23.1% (95% CI, 22.3%-23.9%). The proportion of RI was higher among men who have sex with men (MSM) (42.8%) than among heterosexuals (16.3%). Among heterosexuals, it varied by current nationality: 27% among French versus 8.4% among Africans. The risk of RI was greater for MSM (aOR=1.8), those of French nationality (aOR=3.9), those with high-economic status (aOR=1.2), those tested after a risk exposure (aOR=1.4), those tested for HIV three or more times during their lifetime (aOR=2.5). The risk of RI decreased with age. A nation-wide implementation of RI monitoring is feasible. The information on RI is very useful for renewing prevention messages, particularly among population in which HIV transmission is on going, such as MSM. | 18,775,291 |
Principles and uses of HIV incidence estimation from recent infection testing--a review. | Since the 1990s, the development of laboratory-based methods has allowed to estimate incidence of human immunodeficiency virus (HIV) infections on single samples. The tests aim to differentiate recent from established HIV infection. Incidence estimates are obtained by using the relationship between prevalence, incidence and duration of recent infection. We describe the principle of the methods and typical uses of these tests to characterise recent infection and derive incidence. We discuss the challenges in interpreting estimates and we consider the implications for surveillance systems. Overall, these methods can add remarkable value to surveillance systems based on prevalence surveys as well as HIV case reporting.The assumptions that must be fulfilled to correctly interpret the estimates are mostly similar to those required in prevalence measurement. However, further research on the specific aspect of window period estimation is needed in order to generalise these methods in various population settings. | 18,775,292 |
Transcriptional ShortCUTs. | Recent work from Kuehner and Brow (2008) and Thiebaut et al. (2008) in Molecular Cell and Jenks et al. (2008) in Molecular and Cellular Biology reveals that regulated expression of central nucleotide synthesis pathway components directs start site-dependent RNA polymerase II termination. | 18,775,320 |
Pediatric tracheal stenosis. | Tracheal stenosis is a rare, potentially life-threatening condition described as innate narrowing of the tracheal lumen. The causes of tracheal stenosis vary widely. The most common forms result from prolonged intubation, although congenital causes usually involve complete tracheal rings or compression from cardiovascular malformations. The condition historically has harbored a poor prognosis, but significant advances in radiologic diagnosis, cardiac bypass, and endoscopic and surgical treatments have led to a range of options, better overall survival, and reduced morbidity. The complex, long-term manifestations of tracheal stenosis point to the need for individualized treatment as well as multidisciplinary care. | 18,775,347 |
Assessment and pharmacologic treatment of sleep disturbance in autism. | Like children with other developmental disabilities, children with autism spectrum disorders suffer with sleep problems at a higher rate than do typically developing children. There is a growing recognition that addressing these sleep problems may improve daytime functioning and decrease family stress. Presented here is a discussion of the sleep problems experienced by children with autism spectrum disorders, focusing on appropriate assessment and pharmacologic treatment. | 18,775,369 |
Developing drugs for core social and communication impairment in autism. | There are many challenges to studying drug effects on core social and language impairment in autism. Drugs such as fenfluramine, naltrexone, and secretin do not appear to be efficacious for these core symptoms. Risperidone has led to improvement in some aspects of social relatedness when used to treat irritability in autism. More research is needed on the utility of selective serotonin reuptake inhibitors, cholinergic drugs, glutamatergic drugs, and oxytocin for core autistic symptoms. | 18,775,370 |
Assessment and behavioral treatment of feeding and sleeping disorders in children with autism spectrum disorders. | Children diagnosed with autism or autism spectrum disorders (ASD) are more likely than other children to exhibit behaviors characteristic of a feeding or sleeping disorder. Parents of children with these disorders may be extremely concerned about the health and safety of their child. Sleeping and feeding problems can cause a great deal of stress to parents and other family members. Behavioral assessment and treatment procedures have been developed to address behavior problems related to sleeping and feeding disorders. This article reviews the literature about assessment and treatment, and provides recommendations regarding services to family members of individuals diagnosed with ASD and feeding or sleeping disorders. | 18,775,376 |
Evaluation of integrative medicine supplements for mitigation of chronic insomnia and constipation in an inpatient eating disorders setting. | The aim of this study was to determine whether patients with eating disorders used fewer conventional sleep and constipation medications when given integrative medicine interventions. Retrospective data from two cohorts were compared; the eating disorder group (ED) received only conventional treatments for insomnia and constipation and the integrative medicine eating disorders group (IMED) received integrative medicine and conventional treatments if needed. Patient reports of insomnia and constipation as well as medication use for these conditions were collected and compared. Patient demographics were similar in the two groups. Although reports of sleeping well were similar, use of conventional sleep medications was significantly lower for the IMED group. Reports of constipation and use of conventional constipation medications were also lower for IMED versus ED, but these differences were not all statistically significant. Integrative medicine interventions for insomnia and constipation appear to benefit patients with eating disorders and may allow these patients more focus for the work of recovery. | 18,775,402 |
Role of sex and time of blood sampling in SOD1 and SOD2 expression variability. | This study investigates how some of human physiological parameters, in particular sex and daytime, can contribute to the normal variation in blood gene expression. The expressions of two genes: SOD1 (Cu/Zn) and SOD2 (Mn) in white blood cells of 19 healthy individuals (10 men and 9 women) were examined by qPCR at 09.00, 12.00, and 15.00 h over three consecutive weeks at 7-day intervals. SOD1 and SOD2 expressions differ between sexes, higher expression being exhibited in males (P<0.005). In the male group both genes had lower expression (P<0.005) with smaller variation at 09.00 h. In females, both inter- and intra-subject, variability in SOD1 expression was increased at ovulation. Intra-individually, the expressions of genes positively correlated in males, but less in females. SOD1 and SOD2 expressions demonstrate how sex and daytime, merit being controlled when human gene expression analyses are evaluated, particularly within the framework of clinical trials or cohort studies. | 18,775,420 |
The role of Mac-1 (CD11b/CD18) in osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand. | Multinuclear osteoclasts are derived from CD11b-positive mononuclear cells in bone marrow and in circulation. FACS sorting experiments showed impaired osteoclastogenesis in RAW264.7 cells with low CD11b expression. Neutralizing antibodies and siRNA against CD11b inhibited osteoclastogenesis induced by RANKL. Although primary cultured mouse bone marrow macrophages expressed CD11a and CD11b, osteoclastogenesis induced by M-CSF and RANKL was inhibited in the presence of anti-CD11b or anti-CD18 but not anti-CD11a antibodies. Furthermore, anti-CD11b antibodies inhibited NFATc1 expression induced by M-CSF and RANKL in BMMs. These findings suggest, at least partly, an important role of CD11b in osteoclastogenesis. | 18,775,427 |
Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. | The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in glioblastoma multiforme (GBM) and other neoplasms. As such it represents a truly tumor-specific target for antitumor immunotherapy. Although endogenous humoral responses to EGFRvIII have been reported in patients with EGFRvIII-expressing breast cancer, it is not known whether de novo responses can be generated or endogenous responses enhanced with an EGFRvIII-specific vaccine. To assess this in clinical trials, we have developed and validated an immunoassay to measure and isolate anti-EGFRvIII and anti-KLH antibodies from the serum of patients vaccinated with an EGFRvIII-specific peptide (PEPvIII) conjugated to keyhole limpet hemocyanin (KLH). Using magnetic beads with immobilized antigen we captured and detected anti-EGFRvIII and anti-KLH antibodies in serum from patients before and after vaccinations. Using this assay, we found that significant levels of antibody for tumor-specific antigen EGFRvIII (>4 microg/mL) and KLH could be induced after vaccination with PEPvIII-KLH. | 18,775,433 |
Reduced-volume cues effectively support fear conditioning despite sleep deprivation. | Sleep deprivation impairs contextual but not cued learned fear, and it has been suggested that this pattern reflects an insensitivity of the amygdala to sleep loss. The lack of effect of sleep deprivation on cued conditioning, however, might simply be due to the strong attention drawn by the typically loud cue tone. We reduced tone volume from our standard 80 dB to either 70 or 60 dB, to test if reduced cue volume allowed effects of sleep deprivation to be detected. Using the platform-over-water method, male C57BL/6 mice were sleep-deprived for 24 h; control mice were moved to novel cages for 24 h. Mice then underwent fear conditioning with a standard "delay" protocol, and were tested for contextual and cued learning the next day. A control group received no footshock during conditioning. In the cue test, and for both cue volumes, SD had no effect on freezing to the tone, which was very robust in conditioned mice regardless of sleep treatment. As expected, freezing to the tone in the no-shock groups was essentially absent. Also, freezing prior to the tone was low in all mice. At the lowest volume, the tone was only ~10 dB above background noise. 24 h sleep deprivation, however, blocked contextual fear in the same mice. These results support a pattern of sleep deprivation sparing amygdaloid function but impairing hippocampal function. | 18,775,445 |
3'-Fluoro substitution in the pyridine ring of epibatidine improves selectivity and efficacy for alpha4beta2 versus alpha3beta4 nAChRs. | The analog of epibatidine having a fluoro substituent at the 3' position of the pyridine ring has been recently developed and shown to possess binding affinity in the pM range to alpha4beta2 nAChRs and in the nM range to alpha7 nAChRs and to exhibit potent agonist activity in nicotine-induced analgesia tests. Here we used patch-clamp technique in a whole-cell configuration to compare functional activity of 3'-fluoroepibatidine to that of epibatidine by itself on recombinant alpha4beta2, alpha7 and alpha3beta4 neuronal nAChRs. The agonist effect of (+/-)-epibatidine was partial and yielded comparable EC50s of 0.012 microM (72% efficacy) and 0.027 microM (81% efficacy) at alpha4beta2 and alpha3beta4 nAChRs, respectively, but was full at alpha7 nAChRs with an EC50 of 4.8 muM. Testing of the analog at different concentrations revealed that it acts as a full agonist with an EC50 of 0.36 microM at alpha4beta2 nAChRs and induces partial agonist effect (66% efficacy) at alpha7 nAChRs with an EC50 of 9.8 microM and an IC50 corresponding to 225 microM. In contrast, the analog caused only 24% maximal activation at the range of concentrations from 0.1 to 100 microM and, in addition, induced an inhibition of alpha3beta4 nAChR function with an IC50 of 8.3 microM. Our functional data, which are in agreement with previous binding and behavioral findings, demonstrate that 3'-fluoro substitution in the pyridine ring of epibatidine results in an improved pharmacological profile as observed by an increased efficacy and selectivity for alpha4beta2 versus alpha3beta4 nAChRs. | 18,775,444 |
Methylated N-(4-pyridinylmethyl) chitosan as a novel effective safe gene carrier. | The objective of this study was to study the transfection efficiency of quaternized N-(4-pyridinylmethyl) chitosan; TM-Py-CS, using the pDNA encoding green fluorescent protein (pEGFP-C2) on human hepatoma cell lines (Huh 7 cells). The factors affecting the transfection efficiency, e.g. degree of quaternization (DQ), the extent of N-pyridinylmethyl substitution (ES) and weight ratio, have been investigated. The results revealed that TM-Py-CS was able to condense with pDNA. Illustrated by agarose gel electrophoresis, complete complexes of TM(69)Py(62)CS/DNA were formed at weight ratio above 1.1, whereas those of TM(53)Py(40)CS/DNA and TM(52)Py(13)CS/DNA were above 1.8 and 8, respectively. TM(69)Py(62)CS showed superior transfection efficiency to TM(53)Py(40)CS, TM(52)Py(13)CS, TM(65)CS and TM(43)CS at all weight ratios tested. The highest transfection efficiency of TM(69)Py(62)CS/DNA complexes was found at weight ratio of 4. The results indicated that the improved gene transfection was possibly due to 4-pyridinylmethyl substitution on CS which promoted the interaction and condensation with DNA as well as N-quaternization which increased CS water solubility. In cytotoxicity studies, high concentration of TM-Py-CS and TM-CS could decrease the Huh 7 cell viability. In conclusion, this novel CS derivative, TM(69)Py(62)CS, showed promising potential as a gene carrier by efficient DNA condensation and mediated higher level of gene transfection. | 18,775,484 |
Current in vitro methods in nanoparticle risk assessment: limitations and challenges. | Nanoparticles are an emerging class of functional materials defined by size-dependent properties. Application fields range from medical imaging, new drug delivery technologies to various industrial products. Due to the expanding use of nanoparticles, the risk of human exposure rapidly increases and reliable toxicity test systems are urgently needed. Currently, nanoparticle cytotoxicity testing is based on in vitro methods established for hazard characterization of chemicals. However, evidence is accumulating that nanoparticles differ largely from these materials and may interfere with commonly used test systems. Here, we present an overview of current in vitro toxicity test methods for nanoparticle risk assessment and focus on their limitations resulting from specific nanoparticle properties. Nanoparticle features such as high adsorption capacity, hydrophobicity, surface charge, optical and magnetic properties, or catalytic activity may interfere with assay components or detection systems, which has to be considered in nanoparticle toxicity studies by characterization of specific particle properties and a careful test system validation. Future studies require well-characterized materials, the use of available reference materials and an extensive characterization of the applicability of the test methods employed. The resulting challenge for nanoparticle toxicity testing is the development of new standardized in vitro methods that cannot be affected by nanoparticle properties. | 18,775,492 |
The CCT/TRiC chaperonin is required for maturation of sphingosine kinase 1. | Sphingosine kinase 1 (SK1) catalyses the generation of sphingosine 1-phosphate (S1P), a bioactive phospholipid that influences a diverse range of cellular processes, including proliferation, survival, adhesion, migration, morphogenesis and differentiation. SK1 is controlled by various mechanisms, including transcriptional regulation, and post-translational activation by phosphorylation and protein-protein interactions which can regulate both the activity and localisation of this enzyme. To gain a better understanding of the regulatory mechanisms controlling SK1 activity and function we performed a yeast two-hybrid screen to identify SK1-interacting proteins. Using this approach we identified that SK1 interacts with subunit 7 (eta) of cytosolic chaperonin CCT (chaperonin containing t-complex polypeptide, also called TRiC for TCP-1 ring complex), a hexadecameric chaperonin that binds unfolded polypeptides and mediates their folding and release in an ATP-dependent manner. Further analysis of the SK1-CCTeta interaction demonstrated that other CCT/TRiC subunits also associated with SK1 in HEK293T cell lysates in an ATP-sensitive manner, suggesting that the intact, functional, multimeric CCT/TRiC complex associated with SK1. Furthermore, pulse-chase studies indicated that CCT/TRiC binds specifically to newly translated SK1. Finally, depletion of functional CCT/TRiC through the use of RNA interference in HeLa cells or temperature sensitive CCT yeast mutants reduced cellular SK1 activity. Thus, combined this data suggests that SK1 is a CCT/TRiC substrate, and that this chaperonin facilitates folding of newly translated SK1 into its mature active form. | 18,775,504 |
Cleavage of syndecan-4 by ADAMTS1 provokes defects in adhesion. | Syndecan-4 is a membrane-bound heparan sulfate proteoglycan that participates in cell-cell and cell-matrix interactions and modulates adhesion and migration of many cell types. Through its extracellular domain, syndecan-4 cooperates with adhesion molecules and binds matrix components relevant for cell migration. Importantly, syndecan-4 is a substrate of extracellular proteases, however the biological significance of this cleavage has not been elucidated. Here, we show that the secreted metalloprotease ADAMTS1, involved in angiogenesis and inflammatory processes, cleaves the ectodomain of syndecan-4. We further showed that this cleavage results in altered distribution of cytoskeleton components, functional loss of adhesion, and gain of migratory capacities. Using syndecan-4 null cells, we observed that ADAMTS1 proteolytic action mimics the outcome of genetic deletion of this proteoglycan with regards to focal adhesion. Our findings suggest that the shedding of syndecan-4 by ADAMTS1 disrupts cell adhesion and promotes cell migration. | 18,775,505 |
Occurrence and structural organization of the exocrine glands in the legs of ants. | Apart from their obvious locomotory function and hence the presence of muscle fibres, ant legs are also endowed with an astonishing variety of exocrine glands. This paper reviews the presence and structural variety of the 20 different glands that have so far been found in the legs of ants. Four of these glands are described for the first time in this paper. Glands have been described in the three leg pairs, although considerable differences may exist. Glands occur in the various leg segments. A number of glands, especially those located in the hindlegs, may have a function in the production of trail pheromones. Other possible functions that have been reported deal with antenna cleaning, production of lubricant substances and sex pheromones. | 18,775,512 |
Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. | To assess short-term trends and the need to monitor intraocular pressure (IOP) changes immediately after intravitreal injections of ranibizumab, bevacizumab, pegaptanib, and triamcinolone acetonide. Retrospective, interventional case series. Charts of 213 consecutive injections to 120 eyes of 112 patients were reviewed. Pressures were measured before injection, immediately after injection (T0), and at five-minute intervals until IOP was less than 30 mm Hg. Optic nerve perfusion was assessed by testing for hand movement vision and by indirect ophthalmoscopic examination. Kaplan-Meier and Chi-square analyses of IOP after injections and correlation of IOP spikes to drug, needle bore size, injection volume, and history of glaucoma were performed. Mean preinjection IOP was 14 mm Hg (range, 7 to 22 mm Hg). Mean IOP at T0 was 44 mm Hg (range, 4 to 87 mm Hg). All but one eye had at least hand movement vision and a perfused optic nerve at T0. IOP was reduced to less than 30 mm Hg in 96% of injections by 15 minutes and in 100% by 30 minutes. Eyes with a history of glaucoma took longer to normalize the IOP (P = .002). Statistically significant IOP spikes were observed with a smaller needle bore size (P < .0001) and in eyes with a history of glaucoma (P = .001). Elevations in IOP immediately after intravitreal injections are common, but are transient. Prolonged monitoring of IOP may not be necessary on the day of injection in most cases if hand movement vision, optic nerve perfusion, and lack of intraocular complications have been verified. However, cautious monitoring should be considered in select cases. | 18,775,528 |
Centile charts of cervical length between 18 and 32 weeks of gestation. | To establish a centile chart of cervical length between 18 and 32 weeks of gestation in a low-risk population of women. A prospective longitudinal cohort study of women with a low risk, singleton pregnancy using public healthcare facilities in Cape Town, South Africa. Transvaginal measurement of cervical length was performed between 16 and 32 weeks of gestation and used to construct centile charts. The distribution of cervical length was determined for gestational ages and was used to establish estimates of longitudinal percentiles. Centile charts were constructed for nulliparous and multiparous women together and separately. Centile estimation was based on data from 344 women. Percentiles showed progressive cervical shortening with increasing gestational age. Averaged over the entire follow-up period, mean cervical length was 1.5 mm shorter in nulliparous women compared with multiparous women (95% CI, 0.4-2.6). Establishment of longitudinal reference values of cervical length in a low-risk population will contribute toward a better understanding of cervical length in women at risk for preterm labor. | 18,775,533 |
Quantification of 2,5-dimethyl-4-hydroxy-3(2H)-furanone using solid-phase extraction and direct microvial insert thermal desorption gas chromatography-mass spectrometry. | A GC-MS method for the determination of furaneol in fruit juice was developed using Lichrolut-EN solid-phase extraction (SPE) coupled to microvial insert thermal desorption. Lichrolut-EN can effectively extract furaneol from juice, and had much less retention for pigments and other non-volatiles than HLB and C18 columns. The furaneol can be completely eluted out from the Lichrolut-EN SPE column with 1mL of methanol, which can be directly analyzed on GC-MS using an automated large volume microvial insert thermal desorption technique without further purification and concentration. The method is sensitive, has good recovery (98%) and reproducibility (CV<4%). The concentration of furaneol in some commonly grown strawberry, raspberry, and blackberry cultivars in Pacific Northwest of the United States was determined. Strawberries had the highest concentration of furaneol with 'Totem' and 'Pinnacle' cultivars over 13mgkg(-1) fruit. 'Marion' blackberry had 5 times more furaneol than 'Black Diamond', and 16 times more than 'Thornless Evergreen' blackberry. Raspberries had furaneol concentration ranged from 0.8 to 1.1mgkg(-1) fruit. | 18,775,541 |
Context-influenced cap-independent translation of Tombusvirus mRNAs in vitro. | Tomato bushy stunt virus (TBSV) possesses a positive-strand RNA genome that is not 5'-capped or 3'-polyadenylated. Previous analysis revealed that the TBSV genome contains a 3'-cap-independent translational enhancer (3'CITE) in its 3'-untranslated region (3'UTR) that facilitates translation of viral mRNAs in vivo. A long-range 5'-3' RNA-RNA interaction between the 3'CITE and the 5'UTR of viral mRNAs is necessary for function, and this RNA bridge has been proposed to mediate delivery of translation-related factors bound to the 3'CITE to the 5'-end of the message. Although fully functional when assayed in plant protoplasts, the TBSV 3'CITE was previously found to be unable to activate translation in vitro in wheat germ extract (wge). In the current report we have determined that (i) another Tombusvirus, Carnation Italian ringspot virus (CIRV), contains a TBSV-like 3'CITE that is active in wge; (ii) the CIRV 3'CITE functions in vitro in a manner analogous to the TBSV 3'CITE in vivo; (iii) the TBSV 3'CITE is able to competitively inhibit CIRV 3'CITE-dependent translation in wge and (iv) the TBSV 3'CITE can enhance translation in wge when present in short viral messages. These results reveal the contrasting activities of different TBSV-like 3'CITEs in vitro and shed light on the nature of the defect in TBSV. | 18,775,547 |
Identifying useable semen. | The "predictors of useable semen" used in most commercial AI centers provide a very conservative estimate of the relative fertility of individual boars. Furthermore, the relatively high sperm numbers used in commercial AI practice (usually >3 x10(9) total sperm per dose of extended semen) usually compensate for reduced fertility, as can be demonstrated in some boars when lower numbers of sperm are used for AI. Differences in relative boar fertility are also masked by the widespread use of pooled semen for commercial AI in many countries. However, the need to continually improve the efficiency of pork production, suggests that commercial AI practice should involve increased use of boars with the highest genetic merit for important production traits. Necessarily, this must be linked to the use of fewer sperm per AI dose, fewer inseminations per sow bred, and hence more sows bred by these superior sires. In turn, this requires improved techniques for evaluating semen characteristics directly related to the fertilization process, such as IVM-IVF assays, analysis of seminal plasma protein markers, more discriminatory tests of sperm motility and morphology, with the goal of identifying high-index boars whose fertility is sustained when low numbers of sperm are used for AI. This paper reviews the current status of laboratory-based boar semen evaluation techniques that meet these criteria. | 18,775,561 |
In vitro and in vivo evidence for lack of endovascular remodeling by third trimester trophoblasts. | The placental-decidual interaction through invading trophoblasts determines whether a physiological transformation of the uterine spiral arteries is established or not. Trophoblast-orchestrated artery remodeling is central to normal placentation. Dysregulated uteroplacental interaction and vascular remodeling are thought to be associated with the molecular events underlying the pathology of late pregnancy anomalies including preeclampsia. Although the exact gestational age at which trophoblast invasion ceases is not known, it remains unclear whether late pregnancy trophoblasts retain the ability to transform the uterine arteries. Here, we have developed a dual cell, in vitro culture system that mimics the vascular remodeling events during normal pregnancy. We demonstrate that first and third trimester trophoblasts respond differentially to interactive signals from endothelial cells when cultured on matrigel. Term primary trophoblasts or immortalized third trimester extravillous TCL1 trophoblasts not only fail to respond to signals from endothelial cells but also inhibit endothelial cell tube formation. In contrast, HTR8 cells, representing a first trimester trophoblast cell line with invasive properties, undergo spontaneous migration and synchronize with the endothelial cells in a capillary network. This disparity in behavior was confirmed in vivo using a matrigel plug assay. Poor expression of VEGF C and VEGF receptors coupled with high E-cadherin expression by term primary trophoblasts and TCL1 cells contributed to their restricted interactive and migratory properties. We further show that the kinase activity of VEGF R2 is essential for proactive crosstalk by HTR8 cells. This unique behavior of first trimester trophoblasts in the presence of endothelial cells offers a potential approach to study cell-cell interactions and to decipher modulatory components in the serum samples from adverse pregnancy outcomes. | 18,775,564 |
Report of the 3rd Havemeyer workshop on allergic diseases of the Horse, Hólar, Iceland, June 2007. | Allergic diseases occur in most mammals, although some species such as humans, dogs and horses seem to be more prone to develop allergies than others. In horses, insect bite hypersensitivity (IBH), an allergic dermatitis caused by bites of midges, and recurrent airway obstruction (RAO), a hyperreactivity to stable born dust and allergens, are the two most prevalent allergic diseases. Allergic diseases involve the interaction of three major factors: (i) genetic constitution, (ii) exposure to allergens, and (iii) a dysregulation of the immune response determined by (i) and (ii). However, other environmental factors such as infectious diseases, contact with endotoxin and degree of infestation with endoparasites have been shown to influence the prevalence of allergic diseases in humans. How these factors may impact upon allergic disease in the horse is unknown at this time. The 3rd workshop on Allergic Diseases of the Horse, with major sponsorship from the Havemeyer Foundation, was held in Hólar, Iceland, in June 2007 and focussed on immunological and genetic aspects of IBH and RAO. This particular venue was chosen because of the prevalence of IBH in exported Icelandic horses. The incidence of IBH is significantly different between Icelandic horses born in Europe or North America and those born in Iceland and exported as adults. Although the genetic factors and allergens are the same, exported adult horses show a greater incidence of IBH. This suggests that environmental or epigenetic factors may contribute to this response. This report summarizes the present state of knowledge and summarizes important issues discussed at the workshop. | 18,775,570 |
Cracking neural circuits in a tiny brain: new approaches for understanding the neural circuitry of Drosophila. | Genetic screens in Drosophila have identified many genes involved in neural development and function. However, until recently, it has been impossible to monitor neural signals in Drosophila central neurons, and it has been difficult to make specific perturbations to central neural circuits. This has changed in the past few years with the development of new tools for measuring and manipulating neural activity in the fly. Here we review how these new tools enable novel conceptual approaches to 'cracking circuits' in this important model organism. We discuss recent studies aimed at defining the cognitive demands on the fly brain, identifying the cellular components of specific neural circuits, mapping functional connectivity in those circuits and defining causal relationships between neural activity and behavior. | 18,775,572 |
Association of psychiatric and substance use disorder comorbidity with cocaine dependence severity and treatment utilization in cocaine-dependent individuals. | The relations among psychiatric and substance dependence disorders and treatment utilization are of interest both for their clinical management and for health services. We examined these relations using six self-reported indices of cocaine dependence severity and three self-reported measures of treatment utilization and self-help group participation for cocaine dependence. The sample consisted of dyads: namely, a cocaine-dependent adult proband (N=449) and a cocaine-dependent sibling (N=449). Psychiatric and substance use disorders were assessed with the Semi-structured Assessment for Drug Dependence and Alcoholism. We controlled for the nesting within families of proband-sibling dyads and for demographic features using generalized estimating equation linear and logistic regression analyses. We found that psychiatric disorders were associated with an increased likelihood of cocaine dependence treatment or self-help group participation, but with only one of six indices of cocaine dependence severity. Bipolar disorder and antisocial personality disorder were associated with greater past heavy cocaine use, and with utilizing self-help but not treatment. Major depressive disorder and posttraumatic stress disorder were associated with treatment utilization and overall services utilization, respectively. The presence of other substance use disorders (SUDs) was the strongest correlate of cocaine dependence severity. Results suggest that co-occurring substance dependence and psychiatric disorders warrant attention in cocaine dependence assessment, treatment, and self-help. | 18,775,607 |
[Treatment of chronic hepatitis B]. | In recent years, marked progress has been made in the treatment of chronic hepatitis B. Several agents have been approved: interferon alpha-(IFN), pegylated interferon alpha2a (PEG-IFN alpha2a), lamivudine, adefovir, entecavir, telbivudine and recently, tenofovir. Each drug has advantages and limitations. IFN and PEG-IFN alpha2a have the advantage of inducing a sustained virologic response after a defined, limited course of treatment. However, these drugs are only effective in a minority of patients and have frequent side effects. Analogues have the advantage of being administered orally, with good safety profiles and a potent antiviral effect. However, these drugs need to be administered indefinitely since withdrawal of therapy is generally associated with reactivation, and a sustained response is uncommon except in HBeAg positive patients who develop HBe seroconversion. In case of HBe seroconversion, therapy should usually be continued for at least another 24 weeks. The efficacy of lamivudine is limited by the emergence of lamivudine-resistant HBV. Adefovir is associated with a moderate incidence of resistance but its antiviral effect is not optimal. Entecavir has shown to be more effective with a favourable safety profile and a low incidence of resistance. Telbivudine is more potent and has a lower rate of resistance than lamivudine but the resistance rate is significantly higher than other approved drugs. Tenofovir has a potent antiviral effect with a good resistance profile. The future of chronic hepatitis B therapy appears to be different drug combinations. Normally the advantage of drug combinations versus monotherapy should be additive or synergistic antiviral effects and a decrease in viral resistance. Unfortunately, there are few data available and none of the evaluated analogue combinations have been shown to be better than monotherapy. The only combination which has shown a synergistic effect is of pegylated interferon alpha2a with lamivudine. Therefore, combinations of pegylated interferon with the most potent analogues need to be evaluated. The ultimate goal of therapy is HBsAg seroconversion which is more often observed with interferon. Indeed, quantification of serum HBsAg will be a useful tool to predict the treatment outcome. More potent drugs and new combinations as well as understanding the mechanisms of viral resistance should be evaluated to improve the efficacy of treatment. | 18,775,613 |
The effects of extended-release naltrexone on holiday drinking in alcohol-dependent patients. | A post hoc analysis examined the effect of extended-release naltrexone (XR-NTX) treatment combined with psychosocial support on alcohol consumption during holiday and nonholiday periods in a cohort of alcohol-dependent patients who had maintained at least 4 days of continuous abstinence before receiving their first treatment. Three parameters of drinking behavior were examined: percentage of drinking days, percentage of heavy drinking days, and the number of drinks per day. Patients receiving XR-NTX 380 mg reported significantly lower median percentages of drinking days, heavy drinking days, and the number of drinks per day compared with the placebo group. Patients treated with XR-NTX 190 mg reported similar results overall. The results suggest that treatment with XR-NTX 380 mg in combination with psychosocial intervention leads to significant reductions in alcohol consumption, with some measures indicating abstinence in alcohol-dependent patients with initial abstinence during holiday periods. | 18,775,624 |
Assessing the effectiveness of an Internet-based videoconferencing platform for delivering intensified substance abuse counseling. | Enhanced schedules of counseling can improve response to routine opioid-agonist treatment, although it is associated with increased time demands that enhance patient resistance and nonadherence. Internet-based counseling can reduce these concerns by allowing patients to participate from home. This study assesses treatment satisfaction and response to Internet-based (CRC Health Group's e-Getgoing) group counseling for partial responders to methadone maintenance treatment. Patients testing positive for an illicit substance (n = 37) were randomly assigned to e-Getgoing or onsite group counseling and followed for 6 weeks. Patients in both conditions responded favorably to intensified treatment by achieving at least 2 consecutive weeks of abstinence and 100% attendance to return to less-intensive care (e-Getgoing: 70% vs. routine: 71%, ns). Treatment satisfaction was good and comparable across conditions. E-Getgoing patients expressed a preference for the Internet-based service, reporting convenience and increased confidentiality as major reasons. Integrating Internet-based group counseling with on-site treatment services could help expand the continuum of care in methadone maintenance clinics. | 18,775,625 |
Micro-metastases in stages I and II colon cancer are a predictor of the development of distant metastases and worse disease-free survival. | Approximately 30% of the patients with Dukes A/B colon carcinoma will develop loco-regional recurrence or distant metastases. The aim of this study was to evaluate if patients with micro-metastases are at higher risk for developing distant metastases and therefore a worse disease-free survival and overall survival. In the period January 2000-January 2002, 137 patients underwent curative surgery for colon cancer. When patients had a Dukes A/B colon carcinoma, additional staining and sectioning on the harvested lymph nodes were performed retrospectively. Lymph nodes were examined using 4 multilevel sections at 250-microm intervals and stained with Pan-Cytokeratin. There were 11 patients with a Dukes A and 61 patients with a Dukes B colon carcinoma. Twenty-two patients developed metastases in time (group I) whereas 50 patients did not (group II). After additional staining and sectioning 41% of the patients of group I and 16% of the patients of group II showed micro-metastases (p<0.05). The 5-year overall survival rate in the group with micro-metastases was 62% against 79% in the group without micro-metastases. The disease-free survival (DFS) was 51% and 72% (p<0.05), respectively. Patients with micro-metastases develop significant more distant metastases in time and have a significant worse DFS. | 18,775,627 |
[French hospital doctors attend many educational programmes but have organisational and financial difficulties for their continuing medical education]. | Few data on the educational needs and practices of the French hospital doctors have been obtained through surveys. Considering that the CME information is now available on www.cnfmc.fr and that providers were accredited, we investigated, on a representative sample of hospital doctors, the CME practices and the knowledge of the CME system. A questionnaire was prepared during 2 working sessions organised by TNS Healtcare Sofres in July 2007. A sample of 300 doctors was set to be representative of hospital doctors through the 5 main regions, and hospital types. Telephone numbers were dialled by an automat in respect of the objectives of quotas. Questionnaires were administered by telephone between August 30 and September 7, 2007, and done by trained operators. Among the 300 interviewed doctors, 218 (73%) were from general or specialised hospitals and 82 (27%) were from Universitary hospitals. They were equally installed all over France. Their specialties were: medicine 130 (43%); biology 51 (17%); pharmacy 45 (15%); surgery 15 (5%); psychiatry 9 (3%); others 49 (16%) including emergency and radiology. Among the 300 doctors, 125 (42%) declared having continuing education for more than 10 days per year, 122 (41%) between 6 and 10 days per year, and 51 (17%) less than 5 days, 2 (<1%) did not answer. 214 (71%) doctors were subscribing medical specialised or general journals, and 86 (29%) did not subscribe to any journal. For the sessions called " présentielles ", about 65% of the funding of the pedagogic expenses, the travel and housing were supported by the doctors and hospitals. The pharmaceutical industry supported 25% of these expenses. To the question " did you performed a clinical audit in your hospital? ", 75 (25%) answered yes (16% for the 82 doctors in Universitary hospitals, and 29% for the 211 doctors in general hospitals), 210 (70%) answered no, including the 134 (45% of the 300) who said that it was programmed. 15 (5%) did not answer. The educational methods that were preferred were congresses, and interactive workshops were demanded for the future, as well as the e-learning methods. Among the 300 doctors, 165 (55%) had organisational difficulties for their education, 143 (48%) had personal difficulties such as availability, and 135 (45%) had financial difficulties. 54 (18%) had no difficulty at all for their education. This survey through telephone interviews of 300 hospital doctors showed that they followed many educational programmes, and they had difficulties to organize their education, with personal and financial difficulties. The e-learning development could be a solution that gives facilities to doctors. | 18,775,631 |
Visual MRI: merging information visualization and non-parametric clustering techniques for MRI dataset analysis. | This paper presents Visual MRI, an innovative tool for the magnetic resonance imaging (MRI) analysis of tumoral tissues. The main goal of the analysis is to separate each magnetic resonance image in meaningful clusters, highlighting zones which are more probably related with the cancer evolution. Such non-invasive analysis serves to address novel cancer treatments, resulting in a less destabilizing and more effective type of therapy than the chemotherapy-based ones. The advancements brought by Visual MRI are two: first, it is an integration of effective information visualization (IV) techniques into a clustering framework, which separates each MRI image in a set of informative clusters; the second improvement relies in the clustering framework itself, which is derived from a recently re-discovered non-parametric grouping strategy, i.e., the mean shift. The proposed methodology merges visualization methods and data mining techniques, providing a computational framework that allows the physician to move effectively from the MRI image to the images displaying the derived parameter space. An unsupervised non-parametric clustering algorithm, derived from the mean shift paradigm, and called MRI-mean shift, is the novel data mining technique proposed here. The main underlying idea of such approach is that the parameter space is regarded as an empirical probability density function to estimate: the possible separate modes and their attraction basins represent separated clusters. The mean shift algorithm needs sensibility threshold values to be set, which could lead to highly different segmentation results. Usually, these values are set by hands. Here, with the MRI-mean shift algorithm, we propose a strategy based on a structured optimality criterion which faces effectively this issue, resulting in a completely unsupervised clustering framework. A linked brushing visualization technique is then used for representing clusters on the parameter space and on the MRI image, where physicians can observe further anatomical details. In order to allow the physician to easily use all the analysis and visualization tools, a visual interface has been designed and implemented, resulting in a computational framework susceptible of evaluation and testing by physicians. Visual MRI has been adopted by physicians in a real clinical research setting. To describe the main features of the system, some examples of usage on real cases are shown, following step by step all the actions scientists can do on an MRI image. To assess the contribution of Visual MRI given to the research setting, a validation of the clustering results in a medical sense has been carried out. From a general point of view, the two main objectives reached in this paper are: (1) merging information visualization and data mining approaches to support clinical research and (2) proposing an effective and fully automated clustering technique. More particularly, a new application for MRI data analysis, named Visual MRI, is proposed, aiming at improving the support of medical researchers in the context of cancer therapy; moreover, a non-parametric technique for cluster analysis, named MRI-mean shift, has been drawn. The results show the effectiveness and the efficacy of the proposed application. | 18,775,655 |
Infections in a surgical intensive care unit of a university hospital in Greece. | We aimed to evaluate the clinical and microbiological characteristics of the patients who developed an infection in our surgical intensive care unit (SICU). This was a prospective study of all patients who sustained an ICU-acquired infection from 2002 to 2004. Among 683 consecutive SICU patients, 123 (18.0%) developed 241 infections (48.3 infections per 1000 patient-days). The mean age of patients was 66.7+/-3.8 years, the mean APACHE II score (acute physiology and chronic health evaluation) on SICU admission was 18.2+/-2.4, and the mean SOFA score (sepsis-related organ failure assessment) at the onset of infection was 8.8+/-2. Of the study patients, 51.2% were women. Infections were: bloodstream (36.1%), ventilator-associated pneumonia (VAP; 25.3%, 20.3/1000 ventilator-days), surgical site (18.7%), central venous catheter (10.4%, 7.1/1000 central venous catheter-days), and urinary tract infection (9.5%, 4.6/1000 urinary catheter-days). The most frequent microorganisms found were: Acinetobacter baumannii (20.3%), Pseudomonas aeruginosa (15.7%), Candida albicans (13.2%), Enterococcus faecalis (10.4%), Klebsiella pneumoniae (9.2%), Enterococcus faecium (7.9%), and Staphylococcus aureus (6.7%). High resistance to the majority of antibiotics was identified. The complication and mortality rates were 58.5% and 39.0%, respectively. Multivariate analysis identified APACHE II score on admission (odds ratio (OR) 4.63, 95% confidence interval (CI) 2.69-5.26, p=0.01), peritonitis (OR 1.85, 95% CI 1.03-3.25, p=0.03), acute pancreatitis (OR 2.27, 95% CI 1.05-3.75, p=0.02), previous aminoglycoside use (OR 2.84, 95% CI 1.06-5.14, p=0.03), and mechanical ventilation (OR 3.26, 95% CI: 2.43-6.15, p=0.01) as risk factors for infection development. Age (OR 1.16, 95% CI 1.01-1.33, p=0.03), APACHE II score on admission (OR 2.53, 95% CI 1.77-3.41, p=0.02), SOFA score at the onset of infection (OR 2.88, 95% CI 1.85-4.02, p=0.02), and VAP (OR 1.32, 95% CI 1.04-1.85, p=0.03) were associated with mortality. Infections are an important problem in SICUs due to high incidence, multi-drug resistance, complications, and mortality rate. In our study, APACHE II score on admission, peritonitis, acute pancreatitis, previous aminoglycoside use, and mechanical ventilation were identified as risk factors for infection development, whereas age, APACHE II score on admission, SOFA score at the onset of infection, and VAP were associated with mortality. | 18,775,663 |
Rotavirus-associated infantile diarrhea in Uberaba, Minas Gerais, on the wake of the Brazilian vaccination program. | Rotaviruses are major causes of diarrhea in children for which vaccines were developed and are currently in use. To investigate the genotypes of rotavirus strains causing dehydrating diarrhea in children in Uberaba, Triângulo Mineiro region, Minas Gerais, during 2005-2006. Rotavirus-associated diarrhea was investigated in fecal specimens by PAGE and strains were characterized for their genotype by RT-PCR and PCR-typing assays. Rotavirus was detected in 15% (39/260) of the fecal specimens by PAGE: 64% of the specimens presented short electrophoretic patterns and G2P[4] genotype; and 36% presented long electropherotypes and G1P[8], G9P[8], G4P[9] and two strains with sill undetermined G and P[8] genotype. A change in the dominant electrophoretic pattern was observed, shifting from long to short patterns and coinciding with the highest incidence of diarrheal cases. Those are the first data on rotavirus strains circulating in the Triângulo Mineiro region. They were obtained over a 16-month period that included the first 10 months after the launch of the national rotavirus immunization program that uses a monovalent G1P[8] attenuated vaccine strain. These results should further our understanding of the dynamics of rotavirus strains and help interpreting the significance of the program. | 18,775,667 |
The antagonistic effect of antipsychotic drugs on a HEK293 cell line stably expressing human alpha1A1-adrenoceptors. | Antipsychotic drugs often cause orthostatic hypotension, probably through antagonist action on resistance vessel alpha(1A)-adrenoceptors. Here we have tested this possibility directly using cells transfected with a relevant human alpha(1A)-adrenoceptor splice variant. To determine a splice variant which was relevant, we used quantitative real-time polymerase chain reaction (qPCR) to determine the prevalence in human subcutaneous small arteries of three of the five splice variants ADRA1A_v1-5, which encode functional protein: alpha(1A1)-, alpha(1A3)-, alpha(1A4)-adrenoceptors. Our statistical analysis showed higher transcription levels of alpha(1A1)- than of alpha(1A3)- and alpha(1A4)-adrenoceptors (1.6 and 5.8 times, respectively). We therefore chose to study the alpha(1A1)-adrenoceptor, and the cDNA encoding it was transfected into the Flp-In-293 (modified from HEK-293) cell line to produce a cell line stably expressing a functional form of this splice variant. The expression of recombinant alpha(1A1)-adrenoceptor subtype was confirmed by Western immunoblot analysis, and its functionality demonstrated using a Fura-2 assay by a rise in intracellular calcium concentration ([Ca(2+)](i)) when challenged with phenylephrine (EC(50)=1.61x10(-8) M). From Schild analysis, prazosin, sertindole, risperidone, and haloperidol caused a concentration-dependent, rightward shift of the cumulative concentration-response curves for phenylephrine in cells expressing human recombinant alpha(1A1)-adrenoceptors to yield pK(B) values of 8.40, 8.05, 8.26 and 7.38, respectively. In [7-methoxy-(3)H]-prazosin binding experiments, high expression was seen (B(max)=48.5+/-16.7 pmol/mg protein, +/-S.E.M.) along with high affinity binding to a single site (K(d)=0.210+/-0.034 nM). The pharmacological profiles of recombinant human alpha(1A1)-adrenoceptors in competition binding studies confirmed much higher antagonist affinity of sertindole and risperidone than haloperidol for these receptors. In summary, it can be concluded that there is an approximately 10-fold higher adrenoceptor affinity of risperidone and sertindole for human alpha(1A1)-adrenoceptors compared to haloperidol. These findings are consistent with the observation that risperidone and sertindole have a higher incidence of orthostatic hypotension than haloperidol. | 18,775,692 |
A conserved dibasic site is essential for correct processing of the peptide hormone AtRALF1 in Arabidopsis thaliana. | Prohormone proteins in animals and yeast are typically processed at dibasic sites by convertases. Propeptide hormones are also found in plants but little is known about processing. We show for the first time that a dibasic site upstream of a plant peptide hormone, AtRALF1, is essential for processing. Overexpression of preproAtRALF1 causes semi-dwarfism whereas overexpression of preproAtRALF1(R69A), the propeptide with a mutation in the dibasic site, shows a normal phenotype. RALF1(R69A) plants accumulate only the mutated proprotein and not the processed peptide. In vitro processing using microsomal fractions suggests that processing is carried out by a kexin-like convertase. | 18,775,699 |
delta-Opioid receptors stimulate ERK1/2 activity in NG108-15 hybrid cells by integrin-mediated transactivation of TrkA receptors. | This study demonstrates that activation of delta-opioid receptors (DORs) in neuroblastomaxglioma (NG108-15) hybrid cells by [D-Ala2, D-Leu5]enkephalin (DADLE) and etorphine significantly enhances cell adhesion to fibronectin-coated wells. This effect is blocked by both naloxone and integrin binding RGDT peptides. In addition, cell adhesion turned out to be a prerequisite for DOR-stimulated transactivation of Tropomyosin-related kinase A (TrkA) and extracellular signal-regulated kinases 1/2 (ERK1/2). Because inhibition of TrkA activation by AG879 completely blocked DOR- and integrin-mediated ERK1/2 signaling, the present results indicate that in NG108-15 cells DOR-stimulated ERK1/2 activation is mediated by integrin-induced transactivation of TrkA. | 18,775,707 |
The role of a conserved histidine residue in a pyruvate-specific Class II aldolase. | Histidine 45 in HpaI was replaced with alanine (H45A) and glutamine (H45Q). In the aldol cleavage reaction, kcat values were lowered by 78- and 2059-fold while Km values were increased by 100- and 42-fold in H45A and H45Q, respectively, compared to the wild-type enzyme. Both mutants displayed higher dissociation constants towards the metal cofactor, pyruvate and the transition state analogue, oxalate. Pyruvate proton exchange rates are consequently reduced in H45A and H45Q. pKa for a catalytic base (6.5) is lost in the mutant enzymes and catalysis is dependent on hydroxide ions. The results show that histidine 45 is important for metal cofactor binding and for facilitating C4-OH proton abstraction of the substrate in the reaction mechanism. | 18,775,708 |
Misacylation of pyrrolysine tRNA in vitro and in vivo. | Methanosarcina barkeri inserts pyrrolysine (Pyl) at an in-frame UAG codon in its monomethylamine methyltransferase gene. Pyrrolysyl-tRNA synthetase acylates Pyl onto tRNAPyl, the amber suppressor pyrrolysine Pyl tRNA. Here we show that M. barkeri Fusaro tRNAPyl can be misacylated with serine by the M. barkeri bacterial-type seryl-tRNA synthetase in vitro and in vivo in Escherichia coli. Compared to the M. barkeri Fusaro tRNA, the M. barkeri MS tRNAPyl contains two base changes; a G3:U70 pair, the known identity element for E. coli alanyl-tRNA synthetase (AlaRS). While M. barkeri MS tRNAPyl cannot be alanylated by E. coli AlaRS, mutation of the MS tRNAPyl A4:U69 pair into C4:G69 allows aminoacylation by E. coli AlaRS both in vitro and in vivo. | 18,775,710 |
Effective Tityus serrulatus anti-venom produced using the Ts1 component. | Scorpion stings are a public health problem in Brazil, with most incidents involving the species Tityus serrulatus. Some T. serrulatus toxins may act as immunogens for the production of a specific anti-venom, but many of the component toxins remain poorly characterized. Here, we describe the immunological characteristics of the toxin Ts1 (also known as TsVII and Ts-gamma) and evaluate production of neutralizing antibodies against the crude venom of T. serrulatus. Recombinant Ts1 with one copy (Ts1(1)) or two copies in tandem (Ts1(2)) was expressed in BL21 (DE3) cells. Rabbits and mice were immunized with the recombinant proteins (inclusion bodies) and then tested for production of neutralizing antibodies. Neutralization assays showed that anti-Ts1(1) and anti-Ts1(2) protected animals challenged with T. serrulatus crude venom and native Ts1. Thus, Ts1 could be used in a mixed "cocktail" of immunogens for T. serrulatus anti-venom production. | 18,775,739 |
Anatomical particularities of the porcine immune system--a physician's view. | In this article the anatomical structure of the porcine immune organs is described. The focus is on their particularities that are related to the use of pigs as an animal model. Key issues of the intrauterine development of the lymphoid organs are presented, such as the specific epithelio-chorial placenta, the appearance of the thymic tissue and the initial development of B cells. The role of the thymus for the development of alpha/beta and gamma/delta T cells and the location of tonsillar tissue in the naso-pharynx, in the oral cavity and at the basis of the tongue are described. The porcine spleen is of interest for surgical techniques to treat splenic trauma adequately. The observation of the inverted lymph node structure of pigs is puzzling and it remains unclear why only few species have this distinct morphological organisation. Based on the functional differences in lymphocyte recirculation observed in pigs, specific lymph cannulation experiments are possible in the porcine immune system. The porcine intestinal lymphoid tissue and the lymphocytes in the mucosal epithelium and lamina propria are of interest for studying the gut immune responses. For use as a model the fact that the pig is a monogastric omnivorous animal represents an advantage, although the porcine ileal Peyer's patch has no obvious anatomical equivalent in man. Based on the detailed knowledge of porcine immune morphology the pig is suitable as model animal for immunology--in addition to the various experimental approaches in physiology, pharmacology, surgery, etc. that are applicable to human medicine. | 18,775,744 |
The role of ethnic identity and perceived ethnic norms in the purchase of ethnical food products. | The role of group and individual variables in the purchasing of ethnical food products was tested through an extended theory of planned behavior (TPB) model. A total of 100 Indian female immigrants, living in Rome, Italy, were administered a self-reported questionnaire measuring the classical TPB variables (attitudes, subjective norms, perceived behavioral control, behavioral intentions and self-reported behaviors) plus 3 additional variables: identification with the Indian ethnic group, perceived norms of the Indian ethnic group, and past behavior. Results confirmed that the new variables introduced are distinct from the original TPB components. As expected, variables at both the individual and group level play a role in predicting purchasing of ethnical foods products. Hierarchical multiple regressions showed that past behavior, ethnical identification, and perceived group norms explain an additional proportion of variance in intentions and self-reported behaviors, independently of attitudes, subjective norms and perceived control. A significant 2-way interaction between ethnical identification and perceived group norms was also detected: as predicted, the highest levels of ethnical food purchasing behavior were reported by high ethnical identifiers with stronger ethnical group norms, while the lowest levels were reported by low ethnical identifiers with weaker ethnical group norms. Theoretical and practical implications of results are discussed. | 18,775,756 |
Mutations that affect coenzyme binding and dimer formation of fungal 17beta-hydroxysteroid dehydrogenase. | The 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl) is an NADPH-dependent member of the short-chain dehydrogenase/reductase superfamily, and it functions as a dimer that is composed of two identical subunits. By constructing the appropriate mutants, we have examined the M204 residue that is situated in the coenzyme binding pocket, for its role in the binding of the coenzyme NADP(H). We have also studied the importance of hydrophobic interactions through F124, F132, F133 and F177 for 17beta-HSDcl dimer formation. The M204G substitution decreased the catalytic efficiency of 17beta-HSDcl, suggesting that M204 sterically coerces the nicotinamide moiety of the coenzyme into the appropriate position for further hydride transfer. Phenylalanine substitutions introduced at the dimer interface produced inactive aggregates and oligomers with high molecular masses, suggesting that these hydrophobic interactions have important roles in the formation of the active dimer. | 18,775,764 |
Lymphocyte recruitment to the liver: molecular insights into the pathogenesis of liver injury and hepatitis. | Recirculation of blood lymphocytes through the liver occurs under normal conditions as part of the process of immune surveillance. In response to injury or infection recruitment from blood increases and the nature and distribution of the infiltrate will determine the type and outcome of the resulting hepatitis. Recruitment from blood occurs via the hepatic sinusoids and is controlled by interactions between circulating lymphocytes and the highly specialised sinusoidal endothelial cells. This is a low flow vascular bed and the molecular basis of recruitment differs from other tissues. In this review we outline the molecular basis of lymphocyte recruitment to the liver and the effect on it of the local tissue microenvironment and how dysregulation of these processes can lead to uncontrolled inflammation and liver damage. | 18,775,762 |
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